FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Collignon, P Powers, JH Chiller, TM Aidara-Kane, A Aarestrup, FM AF Collignon, Peter Powers, John H. Chiller, Tom M. Aidara-Kane, Awa Aarestrup, Frank M. TI World Health Organization Ranking of Antimicrobials According to Their Importance in Human Medicine: A Critical Step for Developing Risk Management Strategies for the Use of Antimicrobials in Food Production Animals SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RESISTANT STAPHYLOCOCCUS-AUREUS; BLOOD-STREAM INFECTIONS; ESCHERICHIA-COLI; ANTIBIOTIC-RESISTANCE; BACTERIAL-INFECTIONS; BETA-LACTAMASE; SUSCEPTIBILITY; CAMPYLOBACTER; PIGS; QUINOLONE AB The use of antimicrobials in food animals creates an important source of antimicrobial-resistant bacteria that can spread to humans through the food supply. Improved management of the use of antimicrobials in food animals, particularly reducing the usage of those that are "critically important" for human medicine, is an important step toward preserving the benefits of antimicrobials for people. The World Health Organization has developed and applied criteria to rank antimicrobials according to their relative importance in human medicine. Clinicians, regulatory agencies, policy makers, and other stakeholders can use this ranking when developing risk management strategies for the use of antimicrobials in food production animals. The ranking allows stakeholders to focus risk management efforts on drugs used in food animals that are the most important to human medicine and, thus, need to be addressed most urgently, such as fluoroquinolones, macrolides, and third-and fourth-generation cephalosporins. C1 [Collignon, Peter] Australian Natl Univ, Infect Dis Unit, Canberra Hosp, Sch Clin Med,Microbiol Dept, Woden, ACT 2607, Australia. [Powers, John H.] NIAID, Sci Applicat Int Corp, Collaborat Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Powers, John H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. [Chiller, Tom M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Aidara-Kane, Awa] WHO, Dept Food Safety Zoonoses & Foodborne Dis, CH-1211 Geneva, Switzerland. [Aarestrup, Frank M.] Tech Univ Denmark, Head Community Reference Lab Antimicrobial Resist, Natl Food Inst, Copenhagen, Denmark. [Aarestrup, Frank M.] Tech Univ Denmark, WHO, Natl Food Inst, Collaborating Ctr Antimicrobial Resistance Foodbo, Copenhagen, Denmark. RP Collignon, P (reprint author), Australian Natl Univ, Infect Dis Unit, Canberra Hosp, Sch Clin Med,Microbiol Dept, Woden, ACT 2607, Australia. EM peter.collignon@act.gov.au FU National Cancer Institute; National Institutes of Health [HHSN261200800001E]; WHO FX The National Cancer Institute; National Institutes of Health (contract HHSN261200800001E); and WHO. NR 46 TC 148 Z9 153 U1 7 U2 44 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL 1 PY 2009 VL 49 IS 1 BP 132 EP 141 DI 10.1086/599374 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 455ND UT WOS:000266766500015 PM 19489713 ER PT J AU Barker, AD Sigman, CC Kelloff, GJ Hylton, NM Berry, DA Esserman, LJ AF Barker, A. D. Sigman, C. C. Kelloff, G. J. Hylton, N. M. Berry, D. A. Esserman, L. J. TI I-SPY 2: An Adaptive Breast Cancer Trial Design in the Setting of Neoadjuvant Chemotherapy SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CLINICAL-TRIALS; MINDACT TRIAL AB I-SPY 2 ( investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the pharmaceutical and biotechnology industries under the auspices of the Foundation for the National Institutes of Health Biomarkers Consortium. C1 [Barker, A. D.; Kelloff, G. J.] NCI, Bethesda, MD 20892 USA. [Sigman, C. C.] CCS Associates, Mountain View, CA USA. [Hylton, N. M.; Esserman, L. J.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Berry, D. A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Barker, AD (reprint author), NCI, Bethesda, MD 20892 USA. EM barkera@mail.nih.gov FU NCI NIH HHS [P30 CA016672] NR 15 TC 238 Z9 244 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD JUL PY 2009 VL 86 IS 1 BP 97 EP 100 DI 10.1038/clpt.2009.68 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 460XJ UT WOS:000267225200018 PM 19440188 ER PT J AU Kalaydjian, A Swendsen, J Chiu, WT Dierker, L Degenhardt, L Glantz, M Merikangas, KR Sampson, N Kessler, R AF Kalaydjian, Amanda Swendsen, Joel Chiu, Wai-Tat Dierker, Lisa Degenhardt, Louisa Glantz, Meyer Merikangas, Kathleen R. Sampson, Nancy Kessler, Ronald TI Sociodemographic predictors of transitions across stages of alcohol use, disorders, and remission in the National Comorbidity Survey Replication SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID AGE-OF-ONSET; UNITED-STATES; EPIDEMIOLOGIC SURVEY; FOLLOW-UP; 1ST INTOXICATION; YOUNG ADULTHOOD; NCS-R; DEPENDENCE; DRINKING; ABUSE AB Background: Although much is known about risk factors for the initiation of alcohol use, abuse, and dependence, few population-based studies have examined the predictors of transitions across these stages. Aim: The aim of this study is to examine the sociodemographic predictors of transitions across 6 stages of alcohol use in the National Comorbidity Survey Replication, a nationally representative household survey of the US population. Methods: A lifetime history of alcohol use, regular use (at least 12 drinks in a year), Diagnostic and Statistical Maimed of Mental Disorders. Fourth Edition alcohol abuse and dependence with abuse was collected in 5692 National Comorbidity Survey Replication respondents using the World Health Organization Composite International Diagnostic Interview, Version 3.0. Results: Lifetime prevalence estimates were 91.7% for lifetime alcohol use, 72.9% for regular use, 13.2% for abuse. and 5.4% for dependence with abuse. Male sex, young age, non-Hispanic white race/ethnicity, low education, student status, and never being married predicted the onset of alcohol use, the transition from use to regular use, and from regular use to abuse. An early age of onset of alcohol use also predicted the latter transition. The transition front abuse to dependence was associated with an early age of onset of regular alcohol use. being previously married, and student status. Remission was predicted by young age and a later age of onset of alcohol abuse. Conclusion: The reduced number and magnitude of factors associated with transitions to dependence and remission suggest qualitatively different risk factors at these stages relative to other stages of progression. Further knowledge is needed concerning the mechanisms underlying these differences to guide selective and indicated prevention programs. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kalaydjian, Amanda; Merikangas, Kathleen R.] NIMH, Intramural Res Program, NIH, Bethesda, MD 20893 USA. [Chiu, Wai-Tat; Sampson, Nancy] Harvard Univ, Dept Hlth Policy, Boston, MA 02115 USA. [Dierker, Lisa] Wesleyan Univ, Dept Psychol, Middletown, CT 06459 USA. [Degenhardt, Louisa; Kessler, Ronald] Univ NSW, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Swendsen, Joel] CNRS 5231, Natl Ctr Sci Res, Paris, France. [Glantz, Meyer] Natl Inst Drug Abuse, Div Epidemiol Prevent & Serv Res, NIH, Bethesda, MD 20893 USA. RP Kalaydjian, A (reprint author), NIMH, Intramural Res Program, NIH, Bethesda, MD 20893 USA. EM kalaydjiana@mail.nih.gov RI Degenhardt, Louisa/D-4515-2012 OI Degenhardt, Louisa/0000-0002-8513-2218 FU National Institute of Mental Health [U01-MH60220]; The Substance Abuse and Mental Health Services Administration [044708]; National Institutes of Health; National Institute of Mental Health; National Institute of Drug Abuse [K01 DA15454]; Patrick & Catherine Weldon Donaghue Medical Research Foundation (Dierker) FX The NCS-R was supported by grant U01-MH60220 from the National Institute of Mental Health with supplemental support from the National Institute of Drug Abuse, The Substance Abuse and Mental Health Services Administration; grant 044708 from The Robert Wood Johnson Foundation and the John W. Alden Trust. Manuscript preparation was also supported by the Intramural Research program of the National Institutes of Health, National Institute of Mental Health (Kalaydjian, Merikangas), grant K01 DA15454 from the National Institute of Drug Abuse (Dierker), and an Investigator Award from the Patrick & Catherine Weldon Donaghue Medical Research Foundation (Dierker). NR 38 TC 41 Z9 41 U1 2 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X EI 1532-8384 J9 COMPR PSYCHIAT JI Compr. Psychiat. PD JUL-AUG PY 2009 VL 50 IS 4 BP 299 EP 306 DI 10.1016/j.comppsych.2008.09.012 PG 8 WC Psychiatry SC Psychiatry GA 456DM UT WOS:000266820100002 PM 19486727 ER PT J AU Yeh, S Fine, HA Smith, JA AF Yeh, Steven Fine, Howard A. Smith, Janine A. TI Corneal Verticillata After Dual Anti-Epidermal Growth Factor Receptor and Anti-Vascular Endothelial Growth Factor Receptor 2 Therapy (Vandetanib) for Anaplastic Astrocytoma SO CORNEA LA English DT Article DE verticillata; vortex keratopathy; vandetanib; ZD6474; astrocytoma; epidermal growth factor; epidermal growth factor receptor; vascular endothelial growth factor receptor ID CELL LUNG-CANCER; PHASE-II; RADIATION-THERAPY; MALIGNANT-TUMORS; CLINICAL-TRIALS; INHIBITOR; ZD6474; COMPLICATIONS; KERATOPATHY; EPITHELIUM AB Purpose: To describe a patient with a history of epithelial basement membrane dystrophy who developed symptomatic corneal verticillata after vandetanib therapy for anaplastic astrocytoma. Methods: Retrospective interventional case report. Results: A 48-year-old female patient with a history of anaplastic astrocytoma status post resection, external beam radiation, and chemotherapy presented with glare symptoms, decreased contrast sensitivity, and increased lacrimation after approximately 12 months of therapy with the anti-epidermal growth factor receptor (EGFR) and anti-vascular endothelial growth factor receptor 2 protein tyrosine kinase inhibitor, vandetanib. Ophthalmic examination revealed diffuse corneal verticillata and fine subepithelial opacities. Schirmer 1 testing was normal bilaterally. Therapy with carboxymethylcellulose, 5% sodium chloride ointment, and a decrease in the dose of vandetanib led to an improvement in the patient's ophthalmic symptoms despite persistence of the corneal findings. The patient remained under surveillance for tumor recurrence. Conclusions: Vandetanib (ZD6474), a protein tyrosine kinase inhibitor with dual anti-EGFR and anti-vascular endothelial growth factor receptor 2 action, may have contributed to the formation Of corneal verticillata in our patient. Inhibition of EGFR, which is involved with corneal epithelial cell migration and wound healing, may play a role in the pathogenesis underlying corneal vortex keratopathy and ocular surface conditions with significant epithelial turnover. C1 [Smith, Janine A.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, NIH, Bethesda, MD 20892 USA. RP Smith, JA (reprint author), NEI, Div Epidemiol & Clin Res, NIH, 10 Ctr Dr Bldg 10,Room 10D45, Bethesda, MD 20892 USA. EM smithja2@od.nih.gov FU Intramural Program of the National Eye Institute; National Institutes of Health; Heed Ophthalmic Foundation FX Supported in part by the Intramural Program of the National Eye Institute, National Institutes of Health. S. Yeh is supported by the Heed Ophthalmic Foundation. NR 27 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD JUL PY 2009 VL 28 IS 6 BP 699 EP 702 PG 4 WC Ophthalmology SC Ophthalmology GA 463EP UT WOS:000267412500015 PM 19512898 ER PT J AU Salazar, KC Nelson, MR Stone, KD AF Salazar, Kimberly C. Nelson, Michael R. Stone, Kelly D. TI A 42-year-old woman with chronic rhinosinusitis and allergic mucin SO CURRENT ALLERGY AND ASTHMA REPORTS LA English DT Editorial Material ID FUNGAL SINUSITIS; MANAGEMENT STRATEGIES; HUMAN EOSINOPHILS; NASAL POLYPOSIS; AMPHOTERICIN-B; DIAGNOSIS C1 [Salazar, Kimberly C.; Nelson, Michael R.] Walter Reed Army Med Ctr, Div Allergy & Immunol, Washington, DC 20307 USA. [Stone, Kelly D.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Nelson, MR (reprint author), Walter Reed Army Med Ctr, Div Allergy & Immunol, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM kimberly.salazar@amedd.army.mil; Michael.Nelson@amedd.army.mil; stonek@niaid.nih.gov FU Intramural NIH HHS NR 28 TC 0 Z9 0 U1 0 U2 0 PU CURRENT MEDICINE GROUP PI PHILADELPHIA PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA SN 1529-7322 J9 CURR ALLERGY ASTHM R JI Curr. Allergy Asthma Rep. PD JUL PY 2009 VL 9 IS 4 BP 255 EP 259 DI 10.1007/s11882-009-0047-9 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 474PM UT WOS:000268296400001 PM 19656469 ER PT J AU Chen, YP Goldstein, JA AF Chen, Yuping Goldstein, Joyce A. TI The Transcriptional Regulation of the Human CYP2C Genes SO CURRENT DRUG METABOLISM LA English DT Review DE Human CYP2C; transcription regulation; drug induction; hepatic nuclear receptor; hypoxia ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; ST-JOHNS-WORT; ACTIVATED PROTEIN-KINASE; DRUG-METABOLIZING-ENZYMES; HUMAN HEPATOCYTE CULTURES; ORPHAN NUCLEAR RECEPTOR; HYPERPOLARIZING FACTOR SYNTHASE; SALT-SENSITIVE HYPERTENSION; COA REDUCTASE INHIBITORS AB In humans, four members of the CYP2C subfamily (CYP2C8, CYP2C9, CYP2C18, and CYP2C19) metabolize more than 20% of all therapeutic drugs as well as a number of endogenous compounds. The CYP2C enzymes are found predominantly in the liver, where they comprise similar to 20% of the total cytochrome P450. A variety of xenobiotics such as phenobarbital, rifampicin, and hyperforin have been shown to induce the transcriptional expression of CYP2C genes in primary human hepatocytes and to increase the metabolism of CYP2C substrates in vivo in man. This induction can result in drug-drug interactions, drug tolerance, and therapeutic failure. Several drug-activated nuclear receptors including CAR, PXR, VDR, and GR recognize drug responsive elements within the 5' flanking promoter region of CYP2C genes to mediate the transcriptional upregulation of these genes in response to xenobiotics and steroids. Other nuclear receptors and transcriptional factors including HNF4, HNF3, C/EBP and more recently RORs, have been reported to regulate the constitutive expression of CYP2C genes in liver. The maximum transcriptional induction of CYP2C genes appears to be achieved through a coordinative cross-talk between drug responsive nuclear receptors, hepatic factors, and coactivators. The transcriptional regulatory mechanisms of the expression of CYP2C genes in extrahepatic tissues has received less study, but these may be altered by perturbations from pathological conditions such as ischemia as well as some of the receptors mentioned above. C1 [Chen, Yuping; Goldstein, Joyce A.] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. RP Goldstein, JA (reprint author), NIEHS, Pharmacol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012 FU NIH; National Institute of Environmental Health Sciences under NIH [Z01ES02124] FX We thank Drs. Masahiko Negishi and Tatsuya Sueyoshi (NIEHS) for comments regarding the manuscript and Anne Motten of NIEHS for editing this manuscript. We thank Dr. Sailesh Surapureddi for assistance with formatting for submission. This study was supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences under NIH intramural project number Z01ES02124. NR 135 TC 62 Z9 64 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD JUL PY 2009 VL 10 IS 6 BP 567 EP 578 PG 12 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 514FR UT WOS:000271380200003 PM 19702536 ER PT J AU Jia, L Zhao, YQ AF Jia, Lee Zhao, Yuqing TI Current Evaluation of the Millennium Phytomedicine-Ginseng (I): Etymology, Pharmacognosy, Phytochemistry, Market and Regulations SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Ginseng; ginsenosides; ginseng market; pharmacognosy; phytomedicine; traditional chinese medicine ID LIQUID-CHROMATOGRAPHIC DETERMINATION; INTESTINAL BACTERIA; MASS-SPECTROMETRY; COMPOUND K; RAT PLASMA; GINSENOSIDES; METABOLITE; GINSAN; RB-1 AB The dawning of this millennium broke new ground in life science and technology, presented us genomic and proteomic revolution, nanotechnology innovation, and high performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) used for separating and identifying new chemical entities at pico-, or even femto-concentrations. Applications of these high technologies to the traditional Chinese medicine (TCM) opened a new chapter in the ancient medicine, and prompted us to re-evaluate the thousand-year-old phytomedicine ginseng from current perspectives. We, therefore, collected the latest information (mostly within 10 years) on ginseng, and condensed the information into two parts of this review serial. The present part covers etymology of ginseng, its pharmacognosy (natural origin, physical appearance, chemical properties, and specie identification), its cultivation and processing-related metabolic changes in active ingredients, standardized analytical methods used for quality control of various ginseng products, modern analytical methods used to identify and classify more than 100 chemical entities (many were recently unfolded) derived from ginseng species and their metabolites. The global markets and production of ginseng and relevant government regulations are herein updated to exchange information and understandings about current people's uses and cultivation of ginseng. The second part of the review serial will classify all these 100 chemical entities separated from various ginseng species into different groups based on their structural similarities, and summarize bioactivities of these entities. The second part of the review serial will also focus on recent findings of ginseng pharmacology and its clinical trials for various diseases, and brief side effects of ginseng. C1 [Jia, Lee] NCI, Dev Therapeut Program, NIH, Rockville, MD 20852 USA. [Zhao, Yuqing] Shenyang Pharmaceut Univ, Res Ctr Tradit Chinese Med, Shenyang 110006, Liaoning, Peoples R China. RP Jia, L (reprint author), NCI, Dev Therapeut Program, NIH, 6130 Execut Blvd,Rm 8042, Rockville, MD 20852 USA. EM jiale@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 49 TC 111 Z9 115 U1 4 U2 38 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD JUL PY 2009 VL 16 IS 19 BP 2475 EP 2484 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 474BV UT WOS:000268258200009 PM 19601793 ER PT J AU Widemann, BC AF Widemann, Brigitte C. TI Current Status of Sporadic and Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors SO CURRENT ONCOLOGY REPORTS LA English DT Article AB Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that rarely occur in the general population but have a lifetime incidence of 8% to 13% in those with neurofibromatosis type 1 (NF1). Complete surgical resection is the standard treatment for MPNSTs. Unresectable MPNSTs carry a poor prognosis, and survival appears to be worse in NF1-associated tumors than in sporadic tumors. The response rate of MPNSTs to standard chemotherapeutic agents used to treat pediatric and adult soft tissue sarcomas is unknown and is currently undergoing evaluation in a multi-institutional clinical trial. With an increasing understanding of the molecular pathogenesis of MPNSTs, clinical trials with targeted agents have become available and have established that histology-specific trials in this rare malignancy are feasible. This knowledge, coupled with the availability of preclinical MPNST models, likely will accelerate the development of effective treatments for this malignancy. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room 1-5750, Bethesda, MD 20892 USA. EM widemanb@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The views expressed do not necessarily represent views of the National Institutes of Health or the US government. NR 83 TC 28 Z9 29 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3790 EI 1534-6269 J9 CURR ONCOL REP JI Curr. Oncol. Rep. PD JUL PY 2009 VL 11 IS 4 BP 322 EP 328 PG 7 WC Oncology SC Oncology GA V16BH UT WOS:000207844600011 PM 19508838 ER PT J AU Kannel, WB Vasan, RS AF Kannel, William B. Vasan, Ramachandran S. TI Triglycerides as vascular risk factors: new epidemiologic insights SO CURRENT OPINION IN CARDIOLOGY LA English DT Review DE cardiovascular disease; epidemiology; risk factors; triglycerides ID HIGH-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; LIVER FAT-CONTENT; NONFASTING TRIGLYCERIDES; MYOCARDIAL-INFARCTION; ARTERY-DISEASE; LIPID-LEVELS; CARDIOVASCULAR EVENTS; CARDIOMETABOLIC RISK; PLASMA TRIGLYCERIDE AB Purpose of review Targeting triglycerides as a vascular risk factor is justified because of the role of triglyceride-rich lipoproteins in atherogenesis. This review examines recent evidence connecting triglycerides with cardiovascular disease (CVD) in the context of advances in insights concerning the pathophysiology, population burden and prognostic impact of fasting versus nonfasting values. Recent findings Cross-sectional surveys indicate that mean triglyceride levels in the United States have increased in recent decades. Although elevated fasting triglycerides are consistently associated with increased CVD risk, adjustment for other risk factors (especially high-density lipoprotein cholesterol (HDL-C)) substantially attenuates this relationship. A recent meta-analysis of 27 prospective studies of western populations reported a triglyceride impact on CVD in both sexes, for both fasting and nonfasting values. Nonfasting triglycerides maintained an independent graded relationship with CVD in fully adjusted analyses, with elevated 4 h postprandial triglyceride imposing a 4.5-fold increment relative to lower levels. Summary Evidence supports a potential role for both fasting and nonfasting triglycerides as vascular risk factors, owing in part to the accompanying burden of atherogenic remnant particles, small dense low-density lipoprotein, reduced HDL-C and a high frequency of accompanying insulin resistance. Triglyceride-associated CVD risk occurs even in patients with low low-density lipoprotein cholesterol (LDL-C), and lowering both lipids provides more benefit than reducing LDL-C alone. C1 NHLBI, NIH, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Kannel, WB (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM billkannel@yahoo.com OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC-25195, 2K24 HL04334] FX This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute Contract N01-HC-25195, and 2K24 HL04334 (Dr R.S.V.). NR 46 TC 82 Z9 91 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0268-4705 J9 CURR OPIN CARDIOL JI Curr. Opin. Cardiol. PD JUL PY 2009 VL 24 IS 4 BP 345 EP 350 DI 10.1097/HCO.0b013e32832c1284 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 461PE UT WOS:000267279500012 PM 19424059 ER PT J AU Tobian, AAR Quinn, TC AF Tobian, Aaron A. R. Quinn, Thomas C. TI Herpes simplex virus type 2 and syphilis infections with HIV: an evolving synergy in transmission and prevention SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE genital ulcer disease; HIV; herpes simplex virus type 2; male circumcision; prevention trials; syphilis; Treponema pallidum AB Purpose of review Herpes simplex virus type 2 (HSV-2) and syphilis are associated with HIV infection. The purpose of this review is to summarize the advances in the relationship of HSV-2 and syphilis with HIV, highlighting intervention trials to prevent HIV acquisition and transmission. Recent findings HIV acquisition has often been linked to genital ulcers due to HSV-2 and syphilis. The latest pathophysiological studies have continued to elucidate the relationship between HSV-2, syphilis and HIV, establishing that both syphilitic and HSV-2-infected tissue have increased numbers of chemokine receptor 5-expressing T cells, and several models have further emphasized the viral synergy between HSV-2 and HIV. In clinical trials, HSV suppressive therapy decreased HIV RNA levels that might affect transmission, but two trials have failed to prevent HIV acquisition. Male circumcision, however, prevents both HIV and HSV-2 acquisition. Summary Genital ulcers from HSV-2 and syphilis are associated with HIV acquisition. The exact role for these HIV cofactors is still unknown and exemplified by the failure of HSV suppressive therapy to decrease HIV acquisition. Male circumcision, however, reduces HSV-2 acquisition. With several HSV suppressive trials to prevent HIV transmission and disease progression currently ongoing, the future promises to provide more critical information for the control of HIV infection. C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Rangos Bldg,Room 530,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Thomas Quinn is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 57 TC 50 Z9 50 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD JUL PY 2009 VL 4 IS 4 BP 294 EP 299 DI 10.1097/COH.0b013e32832c1881 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V19PB UT WOS:000208083200010 PM 19532067 ER PT J AU Chen, HX Cleck, JN Coelho, R Dancey, JE AF Chen, Helen X. Cleck, Jessica N. Coelho, Rochelle Dancey, Janet E. TI Epidermal Growth Factor Receptor Inhibitors: Current Status and Future Directions SO CURRENT PROBLEMS IN CANCER LA English DT Review ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; PHASE-II TRIAL; TYROSINE KINASE INHIBITORS; GENE COPY NUMBER; CETUXIMAB PLUS IRINOTECAN; PREVIOUSLY TREATED PATIENTS; ACQUIRED-RESISTANCE; 1ST-LINE TREATMENT; DRUG-RESISTANCE C1 [Chen, Helen X.] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD USA. [Cleck, Jessica N.; Coelho, Rochelle] Tech Resources Int Inc, Bethesda, MD USA. [Dancey, Janet E.] Ontario Inst Canc Res, Toronto, ON, Canada. RP Chen, HX (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Rockville, MD USA. NR 179 TC 6 Z9 6 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0147-0272 EI 1535-6345 J9 CURR PROB CANCER JI Curr. Probl. Cancer PD JUL-AUG PY 2009 VL 33 IS 4 BP 245 EP + DI 10.1016/j.currproblcancer.2009.10.002 PG 51 WC Oncology SC Oncology GA 542BH UT WOS:000273465700001 PM 20082842 ER PT J AU Valera, VA Walter, BA Linehan, WM Roberts, DD Merino, MJ AF Valera, Vladimir A. Walter, Beatriz A. Linehan, W. Marston Roberts, David D. Merino, Maria J. TI Proteomic Analysis of Formalin-Fixed Paraffin Embedded (FFPE) Samples: Pitfalls and Potentials SO CURRENT PROTEOMICS LA English DT Review DE Proteomics; formalin-fixed paraffin embedded tissues; antigen retrieval; immunohistochemistry; protein extraction; imaging mass spectrometry; liquid chromatography; mass spectrometry ID IMAGING MASS-SPECTROMETRY; FORMALDEHYDE-INDUCED MODIFICATIONS; TEMPERATURE ANTIGEN RETRIEVAL; TISSUE-SECTIONS; PROTEIN EXTRACTION; CROSS-LINKING; PAP TECHNIQUE; IMMUNOHISTOCHEMISTRY; FIXATION; IDENTIFICATION AB Proteomic analysis of clinical samples has been traditionally performed using fresh or frozen tissues. However, millions of embedded samples are stored worldwide in pathology repositories with linked long-term outcome data. Such samples are believed to be unsuitable for proteome analysis because of the extensive protein modification attained during tissue processing. Formaldehyde, in the form of buffered formalin, is the most commonly used fixative during processing before embedding in paraffin. These formalin-fixed paraffin embedded (FFPE) tissue samples are widely used in pathology labs for qualitative protein analysis using immunohistochemistry (IHC). For this purpose, FFPE tissues are treated in different ways in order to reverse chemical modifications by formaldehyde that limit protein antigen detection by specific antibodies. Accordingly, intensive research efforts are now attempting to adapt the sample pretreatments used in immunohistochemistry to facilitate high throughput proteome analysis of FFPE tissues. Two such approaches have been successful: a liquid-based proteomic approach and an in situ approach, mainly based on separation and identification technologies such as liquid chromatography and mass spectrometry. These efforts have proven that similar protein profiles and numbers of polypeptides can be attained as using frozen sections. In this article, a review is provided of methods and current trends for the extraction of peptides and proteins from FFPE tissues for use proteomic analysis. Limitations in these methods and future directions to overcome these are also outlined. Ongoing improvements in protein extraction technology and analysis techniques will enable identification of novel disease biomarkers from FFPE tissues. C1 [Valera, Vladimir A.; Walter, Beatriz A.; Roberts, David D.; Merino, Maria J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Valera, Vladimir A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), 10 Ctr Dr,MSC1500,Bldg 10-2B50, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural Research Program of the NIH; NCI; Center for Cancer Research FX This work was supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research (MJM, WML, DDR). NR 81 TC 2 Z9 2 U1 0 U2 9 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1646 J9 CURR PROTEOMICS JI Curr. Proteomics PD JUL PY 2009 VL 6 IS 2 BP 122 EP 139 PG 18 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 486OI UT WOS:000269206200005 ER PT J AU Kling, MA Coleman, VH Schulkin, J AF Kling, Mitchel A. Coleman, Victoria H. Schulkin, Jay TI GLUCOCORTICOID INHIBITION IN THE TREATMENT OF DEPRESSION: CAN WE THINK OUTSIDE THE ENDOCRINE HYPOTHALAMUS? SO DEPRESSION AND ANXIETY LA English DT Review DE antiglucocorticoids; depression; mifepristone; ketoconazole; CRH; cortisol; glucocorticoid inhibition ID CORTICOTROPIN-RELEASING HORMONE; PSYCHOTIC MAJOR DEPRESSION; ACOUSTIC STARTLE REFLEX; FACTOR MESSENGER-RNA; STRIA TERMINALIS; BED NUCLEUS; PARAVENTRICULAR NUCLEUS; ANTIGLUCOCORTICOID TREATMENT; RECEPTOR ANTAGONIST; AMYGDALOID NUCLEUS AB Background: Major depressive disorder affects a substantial percentage of the U.S. population, and can be highly debilitating. Selective serotonin reuptake inhibitors are commonly prescribed to treat depression, but may not be as effective for more severe or persistent depression. Methods: The authors review data. concerning the effects of corticosteroid synthesis inhibitors (CSIs) in the,management of depressive disorders, present a hypothesis as to their possible mechanisms of action based on recent data. suggesting Synergistic effects of glucocorticoids on extrahypothalamic corticotropin-releasing hormone (CRH), and consider alternative hypotheses. Published reports evaluating the efficacy of CSIs in treating depression are reviewed and presented in light of recent findings regarding actions of glucocorticoids on the central CRH system. Results: Results from open label and double-blind studies by several groups have indicated that CSIs may be efficacious or of adjunctive value in some patients with depression, including those refractory to other agents; however, there is a need for more controlled studies. Several lines of data suggest that the mechanism of action of these agents may not be solely a function of inhibition of adrenal cortisol production. Conclusions: The authors propose that CSIs may be efficacious in part by reducing glucocorticoid enhancement of CRH action in neurons of the central nucleus of the amygdala and other structures outside the endocrine hypothalamus. Possible effects of systemically administered CSIs oil glucocorticoid receptor regulation, neuroactive steroids, and classical monoamine systems are also discussed. We conclude that available clinical data suggest a potential role for CSIs in the management of depressive disorders, especially major depression with psychotic features. Depression and Anxiety 26:641-649, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Kling, Mitchel A.] Wyeth Res, Dept Clin Translat Med, Collegeville, PA USA. [Coleman, Victoria H.; Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, Res Dept, Washington, DC USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Dept Physiol & Biophys, Mol Neuroimaging Branch,Natl Inst Mental Hlth, Washington, DC 20007 USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Dept Neurosci, Mol Neuroimaging Branch,Natl Inst Mental Hlth, Washington, DC USA. RP Coleman, VH (reprint author), Chestnut Hlth Syst, 448 Wylie Dr, Normal, IL 61761 USA. EM vhcoleman@gmail.com RI Kling, Mitchel/F-4152-2010; OI Kling, Mitchel/0000-0002-2232-1409; Coleman-Cowger, Victoria/0000-0002-7745-7223 FU Intramural NIH HHS [Z01 MH002659-15] NR 75 TC 19 Z9 22 U1 5 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1091-4269 EI 1520-6394 J9 DEPRESS ANXIETY JI Depress. Anxiety PD JUL PY 2009 VL 26 IS 7 BP 641 EP 649 DI 10.1002/da.20546 PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 467KQ UT WOS:000267738000007 PM 19133699 ER PT J AU Toyama, R Chen, XF Jhawar, N Aamar, E Epstein, J Reany, N Alon, S Gothilf, Y Klein, DC Dawid, IB AF Toyama, Reiko Chen, Xiongfong Jhawar, Nupur Aamar, Emil Epstein, Jonathan Reany, Nir Alon, Shahar Gothilf, Yoav Klein, David C. Dawid, Igor B. TI Transcriptome Analysis of the Zebrafish Pineal Gland SO DEVELOPMENTAL DYNAMICS LA English DT Article DE pineal gland; epiphysis; zebrafish; circadian rhythm; microarray ID LEFT-RIGHT DIFFERENCE; RETINAL DEGENERATION; MIDBRAIN TARGET; GENE-EXPRESSION; HOMEOBOX GENE; FLOATING HEAD; PROTEIN; PHOTORECEPTOR; FOREBRAIN; ASYMMETRY AB The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pace maker. Here, we have used microarray technology to study the zebrafish pineal transcriptome. Analysis of gene expression at three larval and two adult stages revealed a highly dynamic transcriptional profile, revealing many genes that are highly expressed in the zebrafish pineal gland. Statistical analysis of the data based on Gene Ontology annotation indicates that many transcription factors are highly expressed during larval stages, whereas genes dedicated to phototransduction are preferentially expressed in the adult. Furthermore, several genes were identified that exhibit day/night differences in expression. Among the multiple candidate genes suggested by these data, we note the identification of a tissue-specific form of the unc119 gene with a possible role in pineal development. Developmental Dynamics 238:1813-1826, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Toyama, Reiko; Jhawar, Nupur; Aamar, Emil; Dawid, Igor B.] Eunice Kennedy Shriver NICHHD, Mol Genet Lab, NIH, Bethesda, MD USA. [Chen, Xiongfong; Epstein, Jonathan] Eunice Kennedy Shriver NICHHD, Unit Biol Computat, NIH, Bethesda, MD USA. [Reany, Nir; Alon, Shahar; Gothilf, Yoav] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Klein, David C.] Eunice Kennedy Shriver NICHHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. RP Toyama, R (reprint author), Bldg 6B,Room 420,9000 Rockville Pike, Bethesda, MD 20852 USA. EM toyamar@mail.nih.gov FU United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel; NICHD, NIH FX We thank Mark Rath for excellent technical assistance. This work was partially supported by a grant from the United States-Israel Binational Science Foundation (BSF), Jerusalem, Israel, and by the Intramural Research Program of the NICHD, NIH. NR 47 TC 15 Z9 17 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUL PY 2009 VL 238 IS 7 BP 1813 EP 1826 DI 10.1002/dvdy.21988 PG 14 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 465VT UT WOS:000267617500017 PM 19504458 ER PT J AU Traurig, M Mack, J Hanson, RL Ghoussaini, M Meyre, D Knowler, WC Kobes, S Froguel, P Bogardus, C Baier, LJ AF Traurig, Michael Mack, Janel Hanson, Robert L. Ghoussaini, Maya Meyre, David Knowler, William C. Kobes, Sayuko Froguel, Philippe Bogardus, Clifton Baier, Leslie J. TI Common Variation in SIM1 Is Reproducibly Associated With BMI in Pima Indians SO DIABETES LA English DT Article ID WILLI-LIKE PHENOTYPE; SINGLE-MINDED GENE; BODY-MASS INDEX; PARAVENTRICULAR NUCLEUS; MOLECULAR-GENETICS; FOOD-INTAKE; OBESITY; DELETION; DROSOPHILA; TRAITS AB OBJECTIVE-Haploinsufficiency of SIM1 is a cause of rare monogenic obesity. To assess the role of SIM1 in polygenic obesity, this gene was analyzed in the Pima Indian population, which has a high prevalence of obesity. RESEARCH DESIGN AND METHODS-SIM1 was sequenced in 96 individuals. Variants (n = 46) were genotyped in a population-based sample of 3,250 full-heritage Pima Indians and in a separate replication sample of 2,944 predominately non-full-heritage subjects from the same community. RESULTS-Variants spanning the upstream region of SIM1 through intron 8 were associated with BMI in the full-heritage Pima Indians, where the strongest associations (P similar to 10(-4) to 10(-6)) were with common variants (risk allele frequency 0.61-0.67). The difference in mean BMI between individuals homozygous for the major allele compared with homozygotes for the minor allele was similar to 2.2 k g/m(2) (P = 2 x 10(-5) for rs3213541). These associations replicated in the separate sample of subjects from the same community (P = 5 x 10(-3) for rs3213541). The strongest associations (P = 4 x 10(-7), controlled for age, sex, birth year, and heritage) were seen in the combined sample (n = 6,194). The risk allele for obesity was more common in full-heritage Pimas than in the mixed-heritage subjects. Two variants (rs3734353 and rs3213541) were also genotyped in 1,275 severely obese and 1,395 lean control subjects of French European ancestry. The Pima risk alleles were the minor alleles in the European samples, and these variants did not display any significant association (P > 0.05). CONCLUSIONS-Common variation in SIM1 is associated with BMI on a population level in Pima Indians where the risk allele is the major allele. Diabetes 58:1682-1689, 2009 C1 [Traurig, Michael; Mack, Janel; Hanson, Robert L.; Knowler, William C.; Kobes, Sayuko; Bogardus, Clifton; Baier, Leslie J.] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Ghoussaini, Maya; Meyre, David; Froguel, Philippe] Inst Pasteur, Inst Biol, CNRS 8090, F-59019 Lille, France. RP Baier, LJ (reprint author), NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. EM lbaier@phx.niddk.nih.go RI Meyre, David/D-7315-2011; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; American Diabetes Association FX This study was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. M.T. was supported by a grant from the American Diabetes Association. NR 39 TC 29 Z9 29 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2009 VL 58 IS 7 BP 1682 EP 1689 DI 10.2337/db09-0028 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466VF UT WOS:000267690700029 PM 19401419 ER PT J AU Prokopenko, I Zeggini, E Hanson, RL Mitchell, BD Rayner, NW Akan, P Baier, L Das, SK Elliott, KS Fu, M Frayling, TM Groves, CJ Gwilliam, R Scott, LJ Voight, BF Hattersley, AT Hu, C Morris, AD Ng, M Palmer, CNA Tello-Ruiz, M Vaxillaire, M Wang, CR Stein, L Chan, J Jia, WP Froguel, P Elbein, SC Deloukas, P Bogardus, C Shuldiner, AR McCarthy, MI AF Prokopenko, Inga Zeggini, Eleftheria Hanson, Robert L. Mitchell, Braxton D. Rayner, N. William Akan, Pelin Baier, Leslie Das, Swapan K. Elliott, Katherine S. Fu, Mao Frayling, Timothy M. Groves, Christopher J. Gwilliam, Rhian Scott, Laura J. Voight, Benjamin F. Hattersley, Andrew T. Hu, Cheng Morris, Andrew D. Ng, Maggie Palmer, Colin N. A. Tello-Ruiz, Marcela Vaxillaire, Martine Wang, Cong-rong Stein, Lincoln Chan, Juliana Jia, Weiping Froguel, Philippe Elbein, Steven C. Deloukas, Panos Bogardus, Clifton Shuldiner, Alan R. McCarthy, Mark I. CA Int Type 2 Diabet 1q Consortium TI Linkage Disequilibrium Mapping of the Replicated Type 2 Diabetes Linkage Signal on Chromosome 1q SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; NUCLEAR FACTOR-4-ALPHA GENE; GK RAT; SUSCEPTIBILITY; LOCI; VARIANTS; RISK; POPULATION; DISEASES; SAMPLES AB OBJECTIVE-Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23-Mb interval in a multiethnic sample to search for variants responsible for this linkage signal. RESEARCH DESIGN AND METHODS-In all, 5,290 single nucleotide polymorphisms (SNPs) were successfully genotyped in 3,179 type 2 diabetes case and control subjects from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q linkage. After imputation, we estimate similar to 80% coverage of common variation across the region (r(2) > 0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in similar to 8,500 case subjects and 12,400 control subjects. RESULTS-Association mapping of the 23-Mb region identified two strong signals, both of which were restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, odds ratio 1.38 [95% CI 1.21-1.571, P = 1.4 x 10(-6), in 999 case subjects and 1,190 control subjects); the second mapped within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, odds ratio 1.48 [1.18-1.761, P = 1.0 x 10(-5), under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), there was no indication that these variants were causally related to type 2 diabetes status. CONCLUSIONS-Detailed fine-mapping of the 23-Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance. Diabetes 58:1704-1709, 2009 C1 [Prokopenko, Inga; Zeggini, Eleftheria; Rayner, N. William; Elliott, Katherine S.; Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Prokopenko, Inga; Rayner, N. William; Groves, Christopher J.; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Zeggini, Eleftheria; Akan, Pelin; Gwilliam, Rhian; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Hanson, Robert L.; Baier, Leslie; Bogardus, Clifton] NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. [Mitchell, Braxton D.; Fu, Mao; Shuldiner, Alan R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Das, Swapan K.; Elbein, Steven C.] Cent Arkansas Vet Healthcare Syst, Endocrinol Sect, Med Serv, Little Rock, AR USA. [Das, Swapan K.] Univ Arkansas Med Sci, Div Endocrinol & Metab, Dept Internal Med, Coll Med, Little Rock, AR 72205 USA. [Frayling, Timothy M.; Hattersley, Andrew T.] Peninsula Med Sch, Inst Clin & Biomed Sci, Exeter, Devon, England. [Scott, Laura J.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Voight, Benjamin F.] Broad Inst Harvard, Cambridge, MA USA. [Voight, Benjamin F.] MIT, Cambridge, MA 02139 USA. [Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Voight, Benjamin F.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Hu, Cheng; Wang, Cong-rong; Jia, Weiping] Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Peoples Hosp 6, Shanghai 200030, Peoples R China. [Morris, Andrew D.] Univ Dundee, Diabet Res Grp, Biomed Res Inst, Dundee, Scotland. [Ng, Maggie; Chan, Juliana] Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. [Palmer, Colin N. A.] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Tello-Ruiz, Marcela; Stein, Lincoln] Cold Spring Harbor Lab, New York, NY USA. [Vaxillaire, Martine; Froguel, Philippe] Univ Lille 2, CNRS, Inst Biol, UMR 8090, Lille, France. [Vaxillaire, Martine; Froguel, Philippe] Univ Lille 2, Inst Pasteur, Lille, France. [Stein, Lincoln] Ontario Inst Canc Res, Toronto, ON, Canada. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, London, England. [McCarthy, Mark I.] Churchill Hosp, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England. RP McCarthy, MI (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM mark.mccarthy@drl.ox.ac.uk RI Study, GoDARTS/K-9448-2016; Hu, Cheng/C-3346-2008; Palmer, Colin/C-7053-2008; Morris, Andrew/C-2837-2009; Voight, Benjamin/F-1775-2011; Hossain, Sarah /C-7332-2009; Jia, Weiping/B-7483-2012; Deloukas, Panos/B-2922-2013; Hanson, Robert/O-3238-2015; Prokopenko, Inga/H-3241-2014; Chan, Juliana /B-7918-2016; OI Palmer, Colin/0000-0002-6415-6560; Hossain, Sarah /0000-0003-1355-0979; Deloukas, Panos/0000-0001-9251-070X; Hanson, Robert/0000-0002-4252-7068; Prokopenko, Inga/0000-0003-1624-7457; Chan, Juliana /0000-0003-1325-1194; Zeggini, Eleftheria/0000-0003-4238-659X; Mitchell, Braxton/0000-0003-4920-4744 FU Intramural NIH HHS; Medical Research Council [G0601201(79675), G0600331, G0601201, G0601261]; NCI NIH HHS [K07-CA67960]; NCRR NIH HHS [M01 RR014288, M01 RR14288]; NIA NIH HHS [T32 AG000219, T32-AG00219]; NIDDK NIH HHS [K24-DK02673, P30 DK079637, R01 DK039311, R01 DK054261, R01 DK073490, R01-DK073490, R01-DK39311, R01-DK54261, U01 DK058026, U01-DK58026]; Wellcome Trust [072960, 077011, 079557, 088885, GR072960] NR 24 TC 18 Z9 20 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2009 VL 58 IS 7 BP 1704 EP 1709 DI 10.2337/db09-0081 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 466VF UT WOS:000267690700032 PM 19389826 ER PT J AU Rother, KI Brown, RJ Morales, MM Wright, E Duan, ZG Campbell, C Harlan, DM Orlander, PR Brod, SA Hardin, DS Popovic, J McEvoy, RC AF Rother, Kristina I. Brown, Rebecca J. Morales, Miriam M. Wright, Elizabeth Duan, Zhigang Campbell, Carol Harlan, David M. Orlander, Philip R. Brod, Staley A. Hardin, Dana S. Popovic, Jadranka McEvoy, Robert C. TI Effect of Ingested Interferon-alpha on beta-Cell Function in Children With New-Onset Type 1 Diabetes SO DIABETES CARE LA English DT Article; Proceedings Paper CT 9th Annual Meeting of the Federation-of-Clinical-Immunology-Societies CY JUN 11-14, 2009 CL San Francisco, CA SP Federat Clin Immunol Soc ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; IFN-ALPHA; INSULIN-SECRETION; MELLITUS; TRIAL; AZATHIOPRINE; CYCLOSPORINE; NICOTINAMIDE; SUPPRESSION; REMISSION AB OBJECTIVE - To evaluate the safety and efficacy of ingested human recombinant interferon-alpha (hrIFN-alpha) for presenation of beta-cell function in young patients with recent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS - Subjects aged 3-25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-alpha at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal. RESULTS - Individuals in the placebo group (n = 30) lost 56 +/- 29% of their C-peptide secretion from 0 to 12 months, expressed as area under the curve (AUC) in response to a mixed meal. In contrast, children treated with hrIFN-alpha lost 29 +/- 54 and 48 +/- 35% (for 5,000 [n = 27] and 30,000 units [n = 31], respectively, P = 0.028, ANOVA adjusted for age, baseline C-peptide AUC, and study site). Bonferroni post hoc analyses for placebo versus 5,000 units and placebo versus 30,000 units demonstrated that the overall trend was deter-mined by the 5,000-unit treatment group. Adverse events occurred at similar rates in all treatment groups. CONCLUSIONS - ingested hrIFN-alpha was safe at the doses used. Patients in the 5,000-unit hrIFN-alpha treatment group maintained more beta-cell function 1 year after study enrollment than individuals in the placebo group, whereas this effect was not observed in patients who received 30,000 units hrIFN-alpha. Further studies of low-dose ingested hrIFN-alpha in new-onset type 1 diabetes are needed to confirm this effect. C1 [Rother, Kristina I.; Brown, Rebecca J.; Wright, Elizabeth; Duan, Zhigang; Campbell, Carol; Harlan, David M.] NIDDK, Bethesda, MD 20892 USA. [Morales, Miriam M.; Brod, Staley A.] Univ Texas Med Sch, Dept Neurol, Houston, TX USA. [Orlander, Philip R.] Univ Texas Med Sch, Dept Internal Med, Houston, TX USA. [Hardin, Dana S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Popovic, Jadranka] Childrens Mercy Hosp & Clin, Kansas City, MO USA. [McEvoy, Robert C.] St Paul Childrens Hosp, St Paul, MN USA. RP Rother, KI (reprint author), NIDDK, Bethesda, MD 20892 USA. EM kr58q@nih.gov FU Intramural NIH HHS [Z01 DK062001-08, Z01 DK062001-09, ZIA DK062001-10, ZIA DK062001-11]; NCRR NIH HHS [UL1 RR024148] NR 23 TC 27 Z9 28 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUL PY 2009 VL 32 IS 7 BP 1250 EP 1255 DI 10.2337/dc08-2029 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 469EK UT WOS:000267878300024 PM 19564474 ER PT J AU Liu, EH Digon, BJ Hirshberg, B Chang, R Wood, BJ Neeman, Z Kam, A Wesley, RA Polly, SM Hofmann, RM Rother, KI Harlan, DM AF Liu, E. H. Digon, B. J., III Hirshberg, B. Chang, R. Wood, B. J. Neeman, Z. Kam, A. Wesley, R. A. Polly, S. M. Hofmann, R. M. Rother, K. I. Harlan, D. M. TI Pancreatic beta cell function persists in many patients with chronic type 1 diabetes, but is not dramatically improved by prolonged immunosuppression and euglycaemia from a beta cell allograft SO DIABETOLOGIA LA English DT Article DE Beta cell regeneration; C-peptide; Islet transplantation; Pancreas transplantation; Type 1 diabetes ID T-CELLS; MELLITUS; REGENERATION; HUMANS; GROWTH; AUTOIMMUNITY; ANTIBODIES; TURNOVER; ADULT; ONSET AB We measured serum C-peptide (at least 0.167 nmol/l) in 54 of 141 (38%) patients with chronic type 1 diabetes and sought factors that might differentiate those with detectable C-peptide from those without it. Finding no differences, and in view of the persistent anti-beta cell autoimmunity in such patients, we speculated that the immunosuppression (to weaken autoimmune attack) and euglycaemia accompanying transplant-based treatments of type 1 diabetes might promote recovery of native pancreatic beta cell function. We performed arginine stimulation tests in three islet transplant and four whole-pancreas transplant recipients, and measured stimulated C-peptide in select venous sampling sites. On the basis of each sampling site's C-peptide concentration and kinetics, we differentiated insulin secreted from the individual's native pancreatic beta cells and that secreted from allografted beta cells. Selective venous sampling demonstrated that despite long-standing type 1 diabetes, all seven beta cell allograft recipients displayed evidence that their native pancreas secreted C-peptide. Yet even if chronic immunosuppression coupled with near normal glycaemia did improve native pancreatic C-peptide production, the magnitude of the effect was quite small. Some native pancreatic beta cell function persists even years after disease onset in most type 1 diabetic patients. However, if prolonged euglycaemia plus anti-rejection immunosuppressive therapy improves native pancreatic insulin production, the effect in our participants was small. We may have underestimated pancreatic regenerative capacity by studying only a limited number of participants or by creating conditions (e.g. high circulating insulin concentrations or immunosuppressive agents toxic to beta cells) that impair beta cell function. ClinicalTrials.gov NCT00246844 and NCT00006505. C1 [Liu, E. H.; Digon, B. J., III; Hirshberg, B.; Rother, K. I.; Harlan, D. M.] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Chang, R.; Wood, B. J.; Neeman, Z.; Kam, A.] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Wesley, R. A.] NIH, Ctr Clin, Off Director, Bethesda, MD 20892 USA. [Polly, S. M.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Hofmann, R. M.] Univ Wisconsin, Dept Med, Madison, WI USA. RP Harlan, DM (reprint author), NIDDKD, Diabet Branch, NIH, 10 Ctr Dr,MSC 1453,CRC 5W-5940, Bethesda, MD 20892 USA. EM davidmh@mail.nih.gov FU Intramural Research Program of the NIDDK/NIH; Clinical Center/NIH FX The authors would like to thank J. Jesson for her help in the pancreas transplant sampling protocol. We also would like to thank P. Swanson and T. Wakefield for their help in protocol preparation and management, and J. Lee, F. Leopardi and P. Brooks for their assistance in obtaining and processing of samples. This research was supported by the Intramural Research Program of the NIDDK/NIH and the Clinical Center/NIH. NR 48 TC 28 Z9 28 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X EI 1432-0428 J9 DIABETOLOGIA JI Diabetologia PD JUL PY 2009 VL 52 IS 7 BP 1369 EP 1380 DI 10.1007/s00125-009-1342-7 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 451UI UT WOS:000266496000021 PM 19418039 ER PT J AU Cox, JT Moriarty, AT Castle, PE AF Cox, J. Thomas Moriarty, Ann T. Castle, Philip E. TI Commentary on: Statement on HPV DNA Test Utilization SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Editorial Material ID CANCER-SOCIETY GUIDELINE; HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; SCREENING-TESTS; NEOPLASIA; COHORT; WOMEN; AMERICAN; RISK; METAANALYSIS C1 [Cox, J. Thomas] Univ Calif Santa Barbara, Gynecol & Colposcopy Clin, Student Hlth Serv, Santa Barbara, CA 93106 USA. [Moriarty, Ann T.] AmeriPath Indiana, Indianapolis, IN 46219 USA. [Castle, Philip E.] NCI, Div Canc Epidemiol, NIH, DHHS, Bethesda, MD 20892 USA. [Castle, Philip E.] NCI, Div Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Cox, JT (reprint author), Univ Calif Santa Barbara, Gynecol & Colposcopy Clin, Student Hlth Serv, Santa Barbara, CA 93106 USA. EM cox-t@sa.ucsb.edu NR 20 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD JUL PY 2009 VL 37 IS 7 BP 471 EP 474 DI 10.1002/dc.21098 PG 4 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 467KV UT WOS:000267738500001 PM 19459174 ER PT J AU Solomon, D Papillo, JL Davey, DD AF Solomon, Diane Papillo, Jacalyn L. Davey, Diane D. CA CETC TI Statement on HPV DNA Test Utilization SO DIAGNOSTIC CYTOPATHOLOGY LA English DT Article ID CANCER C1 [Solomon, Diane] NCI, Canc Prevent Div, NIH, US Dept HHS, Rockville, MD USA. [Papillo, Jacalyn L.] Fletcher Allen Hlth Care, Dept Anat Pathol, Burlington, VT USA. [Davey, Diane D.] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. RP Solomon, D (reprint author), Execut Plaza N Room 2130,6130 Execut Blvd, Rockville, MD 20852 USA. EM ds87v@nih.gov FU A.S.C.P.; American Society of Cytopathology; International Academy of Cytology; American Society of Cytology; American Society for Clinical Pathology; Papanicolaou Society of Cytopathology; American Society for Cytotechnology; College of American Pathologists FX On behalf of the Cytopathology Education and Technology Consortium (CETC) members and sponsoring organizations: Karen Atkison, M.P.A., C.T. (A.S.C.P.), (American Society of Cytopathology); Marluce Bibbo, M.D., F.I.A.C., (International Academy of Cytology); George Birdsong, M.D., (American Society of Cytology); Toni Bonfiglio, M.D., (American Society for Clinical Pathology); Lydia Howell, M.D., (Papanicolaou Society of Cytopathology); Elizabeth Jenkins, M.S., (American Society of Cytopathology, administrative support); Lynnette Savaloja, S.C.T. (A.S.C.P.), (American Society for Cytotechnology); David Wilbur, M.D., (College of American Pathologists) NR 4 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 8755-1039 J9 DIAGN CYTOPATHOL JI Diagn. Cytopathol. PD JUL PY 2009 VL 37 IS 7 BP 542 EP 543 DI 10.1002/dc.21097 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 467KV UT WOS:000267738500017 PM 19459173 ER PT J AU Mathews, LA Crea, F Farrar, WL AF Mathews, Lesley A. Crea, Francesco Farrar, W. L. TI Epigenetic gene regulation in stem cells and correlation to cancer SO DIFFERENTIATION LA English DT Review DE Epigenetics; Embryonic stem cells; Normal and cancerous adult stem/progenitor cells ID CHRONIC MYELOID-LEUKEMIA; MOUSE MAMMARY-GLAND; HISTONE DEACETYLASE INHIBITION; NEURAL STEM/PROGENITOR CELLS; ANDROGEN RECEPTOR EXPRESSION; DNA METHYLATION; PROSTATE-CANCER; BREAST-CANCER; PANCREATIC-CANCER; SELF-RENEWAL AB Through the classic study of genetics, much has been learned about the regulation and progression of human disease. Specifically, cancer has been defined as a disease driven by genetic alterations, including mutations in tumor-suppressor genes and oncogenes, as well as chromosomal abnormalities. However, the study of normal human development has identified that in addition to classical genetics, regulation of gene expression is also modified by 'epigenetic' alterations including chromatin remodeling and histone variants, DNA methylation, the regulation of polycomb group proteins, and the epigenetic function of non-coding RNA. These changes are modifications inherited during both meiosis and mitosis, yet they do not result in alterations of the actual DNA sequence. A number of biological questions are directly influenced by epigenetics, such as how does a cell know when to divide, differentiate or remain quiescent, and more importantly, what happens when these pathways become altered? Do these alterations lead to the development and/or progression of cancer? This review will focus on summarizing the limited current literature involving epigenetic alterations in the context of human cancer stems cells (CSCs). The extent to which epigenetic changes define cell fate, identity, and phenotype are still under intense investigation, and many questions remain largely unanswered. Before discussing epigenetic gene silencing in CSCs, the different classifications of stem cells and their properties will be introduced. This will be followed by an introduction to the different epigenetic mechanisms. Finally, there will be a discussion of the current knowledge of epigenetic modifications in stem cells, specifically what is known from rodent systems and established cancer cell lines, and how they are leading us to understand human stem cells. Published by Elsevier Ltd. on behalf of International Society of Differentiation C1 [Mathews, Lesley A.; Farrar, W. L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Canc Res Ctr, Frederick, MD 21702 USA. [Crea, Francesco] Scuola Normale St Anna, Pisa, Italy. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Canc Res Ctr, 1050 Boyles St,Bldg 560,Room 21-81, Frederick, MD 21702 USA. EM farrar@mail.ncifcrf.gov RI Crea, Francesco /I-8383-2015; OI Crea, Francesco/0000-0002-4903-2973 FU Intramural NIH HHS [Z01 BC010794-01]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 192 TC 48 Z9 50 U1 1 U2 21 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD JUL PY 2009 VL 78 IS 1 BP 1 EP 17 DI 10.1016/j.diff.2009.04.002 PG 17 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 555RP UT WOS:000274532000001 PM 19443100 ER PT J AU Yadav, H Jain, S Yadav, M Sinha, PR Prasad, GBKS Marotta, F AF Yadav, H. Jain, S. Yadav, M. Sinha, P. R. Prasad, G. B. K. S. Marotta, F. TI Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats SO DIGESTIVE AND LIVER DISEASE LA English DT Article DE Gluconeogenesis; High fructose diets; Hepatic steatosis; Insulin resistance; NAFLD; Rosiglitazone; Type 2 diabetes ID FATTY LIVER-DISEASE; TRANSCRIPTIONAL COACTIVATOR; INSULIN-RESISTANCE; GLUCONEOGENESIS; CONSUMPTION; EPIDEMIC; PGC-1 AB Background. The high consumption of fructose leads to the increasing incidence of insulin resistance by several unknown mechanisms. Hepatic glucose metabolism may also be an important target of fructose-induced-metabolic alterations. Aim. The aim of present study was to investigate alterations in hepatic glycogenolysis, glycogenesis and gluconeogenic fluxes by feeding of 21% high fructose diet and the effects of Rosiglitazone treatment to prevent these derangements in rats. Methods. Rats were maintained on normal chow and high fructose diet with or without Rosiglitazone for 8 weeks and various biochemical and gene expression measures were estimated. Results. The feeding of high fructose diet impaired glucose, insulin and pyruvate tolerance tests and increased blood HbA(1c), insulin, triglyceride, free fatty acids and homeostasis model assessment after 8 weeks. In addition, high fructose diet feeding increased expression of phosphoenol-pyruvatecorboxykinase, glucose-6-phosphatase, sterol regulatory element binding proteins-1 and fatty acid synthase through enhanced expression of fork-head receptor, peroxisome proliferator activated receptor-gamma-co-activator 1 and cAMP reactive element binding protein. The treatment with Rosiglitazone inhibited all these derangements, i.e. hepato-lipogenic and gluconeogenic effects of high fructose diet feeding in rats. Conclusions. Together these findings suggest that high fructose diet induced hepatic gluconeogenic and lipogenic rate, and increased circulating triglycerides and free fatty acids, which may be the major risk factors for glucose intolerance, hyperglycemia and insulin resistance in rats. In such situations high fructose flux also induces transcriptional cascade of gluconeogenic enzymes through the modulation of various associated transcriptional factors. (C) 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. C1 [Yadav, H.; Jain, S.; Sinha, P. R.] Natl Dairy Res Inst, Anim Biochem Div, Karnal 132001, Haryana, India. [Yadav, M.] Jiwaji Univ, Sch Studies Chem, Gwalior 474011, Madhya Pradesh, India. [Prasad, G. B. K. S.] Jiwaji Univ, Sch Studies Biochem, Gwalior, Madhya Pradesh, India. [Marotta, F.] Univ Milan, WHO Ctr Biotechnol & Nat Med, I-20122 Milan, Italy. RP Yadav, H (reprint author), NIDDK, Diabet Branch, NIH, Clin Res Ctr,W Labs, Bldg 10,S Dr & Old Georgetown Rd, Bethesda, MD USA. EM yadavhariom@gmail.com OI Yadav, Hariom/0000-0003-4504-1597 NR 36 TC 13 Z9 13 U1 1 U2 2 PU PACINI EDITORE PI PISA PA VIA DELLA GHERARDESCA-ZONA INDUSTRIALE OSPEDALETTO, 56121 PISA, ITALY SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD JUL PY 2009 VL 41 IS 7 BP 500 EP 508 DI 10.1016/j.dld.2008.11.012 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 467YU UT WOS:000267780600009 PM 19196556 ER PT J AU Kahn, R Biswas, K Childress, AR Shoptaw, S Fudala, PJ Gorgon, L Montoya, I Collins, J McSherry, F Li, SH Chiang, N Alathari, H Watson, D Liberto, J Beresford, T Stock, C Wallace, C Gruber, V Elkashef, A AF Kahn, Roberta Biswas, Kousick Childress, Anna-Rose Shoptaw, Steve Fudala, Paul J. Gorgon, Liza Montoya, Ivan Collins, Joseph McSherry, Frances Li, Shou-Hua Chiang, Nora Alathari, Husam Watson, Donnie Liberto, Joseph Beresford, Thomas Stock, Christopher Wallace, Christopher Gruber, Valerie Elkashef, Ahmed TI Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Cocaine; Dependence; Baclofen ID RECEPTOR AGONISTS BACLOFEN; LONGITUDINAL DATA-ANALYSIS; HIGH-DOSE BACLOFEN; GABA(B) RECEPTOR; ALCOHOL-DEPENDENCE; SEEKING BEHAVIOR; RATS; SYMPTOMS; NICOTINE; REINSTATEMENT AB Background: Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Baclofen is a GABA(B) receptor agonist that in preclinical and early pilot clinical trials has shown promise for the treatment of cocaine dependence. The purpose of this multi-site, double-blind study, was to compare the safety and efficacy of baclofen (60 mg/day) vs placebo in an 8-week treatment of individuals with severe cocaine dependence. The primary Outcome measure was subjects' self-reported cocaine use substantiated by urine benzoylecgonine (BE). Analysis of the data did not show a significant difference between the groups treated with baclofen and placebo. The current results do not support a role for 60 mg baclofen in treating cocaine dependence in the population studied. The contrast of this result to earlier, preclinical and human pilot data with baclofen may reflect the trial's focus on severe cocaine-dependent users, and/or the need for a higher baclofen dose. Baclofen's potential as a relapse prevention agent was not tested by the current design, but may be a useful target for future studies. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kahn, Roberta; Gorgon, Liza; Montoya, Ivan; Li, Shou-Hua; Chiang, Nora; Elkashef, Ahmed] NIDA, DPMCDA, Bethesda, MD 20892 USA. [Biswas, Kousick; Collins, Joseph; McSherry, Frances] Cooperat Studies Program Coordinating Ctr 151E, DVA, Perry Point, MD 21902 USA. [Fudala, Paul J.] Reckitt Benckiser Pharmaceut Inc, Richmond, VA 23235 USA. [Shoptaw, Steve; Watson, Donnie] Friends Res Inst Inc, Los Angeles, CA USA. [Childress, Anna-Rose] Univ Penn, Sch Med, Dept Psychiat, Addict Treatment Res Ctr, Philadelphia, PA 19104 USA. [Alathari, Husam] Inova Ctr Addict Treatment Serv, Falls Church, VA 22042 USA. [Watson, Donnie] Univ Calif Los Angeles, Integrated Substance Abuse Program, Torrance, CA 90502 USA. [Liberto, Joseph] VA Maryland Hlth Care Syst MH 116, Baltimore, MD 21201 USA. [Beresford, Thomas] Eastern Colorado Vet Affairs Healthcare Syst, Psychiat Serv 116, Denver, CO 80220 USA. [Stock, Christopher] Vet Affairs Salt Lake City Healthcare Syst, Salt Lake City, UT 84148 USA. [Wallace, Christopher] S Texas Vet Healthcare Syst, Vet Affairs Med Ctr Psychiat Serv 116A, San Antonio, TX 78229 USA. [Gruber, Valerie] San Francisco Gen Hosp, San Francisco, CA 94110 USA. RP Kahn, R (reprint author), NIDA, DPMCDA, 6001 Execut Blvd,Rm 4123,MSC 9551, Bethesda, MD 20892 USA. EM rkan@nida.nih.gov FU National Institute on Drug Abuse [Y1-DA4006] FX This study was Supported by the National Institute on Drug Abuse through the Department of Veterans Affairs Cooperative Studies Program (Interagency Agreement No. Y1-DA4006). NR 35 TC 42 Z9 42 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2009 VL 103 IS 1-2 BP 59 EP 64 DI 10.1016/j.drugalcdep.2009.03.011 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 455LG UT WOS:000266760700009 PM 19414226 ER PT J AU Brown, TG Ouimet, MC Nadeau, L Gianoulakis, C Lepage, M Tremblay, J Dongier, M AF Brown, Thomas G. Ouimet, Marie Claude Nadeau, Louise Gianoulakis, Christina Lepage, Martin Tremblay, Jacques Dongier, Maurice TI From the brain to bad behaviour and back again: Neurocognitive and psychobiological mechanisms of driving while impaired by alcohol SO DRUG AND ALCOHOL REVIEW LA English DT Review DE neuropsychology; psychobiology; driving under the influence; DUI; alcohol ID PITUITARY-ADRENAL AXIS; EMPIRICALLY DERIVED TYPOLOGY; WHILE-INTOXICATED OFFENDERS; SUBSTANCE-ABUSE TREATMENT; SIMULATED CAR CRASHES; OXIDASE MAO ACTIVITY; GENDER-DIFFERENCES; COGNITIVE IMPAIRMENT; PERSONALITY-TRAITS; SENSATION-SEEKING AB Issues. Driving while impaired by alcohol (DWI) is responsible for substantial mortality and injury. Significant gaps in our understanding of DWI re-offending, or recidivism, reduce our ability to practically assess recidivism probability and to match interventions to individual risk profiles. These shortcomings reflect the baffling heterogeneity in the DWI population and the limited focus of much existing DWI recidivism research to psychosocial, psychological and substance use correlates. Approach. This narrative review summarises the evidence for the contribution of neurocognitive and psychobiological mechanisms to DWI behaviour and recidivism. Given the nascent nature of this literature, insight into the putative contribution of these mechanisms to DWI is also drawn from other experimental literatures, particularly those on alcohol use disorders and cognitive and behavioural neuroscience. Key Findings. Alcohol-related neurotoxicity and dysregulation of hypothalamic-pituitary-adrenal axis and serotonergic systems may underlie certain offender characteristics consistently correlated with heightened DWI risk, persistence and intervention resistance. Their markers are less vulnerable to sources of bias than subjective psychosocial indices and are more far-reaching than alcohol abuse in explaining DWI behaviour and recidivism. Implications. The investigation of neurocognitive and psychobiological mechanisms in DWI research is a promising avenue for discerning clinically meaningful subgroups within the DWI population. This can lead to research and development in alternative assessment and more targeted intervention technologies. Conclusion. Multidimensional research in DWI and recidivism offers novel avenues for increasing road safety. [Brown TG, Ouimet MC, Nadeau L, Gianoulakis C, Lepage M, Tremblay J, Dongier M. From the brain to bad behaviour and back again: Neurocognitive and psychobiological mechanisms of driving while impaired by alcohol. Drug Alcohol Rev 2009;28:406-418]. C1 [Brown, Thomas G.; Ouimet, Marie Claude; Nadeau, Louise; Gianoulakis, Christina; Lepage, Martin; Tremblay, Jacques; Dongier, Maurice] Douglas Hosp, Res Ctr, Verdun, PQ H4H 1R3, Canada. [Brown, Thomas G.; Gianoulakis, Christina; Lepage, Martin; Tremblay, Jacques; Dongier, Maurice] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Brown, Thomas G.] Pavillon Foster Addict Treatment Program, St Philippe De Laprairie, PQ, Canada. [Ouimet, Marie Claude] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Nadeau, Louise] Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. RP Brown, TG (reprint author), Douglas Hosp, Res Ctr, 6875 Lasalle BLVD, Verdun, PQ H4H 1R3, Canada. EM thomas.brown@mcgill.ca NR 155 TC 9 Z9 14 U1 8 U2 16 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0959-5236 J9 DRUG ALCOHOL REV JI Drug Alcohol Rev. PD JUL PY 2009 VL 28 IS 4 BP 406 EP 418 DI 10.1111/j.1465-3362.2009.00053.x PG 13 WC Substance Abuse SC Substance Abuse GA 466JR UT WOS:000267658500010 PM 19594795 ER PT J AU Phillips, TM Wellner, EF AF Phillips, Terry M. Wellner, Edward F. TI Chip-based immunoaffinity CE: Application to the measurement of brain-derived neurotrophic factor in skin biopsies SO ELECTROPHORESIS LA English DT Article DE Allergic dermatitis; Chip-based CE; Clinical assessment; Immunoaffinity; Inflammation ID AFFINITY CAPILLARY-ELECTROPHORESIS; SOLID-PHASE EXTRACTION; ATOPIC-DERMATITIS; DISEASE SEVERITY; HUMAN PLASMA; MICROCHIP; NEUROPEPTIDES; BIOMARKERS; DEVICE; FLUIDS AB A chip-based immunoaffinity CE system has been employed to measure the concentrations of brain-derived neurotrophic factor in human skin biopsies, taken during atopic inflammatory events. The device employs a replaceable immunoaffinity disk to which capture antibodies have been chemically immobilized. Homogenates obtained from micro-dissected human skin samples were injected into the system, where the analyte of interest was captured in the immunoextraction port, thus allowing non-reactive materials to be removed prior to analysis. The captured analyte was labeled in situ with a red-emitting laser dye before being released from the capture antibody, separated by electrophoresis, and the resolved peaks detected by online LIF. Comparison of this chip-based system with conventional immunoassay demonstrated good correlation when analyzing both standards and patient samples. The system was semi-automated resulting in a CE analysis within 1.5 min and a total of circa 5 min. Intra- and inter-assay CV's of 3.85 and 4.19 were achieved with circa 98.8% recovery of brain-derived neurotrophic factor at a concentration of 100 pg/mL. The assay demonstrated clear differences between clinical stages of atopic dermatitis in human patients and could run 10-15 samples per hour. This system holds the potential for being modified to be a portable unit that could be used in clinics and other biomedical screening studies. C1 [Phillips, Terry M.; Wellner, Edward F.] Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Phillips, TM (reprint author), Natl Inst Biomed Imaging & Bioengn, Ultramicro Immunodiagnost Sect, Lab Bioengn & Phys Sci, NIH, 13-3N15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM phillipt@mail.nih.gov FU National Institutes of Health, Bethesda, MD, USA FX This work was supported by the Intramural Program of the National Institutes of Health, Bethesda, MD, USA. NR 38 TC 17 Z9 17 U1 1 U2 11 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD JUL PY 2009 VL 30 IS 13 BP 2307 EP 2312 DI 10.1002/elps.200900095 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 478ZI UT WOS:000268626900009 PM 19569127 ER PT J AU Reilly, KM AF Reilly, Karlyne M. TI Neurofibromatosis and lessons for the war on cancer SO EMBO MOLECULAR MEDICINE LA English DT Editorial Material DE malignant peripheral nerve sheath tumour; neurofibroma; Neurofibromatosis; Schwann cell; Sox9 ID NF1; HAPLOINSUFFICIENCY AB In the war on cancer, a great deal of attention is being paid to knowing the 'enemy'. It is widely believed that by understanding the driving forces underlying cancer, researchers can develop better ways to target the disease. Currently, large-scale efforts have been under taken to completely characterize molecular changes in common human cancers (http://cancergenome.nih.gov/) (Collins & Barker, 2007). However, as more is learned about cancer, the debate increases on what exactly the enemy is: cells making up the bulk of the tumour, rare tumour stem cells that can regrow the tumour, tumour microenvironment, the subset of cancer cells with metastatic potential, etc. Studies of the cancers associated with Neurofibromatosis type 1 (NF1) are helping to define the relationship between many of these different cell types. It is still unclear how these different enemies are related to each other and how they interact to wage cancer's war on the patient. C1 NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. RP Reilly, KM (reprint author), NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. EM kreilly@ncifcrf.gov FU Intramural NIH HHS [Z99 CA999999] NR 8 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD JUL PY 2009 VL 1 IS 4 BP 198 EP 200 DI 10.1002/emmm.200900029 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 543GY UT WOS:000273563200003 PM 20049721 ER PT J AU Schwan, TG Raffel, SJ Schrumpf, ME Webster, LS Marques, AR Spano, R Rood, M Burns, J Hu, RJ AF Schwan, Tom G. Raffel, Sandra J. Schrumpf, Merry E. Webster, Larry S. Marques, Adriana R. Spano, Robyn Rood, Michael Burns, Joe Hu, Renjie TI Tick-borne Relapsing Fever and Borrelia hermsii, Los Angeles County, California, USA SO EMERGING INFECTIOUS DISEASES LA English DT Article ID MONOCLONAL-ANTIBODY; NORTH-AMERICA; STATES; GLPQ AB The primary cause of tick-borne relapsing fever in western North America is Borrelia hermsii, a rodent-associated spirochete transmitted by the fast-feeding soft tick Ornithodoros hermsii. We describe a patient who had an illness consistent with relapsing fever after exposure in the mountains near Los Angeles, California, USA. The patient's convalescent-phase serum was seropositive for B. hermsii but negative for several other vector-borne bacterial pathogens. Investigations at the exposure site showed the presence of O. hermsi ticks infected with B. hermsii and the presence of rodents that were seropositive for the spirochete. We determined that this tick-borne disease is endemic to the San Gabriel Mountains near the greater Los Angeles metropolitan area. C1 [Schwan, Tom G.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Webster, Larry S.] Mt Wilson Observ, Mt Wilson, CA USA. [Marques, Adriana R.] NIAID, Bethesda, MD 20892 USA. [Spano, Robyn; Rood, Michael] Los Angeles Cty Dept Publ Hlth, Baldwin Pk, CA USA. [Burns, Joe; Hu, Renjie] Calif Dept Publ Hlth, Ontario, CA USA. RP Schwan, TG (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. NR 28 TC 22 Z9 23 U1 0 U2 2 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD JUL PY 2009 VL 15 IS 7 BP 1026 EP 1031 DI 10.3201/eid1507.090223 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 467GK UT WOS:000267726100004 PM 19624916 ER PT J AU Borg, J Klint, C Wierup, N Strom, K Larsson, S Sundler, F Lupi, R Marchetti, P Xu, GH Kimmel, A Londos, C Holm, C AF Borg, Joergen Klint, Cecilia Wierup, Nils Stroem, Kristoffer Larsson, Sara Sundler, Frank Lupi, Roberto Marchetti, Piero Xu, Guoheng Kimmel, Alan Londos, Constantine Holm, Cecilia TI Perilipin Is Present in Islets of Langerhans and Protects against Lipotoxicity When Overexpressed in the beta-Cell Line INS-1 SO ENDOCRINOLOGY LA English DT Article ID HORMONE-SENSITIVE LIPASE; STIMULATED INSULIN-SECRETION; LIPID STORAGE DROPLET; A-MEDIATED LIPOLYSIS; FATTY-ACIDS; TRIGLYCERIDE ACCUMULATION; ADIPOCYTE LIPOLYSIS; PANCREATIC-ISLETS; MESSENGER-RNA; RAT ISLETS AB Lipids have been shown to play a dual role in pancreatic beta-cells: a lipid-derived signal appears to be necessary for glucose-stimulated insulin secretion, whereas lipid accumulation causes impaired insulin secretion and apoptosis. The ability of the protein perilipin to regulate lipolysis prompted an investigation of the presence of perilipin in the islets of Langerhans. In this study evidence is presented for perilipin expression in rat, mouse, and human islets of Langerhans as well as the rat clonal beta-cell line INS-1. In rat and mouse islets, perilipin was verified to be present in beta-cells. To examine whether the development of lipotoxicity could be prevented by manipulating the conditions for lipid storage in the beta-cell, INS-1 cells with adenoviral-mediated overexpression of perilipin were exposed to lipotoxic conditions for 72 h. In cells exposed to palmitate, perilipin overexpression caused increased accumulation of triacylglycerols and decreased lipolysis compared with control cells. Whereas glucose-stimulated insulin secretion was retained after palmitate exposure in cells overexpressing perilipin, it was completely abolished in control beta-cells. Thus, overexpression of perilipin appears to confer protection against the development of beta-cell dysfunction after prolonged exposure to palmitate by promoting lipid storage and limiting lipolysis. (Endocrinology 150: 3049-3057, 2009) C1 [Borg, Joergen; Klint, Cecilia; Wierup, Nils; Stroem, Kristoffer; Larsson, Sara; Sundler, Frank; Holm, Cecilia] Lund Univ, Dept Expt Med Sci, Biomed Ctr, SE-22184 Lund, Sweden. [Lupi, Roberto; Marchetti, Piero] Univ Pisa, Metab Unit, Dept Endocrinol & Metab, I-56126 Pisa, Italy. [Xu, Guoheng; Kimmel, Alan; Londos, Constantine] NIDDK, Lab Cellular & Dev Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Holm, C (reprint author), Lund Univ, Dept Expt Med Sci, Div Endocrinol Diabet & Metab, Biomed Ctr C11, SE-22184 Lund, Sweden. EM cecilia.holm@med.lu.se RI Marchetti, Piero/J-7439-2013 OI Marchetti, Piero/0000-0003-4907-0635 FU Swedish Research Council [112 84]; European Union [LSHM-CT-2006518153]; Swedish Diabetes Association; Swedish Foundation for Strategic Research FX This work was supported by the Swedish Research Council Project 112 84 (to C. H.); the European Union (Eurodia LSHM-CT-2006518153); the Swedish Diabetes Association; Cell Factory for Functional Genomics, a program funded by the Swedish Foundation for Strategic Research; the intramural research program of National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and the following foundations: Novo Nordisk, A. Pahlsson, Salubrin/Druvan, and Torsten and Ragnar Soderberg. NR 48 TC 15 Z9 15 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2009 VL 150 IS 7 BP 3049 EP 3057 DI 10.1210/en.2008-0913 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467ZB UT WOS:000267781300011 PM 19299455 ER PT J AU Constantin, S Caraty, A Wray, S Duittoz, AH AF Constantin, Stephanie Caraty, Alain Wray, Susan Duittoz, Anne H. TI Development of Gonadotropin-Releasing Hormone-1 Secretion in Mouse Nasal Explants SO ENDOCRINOLOGY LA English DT Article ID EMBRYONIC OLFACTORY PLACODE; PULSATILE LUTEINIZING-HORMONE; PRIMARY-CELL CULTURE; SHEEP OVIS-ARIES; LHRH NEURONS; RHESUS-MONKEY; ELECTRICAL-ACTIVITY; GNRH SECRETION; IN-VITRO; RATS AB Pulsatile release of GnRH-1 is critical to stimulate gonadotropes of the anterior pituitary. This secretory pattern seems to be inherent to GnRH-1 neurons, however, the mechanisms underlying such episodical release remain unknown. In monkey nasal explants, the GnRH-1 population exhibits synchronized calcium events with the same periodicity as GnRH-1 release, suggesting a link, though the sequence of events was unclear. GnRH-1 neurons in mouse nasal explants also exhibit synchronized calcium events. In the present work, GnRH-1 release was assayed in mouse nasal explants using radioimmunology and its relationship with calcium signaling analyzed. GnRH-1 neurons generated episodical release as early as 3 d in vitro (div) and maintained such release throughout the period studied (3-21 div). The pulse frequency remained constant, suggesting that the pulse generator is operative at an early developmental stage. In contrast, pulse amplitude increased 2-fold between 3 and 7 div, and again between 7 and 14 div, suggesting maturation in synthesizing and/or secretory mechanisms. To evaluate these possibilities, total GnRH-1 content was measured. Only a small increase in GnRH-1 content was detected between 7 and 14 div, whereas a large increase occurred between 14 and 21 div. These data indicate that GnRH-1 content was not a limiting factor for the amplitude of the pulses at 7 div but that the secretory mechanisms mature between 3 and 14 div. The application of kisspeptin-10 revealed the ability of GnRH-1 neurons to integrate signals from natural ligands into a secretory response. Finally, simultaneous sampling of medium and calcium imaging recordings indicated that the synchronized calcium events and secretory events are congruent. (Endocrinology 150: 3221-3227, 2009) C1 [Constantin, Stephanie] Univ Otago, Dept Physiol, Ctr Neuroendocrinol, Dunedin 9054, New Zealand. [Constantin, Stephanie; Caraty, Alain; Duittoz, Anne H.] Univ Toulouse, INRA, CNRS, UMR 6175, F-37380 Nouzilly, France. [Constantin, Stephanie; Wray, Susan] NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Constantin, S (reprint author), Univ Otago, Dept Physiol, Ctr Neuroendocrinol, Dunedin 9054, New Zealand. EM const95p@otago.ac.nz RI Constantin, Stephanie/C-5264-2009; OI Constantin, Stephanie/0000-0003-0596-9737; wray, susan/0000-0001-7670-3915 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 42 TC 30 Z9 30 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2009 VL 150 IS 7 BP 3221 EP 3227 DI 10.1210/en.2008-1711 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467ZB UT WOS:000267781300031 PM 19213830 ER PT J AU Walker, DM Kajon, AE Torres, SM Carter, MM McCash, CL Swenberg, JA Upton, PB Hardy, AW Olivero, OA Shearer, GM Poirier, MC Walker, VE AF Walker, Dale M. Kajon, Adriana E. Torres, Salina M. Carter, Meghan M. McCash, Consuelo L. Swenberg, James A. Upton, Patricia B. Hardy, Andrew W. Olivero, Ofelia A. Shearer, Gene M. Poirier, Miriam C. Walker, Vernon E. TI WR1065 Mitigates AZT-ddI-Induced Mutagenesis and Inhibits Viral Replication SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Article DE antimutagenesis; antiviral; amifostine; WR1065; cytoprotection ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN LYMPHOBLASTOID-CELLS; TOPOISOMERASE-II-ALPHA; TO-CHILD TRANSMISSION; IN-VITRO EXPOSURE; NUCLEOSIDE ANALOGS; V79 CELLS; MITOCHONDRIAL TOXICITY; RADIOPROTECTOR WR1065; PERINATAL EXPOSURE AB The success of nucleoside reverse transcriptase inhibitors (NRTIs) in treating HIV-1 infection and reducing mother-to-child transmission of the virus during pregnancy is accompanied by evidence that NRTIs cause long-term health risks for cancer and mitochondrial disease. Thus agents that mitigate toxicities of the current combination drug therapies are needed. Previous work had shown that the NRTI-drug pair zidovudine (AZT)-didanosine (ddl) was highly cytotoxic and mutagenic; thus, we conducted preliminary studies to investigate the ability of the active moiety of amifostine, WR1065, to protect against the deleterious effects of this NRTI-drug pair. In TK6 cells exposed to 100 mu M AZT-ddI (equimolar) for 3 days with or without 150 mu M WR1065, WR1065 enhanced long-term cell survival and significantly reduced AZT-ddI-induced mutations. Follow-up studies were conducted to determine if coexposure to AZT and C1 [Walker, Dale M.; Walker, Vernon E.] BioMosaics Inc, Burlington, VT 05405 USA. [Walker, Dale M.; Kajon, Adriana E.; Torres, Salina M.; Carter, Meghan M.; McCash, Consuelo L.; Walker, Vernon E.] Lovelace Resp Res Inst, Albuquerque, NM USA. [Torres, Salina M.; Walker, Vernon E.] Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. [Swenberg, James A.; Upton, Patricia B.] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC USA. [Hardy, Andrew W.; Shearer, Gene M.] NCI, AMRV, CCR, NIH, Bethesda, MD 20892 USA. [Olivero, Ofelia A.; Poirier, Miriam C.] NCI, CDI Sect, LCBG, CCR,NIH, Bethesda, MD 20892 USA. RP Walker, VE (reprint author), BioMosaics, 655 Spear St,Bldg C, Burlington, VT 05405 USA. EM v.walker@biomosaics.com FU Intramural NIH HHS; NCI NIH HHS [R01 CA095741]; NHLBI NIH HHS [1 F31 HL081928, R01 HL072727, F31 HL081928]; NICHD NIH HHS [R01 HD033648] NR 63 TC 8 Z9 8 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD JUL PY 2009 VL 50 IS 6 BP 460 EP 472 DI 10.1002/em.20482 PG 13 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 467XS UT WOS:000267777300003 PM 19334055 ER PT J AU Liebow, E Phelps, J Van Houten, B Rose, S Orians, C Cohen, J Monroe, P Drew, CH AF Liebow, Edward Phelps, Jerry Van Houten, Bennett Rose, Shyanika Orians, Carlyn Cohen, Jennifer Monroe, Philip Drew, Christina H. TI Toward the Assessment of Scientific and Public Health Impacts of the National Institute of Environmental Health Sciences Extramural Asthma Research Program Using Available Data SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE asthma; children; evaluation methodology; health impact analysis; minorities; policy; pulmonary organ systems/disease processes; susceptible populations ID COMMUNITY; CHILDREN; CARE AB BACKGROUND: In the past 15 years, asthma prevalence has increased and is disproportionately distributed among children, minorities, and low-income persons. The National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training developed a framework to measure the scientific and health impacts of its extramural asthma research to improve the scientific basis for reducing the health effects of asthma. OBJECTIVES: Here we apply the framework to characterize the NIEHS asthma portfolio's impact in terms of publications, clinical applications of findings, community interventions, and technology developments. METHODS: A logic model was tailored to inputs, outputs, and outcomes of the NIEHS asthma portfolio. Data from existing National Institutes of Health (NIH) databases are used, along with publicly available bibliometric data and structured elicitation of expert judgment. RESULTS: NIEHS is the third largest source of asthma-related research grant funding within the NIH between 1975 and 2005, after the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases. Much of NIEHS-funded asthma research focuses on basic research, but results are often published in journals focused on clinical investigation, increasing the likelihood that the work is moved into practice along the "bench to bedside" continuum. NIEHS support has led to key breakthroughs in scientific research concerning susceptibility to asthma, environmental conditions that heighten asthma symptoms, and cellular mechanisms that may be involved in treating asthma. CONCLUSIONS: If gaps and limitations in publicly available data receive adequate attention, further linkages can be demonstrated between research activities and public health improvements. This logic model approach to research impact assessment demonstrates that it is possible to conceptualize program components, mine existing databases, and begin to show longer-term impacts of program results. The next challenges will be to modify current data structures, improve the linkages among relevant databases, incorporate as much electronically available data as possible, and determine how to improve the quality and health impact of the science that we support. C1 [Liebow, Edward; Rose, Shyanika; Orians, Carlyn; Cohen, Jennifer; Monroe, Philip] Battelle Hlth & Life Sci, Seattle, WA 98109 USA. [Phelps, Jerry; Drew, Christina H.] Natl Inst Environm Hlth Sci, Div Extramural Res & Training, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Van Houten, Bennett] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. RP Liebow, E (reprint author), Battelle Hlth & Life Sci, 1100 Dexter Ave N,Suite 400, Seattle, WA 98109 USA. EM liebowe@battelle.org OI Liebow, Edward/0000-0002-1101-629X FU National Institute of Environmental Health Sciences (NIEHS) [HHSP23320045006XI/T.O, HHSP233000015T] FX This work was completed with support from National Institute of Environmental Health Sciences (NIEHS) contract HHSP23320045006XI/T.O HHSP233000015T. NR 22 TC 7 Z9 7 U1 1 U2 11 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2009 VL 117 IS 7 BP 1147 EP 1154 DI 10.1289/ehp.0800476 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 465WV UT WOS:000267621200036 PM 19654926 ER PT J AU Winuthayanon, W Piyachaturawat, P Suksamrarn, A Ponglikitmongkol, M Arao, Y Hewitt, SC Korach, KS AF Winuthayanon, Wipawee Piyachaturawat, Pawinee Suksamrarn, Apichart Ponglikitmongkol, Mathurose Arao, Yukitomo Hewitt, Sylvia C. Korach, Kenneth S. TI Diarylheptanoid Phytoestrogens Isolated from the Medicinal Plant Curcuma comosa: Biologic Actions in Vitro and in Vivo Indicate Estrogen Receptor-Dependent Mechanisms SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE Curcuma comosa; diarylheptanoid; ER dependent; ERE dependent; ERE independent; estrogen-regulated genes; uterotrophic activity ID BREAST-CANCER-CELLS; LACTOFERRIN GENE-EXPRESSION; MYC ONCOGENE EXPRESSION; PROGESTERONE-RECEPTOR; INDUCED PROLIFERATION; RESPONSIVE ELEMENT; ALPHA; UTERUS; IDENTIFICATION; ACTIVATION AB BACKGROUND: Diarylheptanoids isolated from Curcuma comosa Roxb. have been recently identified as phytoestrogens. However, the mechanism underlying their actions has not yet been identified. OBJECTIVES: We characterized the estrogenic activity of three active naturally occurring diarylheptanoids both in vitro and in vivo. METHODS: We characterized mechanisms of estrogenic action of the diarylheptanoids (3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D I), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diplienyl-(4E,6,E)-4,6-heptadien-3-o1 (D3) by using a real-time polymerase chain reaction assay, a mammalian transfection model, and a uterotrophic assay in mice. RESULTS: All diarylheptanoids Lip-regulated estrogen-responsive genes in estrogen-responsive breast cancer cells (MCF-7). In HepG2 cells transfected with estrogen receptor (ER) beta or different ER alpha functional receptor mutants and the Vit-ERE-TATA-Luc reporter gene, all diarylheptanoids induced transcription through a ligand-dependent human ER alpha-ERE-driven pathway, which was abolished with ICI 182,780 (ER antagonist), whereas only D2 was active with ER beta. An ER alpha mutant lacking the functional AF2 (activation function 2) region was not responsive to 17 beta-estradiol (E(2)) or to any of the diarylheptanoids, whereas ER alpha lacking the AF1 domain exhibited wild-type-like activity. D3 markedly increased uterine weight and proliferation of the uterine epithelium in ovariectomized mice, whereas D1 and D2 were inactive. D3, like E(2), up-regulated lactoferrin (Ltf) gene expression. The responses to D3 in the uterus were inhibited by ICI 182,780. In addition, D3 stimulated both classical (Aqp5) and nonclassical (Cdkn1a) ER-mediated gene regulation. CONCLUSIONS:, Me results suggest that the D3 diaryllieptanoid is an agonist for ER both in vitro and in vivo, and its biological action is ER alpha selective, specifically requiring AF2 function, and involves direct binding via ER as well as ERE-independent gene regulation. C1 [Winuthayanon, Wipawee; Arao, Yukitomo; Hewitt, Sylvia C.; Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Winuthayanon, Wipawee; Piyachaturawat, Pawinee] Mahidol Univ, Fac Sci, Dept Physiol, Bangkok 10400, Thailand. [Suksamrarn, Apichart] Ramkhamhang Univ, Fac Sci, Dept Chem, Bangkok, Thailand. [Ponglikitmongkol, Mathurose] Mahidol Univ, Fac Sci, Dept Biochem, Bangkok 10400, Thailand. RP Korach, KS (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Royal Golden Jubilee PhD Program [PHD/0255/2546]; Thailand Research Fund [DBG5180020]; National Research Council of Thailand; National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency; National Institute of Environmental Health Sciences Division of Intramural Research FX This study was Supported by the Royal Golden Jubilee PhD Program (grant PHD/0255/2546 to W.W. and P.P.), The Thailand Research Fund (DBG5180020), the National Research Council of Thailand, and the Research Team Strengthening Grant of the National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency. This research was supported by the National Institute of Environmental Health Sciences Division of Intramural Research (funding to W.W., Y.A., S.C.H., and K.S.K). NR 57 TC 32 Z9 32 U1 0 U2 10 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2009 VL 117 IS 7 BP 1155 EP 1161 DI 10.1289/ehp.0900613 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 465WV UT WOS:000267621200037 PM 19654927 ER PT J AU Birnbaum, LS Tilson, HA AF Birnbaum, Linda S. Tilson, Hugh A. TI Editorial Independence for EHP SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov; tilsonha@niehs.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2009 VL 117 IS 7 BP A282 EP A282 DI 10.1289/ehp.12927 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 465WV UT WOS:000267621200001 ER PT J AU Eggesbo, M Stigum, H Longnecker, MP Polder, A Aldrin, M Basso, O Thomsen, C Skaare, JU Becher, G Magnus, P AF Eggesbo, Merete Stigum, Hein Longnecker, Matthew P. Polder, Anuschka Aldrin, Magne Basso, Olga Thomsen, Cathrine Skaare, Janneche Utne Becher, Georg Magnus, Per TI Levels of hexachlorobenzene (HCB) in breast milk in relation to birth weight in a Norwegian cohort SO ENVIRONMENTAL RESEARCH LA English DT Article DE Hexachlorobenzene; Small for gestational age; Birth weight; Ponderal index; POPs ID PERSISTENT ORGANOCHLORINE COMPOUNDS; POLYCHLORINATED-BIPHENYLS; REPRODUCTIVE OUTCOMES; GESTATIONAL-AGE; PESTICIDES; EXPOSURE; WOMEN; TOXICITY; CONTAMINATION; ASSOCIATION AB Background: Hexachlorobenzene (HCB) is a ubiquitous environmental contaminant that, even at low doses, causes destruction of ovarian primordial germ cells in experimental studies. However, its potential for reproductive toxicity in humans exposed to background levels has not been fully evaluated. Here we examined the association between maternal levels of HCB and their infants' birth weight. Methods: HCB was measured in milk samples from a subset of women in the Norwegian Human Milk Study (HUMIS), 2003-2006; 300 subjects were randomly chosen from the cohort and 26 from all small for gestational age (SGA) children. Additional information was obtained through questionnaires and the Medical Birth Registry. Results: Overall, HCB was associated with birth weight (adjusted b = -90 g per 8 mu g/kg milk fat, 95% CI-275 to 8) and with SGA (odds ratio 1.8, 95% CI 0.9-3.7 per 8 mu g/kg milk fat (difference between the 10th and the 90th percentile)). After stratification, however, the association was present only among smokers. For birth weight for past or current smokers: b = -282, CI -467 to -98; for never smokers: b = 0.5, CI -149 to 150, p-value for interaction: 0.01. Similar results were observed for head circumference, crown-heel length, and SGA. Conclusions: We saw a moderate association between HCB and markers of impaired fetal growth among past and current smokers. This finding may be non-causal and due to underlying genetic variants tied to both growth and breakdown of HCB or to confounding by unmeasured toxicants that coexist in exposure sources. It may, however, also result from HCB exposure. (C) 2009 Elsevier Inc. All rights reserved. C1 [Eggesbo, Merete; Stigum, Hein; Magnus, Per] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, N-0403 Oslo, Norway. [Eggesbo, Merete; Longnecker, Matthew P.; Basso, Olga] NIEHS, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. [Polder, Anuschka; Skaare, Janneche Utne] Norwegian Sch Vet Sci, Oslo, Norway. [Aldrin, Magne] Norwegian Comp Ctr, Oslo, Norway. [Thomsen, Cathrine; Becher, Georg] Norwegian Inst Publ Hlth, Div Environm Med, N-0403 Oslo, Norway. [Skaare, Janneche Utne] Natl Vet Inst, Oslo, Norway. RP Eggesbo, M (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, POB 4404, N-0403 Oslo, Norway. EM merete.eggesbo@fhi.no RI Basso, Olga/E-5384-2010; Aldrin, Magne/A-7425-2017; OI Basso, Olga/0000-0001-9298-4921; Aldrin, Magne/0000-0003-2718-8528; Longnecker, Matthew/0000-0001-6073-5322; Eggesbo, Merete/0000-0002-0006-5336 FU Intramural NIH HHS [Z01 ES044008-07] NR 37 TC 34 Z9 36 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD JUL PY 2009 VL 109 IS 5 BP 559 EP 566 DI 10.1016/j.envres.2009.04.001 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 461OO UT WOS:000267277600008 PM 19410245 ER PT J AU Schisterman, EF Cole, SR Platt, RW AF Schisterman, Enrique F. Cole, Stephen R. Platt, Robert W. TI Overadjustment Bias and Unnecessary Adjustment in Epidemiologic Studies SO EPIDEMIOLOGY LA English DT Article ID INTERMEDIATE VARIABLES; CAUSAL INFERENCE; UNITED-STATES; MORTALITY; PREECLAMPSIA; DIAGRAMS; MODELS; TRENDS AB Overadjustment is defined inconsistently. This term is meant to describe control (eg, by regression adjustment, stratification, or restriction) for a variable that either increases net bias or decreases precision without affecting bias. We define overadjustment bias as control for an intermediate variable (or a descending proxy for an intermediate variable) on a causal path from exposure to outcome. We define unnecessary adjustment as control for a variable that does not affect bias of the causal relation between exposure and outcome but may affect its precision. We use causal diagrams and an empirical example (the effect of maternal smoking on neonatal mortality) to illustrate and clarify the definition of overadjustment bias, and to distinguish overadjustment bias from unnecessary adjustment. Using simulations, we quantify the amount of bias associated with overadjustment. Moreover, we show that this bias is based on a different causal structure from confounding or selection biases. Overadjustment bias is not a finite sample bias, while inefficiencies due to control for unnecessary variables are a function of sample size. C1 [Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Cole, Stephen R.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Platt, Robert W.] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Platt, Robert/G-5847-2012; OI Platt, Robert/0000-0002-5981-8443; Schisterman, Enrique/0000-0003-3757-641X FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; NIH; NIAID [R03-AI 071763]; Fonds de Recherche en Sante du Quebec FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health (to E.F.S.). The NIH, NIAID through R03-AI 071763 (to S.C.). Chercheur-boursier award, and by core support to the Montreal Children's Hospital Research Institute, from the Fonds de Recherche en Sante du Quebec (to R.P.). NR 35 TC 391 Z9 392 U1 3 U2 33 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2009 VL 20 IS 4 BP 488 EP 495 DI 10.1097/EDE.0b013e3181a819a1 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 458YJ UT WOS:000267065500003 PM 19525685 ER PT J AU Golding, J Steer, C Emmett, P Davis, JM Hibbeln, JR AF Golding, Jean Steer, Colin Emmett, Pauline Davis, John M. Hibbeln, Joseph R. TI High Levels of Depressive Symptoms in Pregnancy With Low Omega-3 Fatty Acid Intake From Fish SO EPIDEMIOLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; POSTPARTUM DEPRESSION; POSTNATAL DEPRESSION; DOUBLE-BLIND; ACID STATUS; SOUTH-WEST; CONSUMPTION; POPULATION; CHILDREN; ENGLAND AB Background: Depression during pregnancy has adverse consequences for both mother and child. Although common in western countries, depression appears to be virtually absent in countries with high seafood intake. We test the hypothesis that low seafood intake during pregnancy is associated with increased prevalence of depressive symptoms. Methods: This study used data prospectively collected from women participating in the Avon Longitudinal Study of Parents and Children in the period 1991-1992. At 32 weeks' gestation, the mother completed a questionnaire that included symptoms of depression and a food frequency questionnaire from which the amount of omega-3 fatty acids from fish was calculated. Statistical analysis took social and lifestyle factors into account. Results: Unadjusted and adjusted analyses showed lower maternal intake of omega-3 from seafood was associated with high levels of depressive symptoms. Compared with women consuming more than 1.5 g omega-3 from seafood per week, those consuming none were more likely to have high levels of depressive symptoms at 32 weeks' gestation (adjusted odds ratios = 1.54; 95% confidence interval 1.25-1.89). Conclusions: These observational data support an association between low omega-3 intake from seafood and increased risk of high levels of depressive symptoms during pregnancy. Eating seafood during pregnancy may have beneficial effects on mental well-being. (Epidemiology 2009-20: 598-603) C1 [Golding, Jean; Steer, Colin; Emmett, Pauline] Univ Bristol, Dept Community Based Med, Ctr Child & Adolescent Hlth, Bristol BS8 2BN, Avon, England. [Davis, John M.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Hibbeln, Joseph R.] NIAAA, NIH, Bethesda, MD USA. RP Golding, J (reprint author), Univ Bristol, Dept Community Based Med, Ctr Child & Adolescent Hlth, Barley House, Bristol BS8 2BN, Avon, England. EM Jean.Golding@bristol.ac.uk OI Emmett, Pauline/0000-0003-1076-4779; Golding, Jean/0000-0003-2826-3307 FU Intramural NIH HHS; Medical Research Council [, G9815508]; Wellcome Trust NR 30 TC 61 Z9 62 U1 3 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2009 VL 20 IS 4 BP 598 EP 603 DI 10.1097/EDE.0b013e31819d6a57 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 458YJ UT WOS:000267065500019 PM 19289957 ER PT J AU Baird, DD Travlos, G Wilson, R Dunson, DB Hill, MC D'Aloisio, AA London, SJ Schectman, JM AF Baird, Donna D. Travlos, Greg Wilson, Ralph Dunson, David B. Hill, Michael C. D'Aloisio, Aimee A. London, Stephanie J. Schectman, Joel M. TI Uterine Leiomyomata in Relation to Insulin-like Growth Factor-I, Insulin, and Diabetes SO EPIDEMIOLOGY LA English DT Article ID FACTOR-BINDING PROTEINS; SMOOTH-MUSCLE TISSUES; IGF-I; TUMORIGENIC FACTORS; EXPRESSION PROFILE; HUMAN MYOMETRIUM; GENE-EXPRESSION; BREAST-CANCER; RISK-FACTORS; WOMEN AB Background: Insulin-like growth factor-I (IGF-I) and insulin stimulate cell proliferation in uterine leiomyoma (fibroid) tissue. We hypothesized that circulating levels of these proteins would be associated with increased prevalence and size of uterine fibroids. Methods: Participants were 35-49-year-old, randomly selected members of an urban health plan who were enrolled in the study in 1996-1999. Premenopausal participants were screened for fibroids with ultrasound. Fasting blood samples were collected. Associations between fibroids and diabetes, plasma IGF-I, IGF binding protein 3 (BP3), and insulin were evaluated for blacks (n = 585) and whites (n 403) by using multiple logistic regression. Results: IGF-I showed no association with fibroids in blacks, but in whites the adjusted odds ratios (aORs) for both mid and upper tertiles compared with the lowest tertile were 0.6 (95% confidence intervals [CI] = 0.3-1.0 and 0.4-1.1, respectively). Insulin and diabetes both tended to be inversely associated with fibroids in blacks. The insulin association was with large fibroids; aOR for the upper insulin tertile relative to the lowest was 0.4 (0.2-0.9). The aOR for diabetes was 0.5 (0.2-1.0). Associations of insulin and diabetes with fibroids were weak for whites. Binding protein 3 showed no association with fibroids. Conclusions: Contrary to our hypothesis, high circulating IGF-I and insulin were not related to increased fibroid prevalence. Instead, there was suggestion of the opposite. The inverse association with diabetes, although based on small numbers, is consistent with previously reported findings. Future studies might investigate vascular dysfunction as a mediator between hyperinsulinemia or diabetes and possible reduced risk of fibroids. (Epidemiology 2009-120: 604-610) C1 [Baird, Donna D.; D'Aloisio, Aimee A.; London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Travlos, Greg; Wilson, Ralph] Natl Inst Environm Hlth Sci, Clin Pathol Grp, Res Triangle Pk, NC 27709 USA. [Dunson, David B.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Hill, Michael C.] George Washington Univ, Med Ctr, Dept Radiol, Washington, DC 20037 USA. [Schectman, Joel M.] George Washington Univ, Med Ctr, Dept Hlth Care Sci, Washington, DC 20037 USA. RP Baird, DD (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, A3-05,111 TW Alexander,Bldg 101,Rm 308,POB 12233, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; London, Stephanie/0000-0003-4911-5290 FU Office of Research on Minority Health; National Institutes of Health; HHS FX Supported by the intramural program at the National Institute of Environmental Health Sciences with support from the Office of Research on Minority Health, National Institutes of Health, HHS. NR 41 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD JUL PY 2009 VL 20 IS 4 BP 604 EP 610 DI 10.1097/EDE.0b013e31819d8d3f PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 458YJ UT WOS:000267065500020 PM 19305350 ER PT J AU Murray, A Cluett, C Bandinelli, S Corsi, AM Ferrucci, L Guralnik, J Singleton, A Frayling, T Melzer, D AF Murray, Anna Cluett, Christie Bandinelli, Stefania Corsi, Anna Maria Ferrucci, Luigi Guralnik, Jack Singleton, Andrew Frayling, Timothy Melzer, David TI Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people SO EUROPEAN HEART JOURNAL LA English DT Article DE Lipid; SNP; Genome-wide association; HDL; LDL; Triglyceride; Myocardial infarction ID DENSITY-LIPOPROTEIN CHOLESTEROL; ISCHEMIC-HEART-DISEASE; CARDIOVASCULAR EVENTS; HDL CHOLESTEROL; NONFASTING TRIGLYCERIDES; CORONARY RISK; MORTALITY; GENOTYPES; HUMANS; WOMEN AB There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. In the InCHIANTI Study of Aging (age >= 65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained < 2.1% of the variance in their respective lipid concentrations, with the exception of the CETP SNP rs1800775 and HDL levels (4.76%). Combined risk allele counts outperformed the largest single-SNP effects for LDL (explaining 7.1% of variance) and triglycerides (4.8%), but not HDL (3.4%). Risk alleles were divided as near as possible into quartiles. The 31% of respondents with 10 or more LDL increasing alleles were more likely to have LDL levels above the intervention threshold (OR 3.00, 95% CI 1.67-5.39, P = 2.5 x 10(-4)), compared with the 21% with 7 or less risk alleles. Similarly, the 35% with 13 or more triglyceride risk alleles were more likely to exceed NCEP intervention thresholds (OR 2.98, 95% CI 1.43-6.22, P = 0.004) compared with the 24% with 10 or less alleles. The number of individuals reporting an MI event was small (n = 67), but an event was more common in the 36% of respondents who had the highest combined risk allele score for all three lipids (OR 3.68, 95% CI 1.21-11.2, P = 0.021) compared with the lowest risk 22%. In a representative older population, the cumulative effects of proven LDL- and triglyceride-altering genetic variants increased the odds of crossing the lipid-level threshold for therapeutic intervention by approximately three-fold. C1 [Murray, Anna; Cluett, Christie; Frayling, Timothy; Melzer, David] Peninsula Med Sch, Exeter EX2 5DW, Devon, England. [Bandinelli, Stefania] Italian Natl Res Council Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. [Corsi, Anna Maria] Tuscany Reg Hlth Agcy, IOT, Florence, Italy. [Corsi, Anna Maria] Univ Florence, Dept Med & Surg Crit Care, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. [Singleton, Andrew] NIA, Neurogenet Lab, Baltimore, MD 21224 USA. RP Melzer, D (reprint author), Peninsula Med Sch, RD&E Wonford Site,Barrack Rd, Exeter EX2 5DW, Devon, England. EM david.melzer@pms.ac.uk RI Singleton, Andrew/C-3010-2009; OI Murray, Anna/0000-0002-2351-2522; Melzer, David/0000-0002-0170-3838 FU National Institutes of Health/NIA [R01 AG24233]; National Institute on Aging, NIH; Italian Ministry of Health [ICS 110.1\RS97.71]; US National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 9164 13, 263 MD 821336] FX This work is supported in part by National Institutes of Health/NIA grant R01 AG24233, and by the Intramural Research Program, National Institute on Aging, NIH. The InCHIANTI study was supported as a 'targeted project' (ICS 110.1\RS97.71) by the Italian Ministry of Health, by the US National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336 and Contracts 263 MD 9164 13 and 263 MD 821336). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding to pay the Open Access publication charges for this article was provided by the Peninsula College of Medicine and Dentistry. NR 21 TC 8 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD JUL PY 2009 VL 30 IS 14 BP 1711 EP 1719 DI 10.1093/eurheartj/ehp161 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 472DO UT WOS:000268109600013 PM 19435741 ER PT J AU Wright, ME Andreotti, G Lissowska, J Yeager, M Zatonski, W Chanock, SJ Chow, WH Hou, LF AF Wright, Margaret E. Andreotti, Gabriella Lissowska, Jolanta Yeager, Meredith Zatonski, Witold Chanock, Stephen J. Chow, Wong-Ho Hou, Lifang TI Genetic variation in sodium-dependent ascorbic acid transporters and risk of gastric cancer in Poland SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Ascorbic acid; Gastric cancer; Single nucleotide polymorphism; Susceptibility ID VITAMIN-C; HELICOBACTER-PYLORI; STOMACH-CANCER; JUICE; WARSAW; DIET AB Higher ascorbic acid consumption is associated with a reduced risk of gastric cancer in numerous epidemiologic studies. We investigated whether single nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 - genes that encode key ascorbic acid transport proteins - affect gastric cancer risk in 279 incident cases and 414 age- and gender-matched controls drawn from a population-based case-control study in Poland. Compared to subjects who were homozygous for the common G allele of the SLC23A2 SNP rs12479919, carriers of the AA genotype had a 41% lower risk of gastric cancer [odds ratio (OR) = 0.59, 95% confidence interval (Cl): 0.36-0.95; P trend = 0.06]. A haplotype that contained the common allele of the rs6139591, rs2681116 and rs14147458 SNPs in SLC23A2 was also significantly inversely associated with gastric malignancy. No other polymorphisms in either gene were related to risk, and there was no effect modification by ascorbic acid intake. These findings suggest that genetic variation in SLC23A2 impacts gastric cancer risk, although confirmation in other studies is required. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Wright, Margaret E.] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Andreotti, Gabriella; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Lissowska, Jolanta; Zatonski, Witold] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. [Lissowska, Jolanta; Zatonski, Witold] Inst Oncol, PL-02781 Warsaw, Poland. [Yeager, Meredith; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD 20892 USA. [Hou, Lifang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol, 840 S Wood St,CSN 130, Chicago, IL 60612 USA. EM mewright@uic.edu OI Lissowska, Jolanta/0000-0003-2695-5799 FU National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This study was supported, in part, by the intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 31 TC 24 Z9 25 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUL PY 2009 VL 45 IS 10 BP 1824 EP 1830 DI 10.1016/j.ejca.2009.01.027 PG 7 WC Oncology SC Oncology GA 472KG UT WOS:000268128900020 PM 19243932 ER PT J AU Bimpaki, EI Nesterova, M Stratakis, CA AF Bimpaki, Eirini I. Nesterova, Maria Stratakis, Constantine A. TI Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID MACRONODULAR ADRENAL-HYPERPLASIA; PHOSPHODIESTERASE 11A; REGULATORY SUBUNIT; CARNEY COMPLEX; PRKAR1A GENE; PROTEIN; KINASE; DISEASE; EXPRESSION; PDE11A AB Context: Bilateral adrenal hyperplasias (BAHs) May be caused by mutations of genes that code for that participate in cAMP signaling. Little is known about cAMP signaling in adrenal lesions associated with ACTH-independent Cushing syndrome (AICS) that do not harbor mutations is known genes. Objective: We assessed the cAMP-signaling pathway by enzymatic and molecular studies. Design: Samples from 27 patients (ages 5-60 years) were studied and compared with normal adrenocortical tissue (n=4) and aldosterone-producing adenomas (APA, n=5). All samples were sequenced for GNAS, PRKAR1A, PDE11A, and PDE8B sequencing defects, cAMP levels and binding, protein kinase A, and phosphodiesterase (PDE) activities were assayed. Immunohistochemistry was used for certain studies and the phosphorylation status of CREB was studied. Patients: A total of 36 samples from patients were used. Results: Cortisol-producing adenomas (CPAs) and other lesions that were GNAS, PRKAR1A, PDE11A, and PDE8B gene mutation-negative were compared with PRKAR1A mutation-positive lesions, normal tissue, and APAs: abnormalities of the cAMP-signaling pathway were found in both BAHs and CPAs. Interestingly, mutation-negative CPAs had significantly decreased PDE activity Conclusion: Lesions of the adrenal associated with AICS. independently of their GNAS, PRKAR1A. PDE11A, and PDE8B mutation status, have functional abnormalities of cAMP signaling. It is probable that epigenetic events or additional defects of genes involved ill this pathway are responsible for this phenomenon. C1 [Bimpaki, Eirini I.; Nesterova, Maria; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SEGEN, PDEGEN, NIH,CRC,East Labs, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SEGEN, PDEGEN, NIH,CRC,East Labs, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU United States National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [Z01-HD-000642-04] FX The present work Was Supported by the United States National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) intramural project Z01-HD-000642-04 to Dr C A Stratakis. Dr Bimpaki was. in part, supported by the Faculty of Medicine University of Crete, Heraklion, Crete. Greece, Postgraduate & Master Program oil the Molecular Basis of Human Disease. NR 22 TC 19 Z9 19 U1 0 U2 0 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 EI 1479-683X J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD JUL PY 2009 VL 161 IS 1 BP 153 EP 161 DI 10.1530/EJE-09-0027 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 534YY UT WOS:000272934700019 PM 19429701 ER PT J AU Touitou, I Rittore, C Philibert, L Yague, J Shinar, Y Aksentijevich, I AF Touitou, I. Rittore, C. Philibert, L. Yaguee, J. Shinar, Y. Aksentijevich, I. TI An international external quality assessment for molecular diagnosis of hereditary recurrent fevers: a 3-year scheme demonstrates the need for improvement SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE EQA/PT; molecular diagnosis; hereditary recurrent fevers ID FAMILIAL MEDITERRANEAN FEVER; NOMENCLATURE; PENETRANCE; MUTATIONS AB Hereditary recurrent fevers (HRF) are rare diseases caused by molecular defects in genes involved in the regulation of innate immunity. Sixty-seven international laboratories participated in an external quality assessment (EQA) scheme, which was developed to appraise the accuracy of genetic testing. Reports were evaluated for the 12 items recommended by the OECD (Organisation for Economic Co-Operation and Development) guidelines for molecular diagnostics. The best documented items were the name of the gene, the biologist, or the patient, whereas information on the test and screening limits, and clinical interpretation of the disease inheritance were scarcely provided. The mutation nomenclature was incomplete in about 70% of the cases. In the first 2 years of EQA, we identified almost 30% genotyping error rate, which decreased markedly in the last year. The combined performance on the basis of the correct identification of all genotypes by a given laboratory in all the 3 years was only 40%, showing a critical need for improvement. European Journal of Human Genetics (2009) 17, 890-896; doi:10.1038/ejhg.2008.253; published online 28 January 2009 C1 [Touitou, I.] CHU Montpellier, Unite Med Malad Autoinflammatoires, CNRS, Inst Gent Humaine,UPR1142, F-34275 Montpellier, France. [Yaguee, J.] IDIBAPS, Hosp Clin Barcelona, Serv Immunol, Unidad Enfermedades Autoinflamatorias & Amiloidos, Barcelona, Spain. [Shinar, Y.] Sheba Med Ctr, Ramat Gan, Israel. [Aksentijevich, I.] NIAMS, NIH, GGB, Bethesda, MD USA. RP Touitou, I (reprint author), CHU Montpellier, Unite Med Malad Autoinflammatoires, CNRS, Inst Gent Humaine,UPR1142, F-34275 Montpellier, France. EM isabelle.touitou@igh.cnrs.fr FU French Ministry of Health; Centre Hospitalo-Universitaire de Montpellier; European Community's FX This work was supported by the French Ministry of Health and the Centre Hospitalo-Universitaire de Montpellier and through Coordination Theme 1 (Health) of the European Community's FP7. We thank Dr J Alexander for editing the paper. We are grateful to Dr P Taschener and Dr J den Dunnen for their help in setting correct nomenclature for HRF mutations as recommended by the HGVS society at http://www.hgvs.org/mutnomen/. We thank all the colleagues who played the game and participated in one or more of these schemes: Dr Akar (TR), Dr Aksentijevich (US), Dr Altiok (TR), Dr Austrup (DE), Dr Bakker (NL), Dr Baldi (IT), Dr Belmahi (MA), Dr Bennetts (AU), Dr Bourmeyster (FR), Dr Burwinkel (DE), Dr Bybee (GB), Dr Ceccherini (IT), Dr Chaabouni (TN), Dr Costa (FR), Dr Costi (CY), Dr Cuisset (FR), Dr Dode (FR), Dr Dutly (CH), Dr Etlik (TR), Dr Franke (DE), Dr Gershoni-Baruch (IL), Dr Goulielmos (GR), Dr Haverkamp (DE), Dr Hilbert (BE), Dr Hujeirat (IL), Dr Ida (JP), Dr Konstantopoulos (GR), Dr Legendre (FR), Dr Lerer (IL), Dr Lohse (DE), Dr Mahfouz (LB), Dr Maiwald (DE), Dr Marschall (DE), Dr Martorana (IT), Dr Mcdermott (GB), Dr Medlej-Hashim (LB), Dr Moritz (AT), Dr Morris (CH), Dr Neri (IT), Dr Nevinny-StickelHinzpeter (DE), Dr Nishikomori (JP), Dr Oberkanins (AT), Dr Obici (IT), Dr Parma (BE), Dr Patrosso (IT), Dr Pingault (FR), Dr Pontillo (IT), Dr Potter (NZ), Dr Renner (AT), Dr Richard (US), Dr Rogge (DE), Dr Ronsin (FR), Dr Sarkisian (AM), Dr Schwartz (DK), Dr Shinar (IL), Dr Sinke (NL), Dr Skladny (DE), Dr Stjernberg-Salmela (FI), Dr Tchernitchko (FR), Dr Thonney (CH), Dr Tighe (GB), Dr Touitou (FR), Dr U " berlacker (DE), Dr Waterham (NL), Dr Wildhardt (DE), Dr Yagu " e Ribes (ES), Dr Yilmaz (TR), and Dr Zeitlhofer (AT). NR 13 TC 8 Z9 8 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD JUL PY 2009 VL 17 IS 7 BP 890 EP 896 DI 10.1038/ejhg.2008.253 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 459VZ UT WOS:000267141600008 PM 19172992 ER PT J AU Chefer, VI Denoroy, L Zapata, A Shippenberg, TS AF Chefer, V. I. Denoroy, L. Zapata, A. Shippenberg, T. S. TI Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanisms SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; GABA; glutamate; knockout mice; mu opioid receptor; ventral tegmental area ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; KNOCKOUT MICE; NEURONS; MORPHINE; RELEASE; RATS; MICRODIALYSIS; SYSTEMS; BRAIN AB Mu opioid receptor (MOR) regulation of somatodendritic dopamine neurotransmission in the ventral tegmental area (VTA) was investigated using conventional microdialysis in freely moving rats and mice. Reverse dialysis of the MOR agonist DAMGO (50 and 100 mu m) into the VTA of rats produced a concentration-dependent increase in dialysate dopamine concentrations. Basal dopamine overflow in the VTA was unaltered in mice lacking the MOR gene. However, basal gamma-aminobutyric acid (GABA) overflow in these animals was significantly increased, whereas glutamate overflow was decreased. Intra-VTA perfusion of DAMGO into wild-type (WT) mice increased dopamine overflow. GABA concentrations were decreased, whereas glutamate concentrations in the VTA were unaltered. Consistent with the loss of MOR, no effect of DAMGO was observed in MOR knockout (KO) mice. These data provide the first direct demonstration of tonically active MOR systems in the VTA that regulate basal glutamatergic and GABAergic neurotransmission in this region. We hypothesize that increased GABAergic neurotransmission following constitutive deletion of MOR is due to the elimination of a tonic inhibitory influence of MOR on GABAergic neurons in the VTA, whereas decreased glutamatergic neurotransmission in MOR KO mice is a consequence of intensified GABA tone on glutamatergic neurons and/or terminals. As a consequence, somatodendritic dopamine release is unaltered. Furthermore, MOR KO mice do not exhibit the positive correlation between basal dopamine levels and the glutamate/GABA ratio observed in WT mice. Together, our findings indicate a critical role of VTA MOR in maintaining an intricate balance between excitatory and inhibitory inputs to dopaminergic neurons. C1 [Chefer, V. I.; Zapata, A.; Shippenberg, T. S.] NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, NIH,IRP, Baltimore, MD 21224 USA. [Denoroy, L.] Univ Lyon, Lyon, France. RP Chefer, VI (reprint author), NIDA, Integrat Neurosci Sect, Behav Neurosci Branch, NIH,IRP, 333 Cassell Dr, Baltimore, MD 21224 USA. EM vchefer@intra.nida.nih.gov FU National Institutes of Health; National Institute on Drug Abuse FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse. The experiments comply with the current laws of the USA, and the authors have no financial interest in or financial conflict with the subject matter or materials discussed in the article. NR 44 TC 30 Z9 30 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 2009 VL 30 IS 2 BP 272 EP 278 DI 10.1111/j.1460-9568.2009.06827.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 472YL UT WOS:000268169200011 PM 19614973 ER PT J AU Bender, G Veldhuizen, MG Meltzer, JA Gitelman, DR Small, DM AF Bender, Genevieve Veldhuizen, Maria G. Meltzer, Jed A. Gitelman, Darren R. Small, Dana M. TI Neural correlates of evaluative compared with passive tasting SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; hedonic evaluation; implicit processing; insula; orbitofrontal cortex ID POSITRON-EMISSION-TOMOGRAPHY; PRIMATE ORBITOFRONTAL CORTEX; ANTERIOR TEMPORAL-LOBE; EVENT-RELATED FMRI; OLD-WORLD MONKEY; HUMAN BRAIN; CORTICAL ACTIVITY; AVERSIVE TASTE; NEURONAL REPRESENTATIONS; MACAQUE MONKEY AB We used functional magnetic resonance imaging to test the hypothesis that the nature of the neural response to taste varies as a function of the task the subject is asked to perform. Subjects received sweet, sour, salty and tasteless solutions passively and while evaluating stimulus presence, pleasantness and identity. Within the insula and overlying operculum the location of maximal response to taste vs. tasteless varied as a function of task; however, the primary taste cortex (anterior dorsal insula/frontal operculum - AIFO), as well as a more ventral region of anterior insula, responded to taste vs. tasteless irrespective of task. Although the response here did not depend upon task, preferential connectivity between AIFO and the amygdala (bilaterally) was observed when subjects tasted passively compared with when they performed a task. This suggests that information transfer between AIFO and the amygdala is maximal during implicit processing of taste. In contrast, a region of the left lateral orbitofrontal cortex (OFC) responded preferentially to taste and to tasteless when subjects evaluated pleasantness, and was preferentially connected to earlier gustatory relays (caudomedial OFC and AIFO) when a taste was present. This suggests that processing in the lateral OFC organizes the retrieval of gustatory information from earlier relays in the service of computing perceived pleasantness. These findings show that neural encoding of taste varies as a function of task beyond that of the initial cortical representation. C1 [Bender, Genevieve; Veldhuizen, Maria G.; Small, Dana M.] John B Pierce Fdn Lab, New Haven, CT 06519 USA. [Bender, Genevieve; Small, Dana M.] Yale Univ, Interdept Neurosci, New Haven, CT USA. [Veldhuizen, Maria G.; Small, Dana M.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Meltzer, Jed A.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Gitelman, Darren R.] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. [Gitelman, Darren R.] Northwestern Univ, Feinberg Sch Med, Dept Radiol, Chicago, IL 60611 USA. [Small, Dana M.] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. RP Small, DM (reprint author), John B Pierce Fdn Lab, 290 Congress Ave, New Haven, CT 06519 USA. EM dsmall@jbpierce.org RI Veldhuizen, Maria/A-3977-2012; OI Meltzer, Jed/0000-0002-4301-1901 FU National Institutes of Health [R01DC6706-02] FX The authors would like to acknowledge Erica Mak for help with pilot testing, design and data collection. Funding for this work was provided by National Institutes of Health (R01DC6706-02) awarded to D.M.S. NR 94 TC 44 Z9 44 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD JUL PY 2009 VL 30 IS 2 BP 327 EP 338 DI 10.1111/j.1460-9568.2009.06819.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 472YL UT WOS:000268169200017 PM 19614981 ER PT J AU Hansel, NN Gao, L Rafaels, NM Mathias, RA Neptune, ER Tankersley, C Grant, AV Connett, J Beaty, TH Wise, RA Barnes, KC AF Hansel, N. N. Gao, L. Rafaels, N. M. Mathias, R. A. Neptune, E. R. Tankersley, C. Grant, A. V. Connett, J. Beaty, T. H. Wise, R. A. Barnes, K. C. TI Leptin receptor polymorphisms and lung function decline in COPD SO EUROPEAN RESPIRATORY JOURNAL LA English DT Article DE Chronic obstructive pulmonary disease; leptin receptor; lung function decline; polymorphisms ID OBSTRUCTIVE-PULMONARY-DISEASE; C-REACTIVE PROTEIN; SMOKING-CESSATION; GLOBAL BURDEN; SMOKERS; HEALTH; MICE; VARIABILITY; INTERVENTION; INFLAMMATION AB Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD) suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina (TM) GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNIPS. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD. C1 [Barnes, K. C.] Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Dept Med, Baltimore, MD 21224 USA. [Tankersley, C.; Beaty, T. H.; Barnes, K. C.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21224 USA. [Mathias, R. A.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Connett, J.] Univ Minnesota, Div Biostat, Sch Publ Hlth, St Paul, MN 55108 USA. RP Barnes, KC (reprint author), Johns Hopkins Univ, Sch Med, Johns Hopkins Asthma & Allergy Ctr, Dept Med, 5501 Hopkins Bayview Circle,Room 3A62, Baltimore, MD 21224 USA. EM kbarnes@jhmi.edu OI Wise, Robert/0000-0002-8353-2349 FU National Heart Lung and Blood institute [HL076322, HL066583, HL010342]; National Institute on Ageing [AG21057]; National Human Genome Research Institute; National Institutes of Health; US Federal Government [N01-HV-48195] FX This study Was Supported by the National Heart Lung and Blood institute (grants HL076322, HL066583 and HI-010342; Bethesda, MD, USA) and the National Institute on Ageing (AG21057; Bethesda). This study was also supported in part by the Intramural Research Program of the National Human Genome Research Institute and National Institutes of Health (Bethesda, MID, USA). Genotyping services were provided by the Johns Hopkins University (Baltimore, MID, USA) under US Federal Government contract number N01-HV-48195 from the NHLBI. K.C. Barnes was supported in part by the Mary Beryl Patch Turnbull Scholar Program (Baltimore, MD, USA). NR 37 TC 23 Z9 23 U1 1 U2 3 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 J9 EUR RESPIR J JI Eur. Resp. J. PD JUL PY 2009 VL 34 IS 1 BP 103 EP 110 DI 10.1183/09031936.00120408 PG 8 WC Respiratory System SC Respiratory System GA 467XP UT WOS:000267777000015 PM 19196818 ER PT J AU Tandle, AT Calvani, M Uranchimeg, B Zahavi, D Melillo, G Libutti, SK AF Tandle, Anita T. Calvani, Maura Uranchimeg, Badarch Zahavi, David Melillo, Giovanni Libutti, Steven K. TI Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1alpha through interaction with PSMA7, a component of the proteasome SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Angiogenesis; EMAP-II; HIF-1 alpha; Proteasome; Integrin receptor ID NECROSIS-FACTOR-ALPHA; FACTOR 1-ALPHA; AUTOCRINE LOOP; EMAP-II; ANGIOGENESIS; FIBRONECTIN; HIF-1-ALPHA; EXPRESSION; INTEGRIN; TUMORIGENESIS AB The majority of human tumors are angiogenesis dependent. Understanding the specific mechanisms that contribute to angiogenesis may offer the best approach to develop therapies to inhibit angiogenesis in cancer. Endothelial monocyte activating polypeptide-II (EMAP-II) is an anti-angiogenic cytokine with potent effects on endothelial cells (ECs). It inhibits EC proliferation and cord formation, and it suppresses primary and metastatic tumor growth in-vivo. However, very little is known about the molecular mechanisms behind the anti-angiogenic activity of EMAP-II. In the present study, we explored the molecular mechanism behind the anti-angiogenic activity exerted by this protein on ECs. Our results demonstrate that EMAP-II binds to the cell surface alpha 5 beta 1 integrin receptor. The cell surface binding of EMAP-II results in its internalization into the cytoplasmic compartment where it interacts with its cytoplasmic partner PSMA7, a component of the proteasome degradation pathway. This interaction increases hypoxia-inducible factor 1-alpha (HIF-1 alpha) degradation under hypoxic conditions. The degradation results in the inhibition of HIF-1 alpha mediated transcriptional activity as well as HIF-1 alpha mediated angiogenic sprouting of ECs. HIF-1 alpha plays a critical role in angiogenesis by activating a variety of angiogenic growth factors. Our results suggest that one of the major anti-angiogenic functions of EMAP-II is exerted through its inhibition of the HIF-1 alpha activities. Published by Elsevier Inc. C1 [Libutti, Steven K.] Albert Einstein Coll Med, Dept Surg, Montefiore Einstein Ctr Canc Care, Bronx, NY 10467 USA. [Calvani, Maura; Uranchimeg, Badarch; Melillo, Giovanni] NCI, SAIC Frederick Inc, DTP Tumor Hypoxia Lab, Frederick, MD 21702 USA. [Tandle, Anita T.; Zahavi, David] NCI, Ctr Canc Res, Tumor Angiogenesis Sect, Bethesda, MD 20892 USA. RP Libutti, SK (reprint author), Albert Einstein Coll Med, Dept Surg, Montefiore Einstein Ctr Canc Care, Greene Med Arts Pavil,4th Floor 3400,Bainbridge A, Bronx, NY 10467 USA. EM slibutti@montefiore.org FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 12 Z9 15 U1 0 U2 2 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JUL 1 PY 2009 VL 315 IS 11 BP 1850 EP 1859 DI 10.1016/j.yexcr.2009.03.021 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 454BG UT WOS:000266656000007 PM 19362550 ER PT J AU Madan, RA Arlen, PM Mohebtash, M Hodge, JW Gulley, JL AF Madan, Ravi A. Arlen, Philip M. Mohebtash, Mahsa Hodge, James W. Gulley, James L. TI Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer SO EXPERT OPINION ON INVESTIGATIONAL DRUGS LA English DT Editorial Material DE immunotherapy; prostate cancer; therapeutic cancer vaccine ID REGULATORY T-CELLS; ANDROGEN-DEPRIVATION THERAPY; ANTIGEN-PRESENTING CELLS; IMMUNOLOGICAL SELF-TOLERANCE; COLONY-STIMULATING FACTOR; NON-HODGKINS-LYMPHOMA; COSTIMULATORY MOLECULES; COMBINATION THERAPY; IMMUNE-RESPONSES; TUMOR-CELLS AB Prostvac is a prostate cancer vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for prostate-specific antigen (PSA) and multiple T-cell co-stimulatory molecules (TRICOM). The PSA-TRICOM vaccines infect antigen-presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor cell destruction. Preliminary clinical trials have indicated negligible toxicity, and Phase 11 trials have suggested a survival benefit after treatment with Prostvac, especially in patients with indolent disease characteristics. Preclinical and clinical data indicate that radiation, hormonal therapy, and chemotherapy may be combined with Prostvac to enhance the vaccine's efficacy. Additional strategies are in development to further enhance the clinical benefits of Prostvac, and a Phase III trial is being planned in metastatic castration-resistant prostate cancer. C1 [Gulley, James L.] NCI, NIH, Ctr Canc Res, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, NIH, Ctr Canc Res, Tumor Immunol & Biol Lab, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Hodge, James/D-5518-2015; Gulley, James/K-4139-2016 OI Hodge, James/0000-0001-5282-3154; Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-03] NR 110 TC 102 Z9 102 U1 0 U2 9 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1354-3784 EI 1744-7658 J9 EXPERT OPIN INV DRUG JI Expert Opin. Investig. Drugs PD JUL PY 2009 VL 18 IS 7 BP 1001 EP 1011 DI 10.1517/13543780902997928 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 467GL UT WOS:000267726200010 PM 19548854 ER PT J AU Zoon, CK Starker, EQ Wilson, AM Emmert-Buck, MR Libutti, SK Tangrea, MA AF Zoon, Christine K. Starker, Elizabeth Q. Wilson, Arianne M. Emmert-Buck, Michael R. Libutti, Steven K. Tangrea, Michael A. TI Current molecular diagnostics of breast cancer and the potential incorporation of microRNA SO EXPERT REVIEW OF MOLECULAR DIAGNOSTICS LA English DT Review DE breast cancer; microarray; microRNA; molecular diagnostics; predictive value; prognostic value ID ESTROGEN-RECEPTOR-ALPHA; CIRCULATING TUMOR-CELLS; GENE-EXPRESSION; CAENORHABDITIS-ELEGANS; PROGESTERONE-RECEPTOR; TAMOXIFEN RESISTANCE; PROGNOSTIC-FACTOR; RNA-INTERFERENCE; AMERICAN-SOCIETY; MESSENGER-RNA AB Although comprehensive molecular diagnostics and personalized medicine have sparked excitement among researchers and clinicians, they have yet to be fully incorporated into today's standard of care. This is despite the discovery of disease-related oncogenes, tumor-suppressor genes and protein biomarkers, as well as other biological anomalies related to cancer. Each year, new tests are released that could potentially supplement or surpass standard methods of diagnosis, including serum, protein and gene expression analyses. All of these novel approaches have shown great promise, but initial enthusiasm has diminished as difficulties in reproducibility, expense, standardization and proof of significance beyond current protocols have emerged. This review will focus on current and novel molecular diagnostic tools applied to breast cancer with special attention to the exciting new field of microRNA analysis. C1 [Emmert-Buck, Michael R.; Tangrea, Michael A.] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zoon, Christine K.; Starker, Elizabeth Q.; Wilson, Arianne M.] NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Libutti, Steven K.] Albert Einstein Coll Med, Montefiore Med Ctr, Bronx, NY 10467 USA. [Emmert-Buck, Michael R.; Tangrea, Michael A.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Tangrea, MA (reprint author), NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. EM tangream@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 112 TC 22 Z9 25 U1 0 U2 2 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7159 J9 EXPERT REV MOL DIAGN JI Expert Rev. Mol. Diagn. PD JUL PY 2009 VL 9 IS 5 BP 455 EP 467 DI 10.1586/ERM.09.25 PG 13 WC Pathology SC Pathology GA 475ND UT WOS:000268365700006 PM 19580430 ER PT J AU Ehrenfeld, E Modlin, J Chumakov, K AF Ehrenfeld, Ellie Modlin, John Chumakov, Konstantin TI Future of polio vaccines SO EXPERT REVIEW OF VACCINES LA English DT Review DE eradication; global vaccination program; immunization; inactivated polio vaccine; infectious disease control; oral polio vaccine ID PARALYTIC POLIOMYELITIS; ENHANCED-POTENCY; NERVOUS-SYSTEM; ERADICATION; ELIMINATION; INFECTION; MICE; EPIDEMIOLOGY; IMMUNIZATION; VACCINATION AB Over the past half-century, global use of highly effective vaccines against poliomyelitis brought this disease to the brink of elimination. Mounting evidence supports the argument that a high level of population immunity must be maintained after wild poliovirus circulation is stopped to preserve a polio-free status worldwide. Shifting factors in the risk-benefit-cost equation favor the creation of new poliovirus vaccines for use in the foreseeable future. Genetically stable attenuated virus strains could be developed for an improved oral poliovirus vaccine, but proving their safety and efficacy would be impractical owing to the enormous size of the clinical trials required. Novel versions of inactivated poliovirus vaccine that could be used globally should be developed. An improved inactivated poliovirus vaccine must be efficacious, inexpensive, safe to manufacture and easy to administer. Combination products containing inactivated poliovirus vaccine and other protective antigens should become part of routine childhood immunizations around the world. C1 [Ehrenfeld, Ellie] NIAID, NIH, Bethesda, MD 20892 USA. [Modlin, John] Dartmouth Hitchcock Med Ctr, Dartmouth Med Sch, Lebanon, NH 03766 USA. [Chumakov, Konstantin] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Ehrenfeld, E (reprint author), NIAID, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM eehrenfeld@niaid.nih.gov; john.modlin@dartmouth.edu; konstantin.chumakov@fda.hhs.gov FU NIAID; NIH; FDA; DHHS FX This work was supported in part by the intramural research programs of the NIAID, NIH and the FDA, DHHS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 45 TC 28 Z9 28 U1 2 U2 13 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD JUL PY 2009 VL 8 IS 7 BP 899 EP 905 DI 10.1586/ERV.09.49 PG 7 WC Immunology SC Immunology GA 471KM UT WOS:000268056500013 PM 19545205 ER PT J AU Klar, A AF Klar, A. TI Asymmetric cell division through epigenetic differentiation of sister chromatids and their selective segregation in mitosis SO FEBS JOURNAL LA English DT Meeting Abstract CT 34th Congress of the Federation-of-European-Biochemical-Societies CY JUL 04-09, 2009 CL Prague, CZECH REPUBLIC SP Federat European Biochem Soc C1 [Klar, A.] NCI, GRCBL, Frederick, MD 21701 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUL PY 2009 VL 276 BP 5 EP 5 PG 1 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 458ZS UT WOS:000267069900012 ER PT J AU Sacha, P Barinka, C Lubkowski, J Hlouchova, K Tykvart, J Starkova, J Mlcochova, P Klusak, V Rulisek, V Konvalinka, J AF Sacha, P. Barinka, C. Lubkowski, J. Hlouchova, K. Tykvart, J. Starkova, J. Mlcochova, P. Klusak, V. Rulisek, V. Konvalinka, J. TI Beyond proteolysis: glutamate carboxypeptidase II as a neuropeptidase and prostate specific membrane antigen SO FEBS JOURNAL LA English DT Meeting Abstract CT 34th Congress of the Federation-of-European-Biochemical-Societies CY JUL 04-09, 2009 CL Prague, CZECH REPUBLIC SP Federat European Biochem Soc C1 [Sacha, P.; Hlouchova, K.; Tykvart, J.; Starkova, J.; Mlcochova, P.; Klusak, V.; Rulisek, V.; Konvalinka, J.] Acad Sci Czech Republic, Inst Organ Chem & Biochem, Prague, Czech Republic. [Barinka, C.; Lubkowski, J.] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RI Konvalinka, Jan/G-7518-2014; Sacha, Pavel/G-9729-2014; Tykvart, Jan/G-6770-2014 OI Sacha, Pavel/0000-0001-6198-9826; Tykvart, Jan/0000-0002-6938-1513 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1742-464X J9 FEBS J JI FEBS J. PD JUL PY 2009 VL 276 BP 17 EP 18 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 458ZS UT WOS:000267069900046 ER PT J AU Concheiro, M Shakleya, DM Huestis, MA AF Concheiro, Marta Shakleya, Diaa M. Huestis, Marilyn A. TI Simultaneous quantification of buprenorphine, norbuprenorphine, buprenorphine-glucuronide and norbuprenorphine-glucuronide in human umbilical cord by liquid chromatography tandem mass spectrometry SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE Umbilical cord; Buprenorphine; LCMS; Ion trap ID HUMAN PLASMA; HUMAN MECONIUM; HUMAN URINE; METABOLITE NORBUPRENORPHINE; DEALKYLATED METABOLITE; PREGNANT-WOMEN; AMNIOTIC-FLUID; FETAL EXPOSURE; ILLICIT DRUGS; HAIR SAMPLES AB A LCMS method was developed and validated for the simultaneous determination of buprenorphine (BUP), norbuprenorphine (NBUP), buprenorphine-glucuronide (BUP-Gluc) and norbuprenorphine-glucuronide (NBUP-Gluc) in human umbilical cord. Quantification was achieved by selected ion monitoring of precursor ions m/z 468.4 for BUP; 414.3 for NBUP; 644.4 for BUP-Gluc and 590 for NBUP-Gluc. BUP and NBUP were identified by MS', with m/z 396, 414 and 426 for BUP, and m/z 340, 364 and 382 for NBUP. Glucuronide conjugates were identified by MS(3) with m/z 396 and 414 for BUP-Gluc and m/z 340 and 382 for NBUP-Gluc. The assay was linear 1-50 ng/g. Intra-day, inter-day and total assay imprecision (%RSD) were <14.5%, and analytical recovery ranged from 94.1% to 112.3% for all analytes. Extraction efficiencies were >66.3%, and process efficiency >73.4%. Matrix effect ranged, in absolute value, from 3.7% to 7.4% (CV < 2 1.8%, n = 8). The method was selective with no endogenous or exogenous interferences from 41 compounds evaluated. Sensitivity was high with limits of detection of 0.8 ng/g. In order to prove method applicability, an authentic umbilical cord obtained from an opioid-dependent pregnant woman receiving BUP pharmacotherapy was analyzed. Interestingly, BUP was not detected but concentrations of the other metabolites were NBUP-Gluc 13.4 ng/g, BUP-Gluc 3.5 ng/g and NBUP 1.2 ng/g. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Huestis, Marilyn A.] NIDA, Biomed Res Ctr, Chem & Drug Metab Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Biomed Res Ctr, Chem & Drug Metab Sect, Intramural Res Program,NIH, 251 Bayview Blvd,Suite 200,Room 05A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Ministerio de Educacion y Ciencia of Spain [EX-2007-1194] FX This research was supported by the National Institutes of Health, Intramural Research Program, National Institute on Drug Abuse, and funding for Marta Concheiro, Ph.D. from the Ministerio de Educacion y Ciencia of Spain (Grant number EX-2007-1194). Authors would like to thank Dr. Fred Askin, Gerrun March, and Leigh Ruane from Johns Hopkins Bayview Medical Center (Baltimore, MD) for their help in obtaining umbilical cord samples. NR 49 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD JUL 1 PY 2009 VL 188 IS 1-3 BP 144 EP 151 DI 10.1016/j.forsciint.2009.04.005 PG 8 WC Medicine, Legal SC Legal Medicine GA 461BK UT WOS:000267239000023 PM 19406593 ER PT J AU Levine, M Espey, MG Chen, Q AF Levine, Mark Espey, Michael Graham Chen, Qi TI Losing and finding a way at C: New promise for pharmacologic ascorbate in cancer treatment SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Editorial Material ID RECOMMENDED DIETARY ALLOWANCE; TERMINAL HUMAN CANCER; DOSE VITAMIN-C; HYDROGEN-PEROXIDE; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT; OXIDATIVE STRESS; INSITU KINETICS; SURVIVAL TIMES; ACID THERAPY C1 [Levine, Mark; Espey, Michael Graham] NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Chen, Qi] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM MarkL@mail.nih.gov RI Chen, Qi/D-8278-2015 OI Chen, Qi/0000-0002-7173-8411 FU Intramural NIH HHS [Z01 DK053212-02] NR 31 TC 25 Z9 25 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUL 1 PY 2009 VL 47 IS 1 BP 27 EP 29 DI 10.1016/j.freeradbiomed.2009.04.001 PG 3 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 456EX UT WOS:000266825200003 PM 19361554 ER PT J AU Marrero, JA Feng, ZD Wang, YH Nguyen, MH Befeler, AS Roberts, LR Reddy, KR Harnois, D Llovet, JM Normolle, D Dalhgren, J Chia, D Lok, AS Wagner, PD Srivastava, S Schwartz, M AF Marrero, Jorge A. Feng, Ziding Wang, Yinghui Nguyen, Mindie H. Befeler, Alex S. Roberts, Lewis R. Reddy, K. Rajender Harnois, Denise Llovet, Josep M. Normolle, Daniel Dalhgren, Jackie Chia, David Lok, Anna S. Wagner, Paul D. Srivastava, Sudhir Schwartz, Myron TI alpha-Fetoprotein, Des-gamma Carboxyprothrombin, and Lectin-Bound alpha-Fetoprotein in Early Hepatocellular Carcinoma SO GASTROENTEROLOGY LA English DT Article ID CHRONIC LIVER-DISEASE; CIRRHOTIC-PATIENTS; CARBOXY PROTHROMBIN; AMERICAN PATIENTS; EARLY-DIAGNOSIS; HEPATITIS-C; FOLLOW-UP; MANAGEMENT; UTILITY AB BACKGROUND & AIMS: alpha-Fetoprotein (AFP) is widely used as a surveillance test for hepatoceitular carcinoma (HCC) among patients with cirrhosis. Des-gamma carboxy-prothrombin (DCP) and lectin-bound AFP (AFP-L3%) are potential surveillance tests for HCC. The alms of this study were to determine performance of DCP and AFP-L3% for the diagnosis of early HCC; whether they complement AFP; and what factors affect DCP, AFP-L3%, or AFP levels. METHODS: We conducted a large phase 2 biomarker case-control study in 7 academic medical centers in the United States. Controls were patients with compensated cirrhosis and cases were patients with HCC. AFP, DCP, and AFP-L3% levels were measured blinded to clinical data in a central reference laboratory. RESULTS: A total of 836 patients were enrolled: 417 (50%) were cirrhosis controls and 419 (50%) were HCC cases, of which 208 (49.6%) had early stage HCC (n = 77 very early, n = 131 early). AFP had the best area under the receiver operating characteristic curve (0.80, 95% confidence interval [CI]: 0.77-0.84), followed by DCP (0.72, 95% CI: 0.68-0.77) and AFP-L3% (0.66, 95% CI: 0.62-0.70) for early stage HCC. The optimal AFP Cutoff value was 10.9 ng/mL leading to a sensitivity of 66%. When only those with very early HCC were evaluated, the area under the receiver operating characteristic curve for AFP was 0.78 (95% CI: 0.72-0.85) leading to a sensitivity of 65% at the same cutoff. CONCLUSIONS: AFP was more sensitive than DCP and AFP-L3% for the diagnosis of early and very early stage HCC at a new cutoff of 10.9 ng/mL. C1 [Marrero, Jorge A.; Normolle, Daniel; Lok, Anna S.] Univ Michigan, Ann Arbor, MI 48109 USA. [Feng, Ziding; Wang, Yinghui; Dalhgren, Jackie] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Nguyen, Mindie H.] Stanford Univ, Palo Alto, CA 94304 USA. [Befeler, Alex S.] St Louis Univ, St Louis, MO 63103 USA. [Roberts, Lewis R.] Mayo Clin, Rochester, MN USA. [Reddy, K. Rajender] Univ Penn, Philadelphia, PA 19104 USA. [Harnois, Denise] Mayo Clin, Jacksonville, FL 32224 USA. [Llovet, Josep M.; Schwartz, Myron] Mt Sinai Univ, Mt Sinai Liver Canc Program, New York, NY USA. [Llovet, Josep M.] Hosp Clin Barcelona, Liver Unit, CIBERehd,IDIBAPS, BCLC Grp,Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain. [Chia, David; Srivastava, Sudhir] Univ Calif Los Angeles, Los Angeles, CA USA. [Wagner, Paul D.] NCI, Bethesda, MD 20892 USA. RP Marrero, JA (reprint author), Univ Michigan, 3912 Taubman Ctr,SPC 5362, Ann Arbor, MI 48109 USA. EM jmarrero@umich.edu RI Lok, Anna /B-8292-2009; Llovet, Josep M /D-4340-2014; OI Llovet, Josep M /0000-0003-0547-2667; Normolle, Daniel/0000-0001-8675-5014; Yang, Shuman/0000-0002-9638-0890 FU NCI NIH HHS [CA-084986, U01 CA084986]; NIDDK NIH HHS [DK064909, K23 DK064909, K23 DK064909-05, R03 DK077707-02] NR 25 TC 193 Z9 210 U1 7 U2 24 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2009 VL 137 IS 1 BP 110 EP 118 DI 10.1053/j.gastro.2009.04.005 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 463DU UT WOS:000267410100021 PM 19362088 ER PT J AU Park, TK Wu, Z Kjellstrom, S Zeng, Y Bush, RA Sieving, PA Colosi, P AF Park, T. K. Wu, Z. Kjellstrom, S. Zeng, Y. Bush, R. A. Sieving, P. A. Colosi, P. TI Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse SO GENE THERAPY LA English DT Article DE retinoschisis; AAV vector; promoter; intravitreal injection ID X-LINKED RETINOSCHISIS; LEBERS CONGENITAL AMAUROSIS; HUMAN GENE-THERAPY; JUVENILE RETINOSCHISIS; NATURAL-HISTORY; MOUSE MODEL; B-WAVE; PROTEIN; KNOCKOUT; RS1 AB X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection. Retinoschisin expression was restricted to the neuroretina using a new vector that uses a 3.5-kb human retinoschisin promoter and an AAV type 8 capsid. Intravitreal administration to Rs1-KO mice resulted in robust retinoschisin expression with a retinal distribution similar to that observed in wild-type retina, including the expression by the photoreceptors lying deep in the retina. No off-target expression was observed. Rs1-KO mice treated with this vector showed a decrease in the schisis cavities and had improved retinal signaling evaluated by recording the electroretinogram 11-15 weeks after the application. Gene Therapy (2009) 16, 916-926; doi:10.1038/gt.2009.61; published online 21 May 2009 C1 [Wu, Z.; Colosi, P.] NEI, Ocular Gene Therapy Lab, NIH, Rockville, MD 20852 USA. [Park, T. K.; Kjellstrom, S.; Zeng, Y.; Bush, R. A.; Sieving, P. A.] NIDCD, STRRMD, NIH, Bethesda, MD USA. [Sieving, P. A.] NEI, NIH, Bethesda, MD 20892 USA. RP Colosi, P (reprint author), NEI, Ocular Gene Therapy Lab, NIH, 5626 Fishers Lane,Room 1S-16, Rockville, MD 20852 USA. EM colosip@nei.nih.gov FU Intramural NIH HHS [Z01 DC000065-06] NR 36 TC 76 Z9 77 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD JUL PY 2009 VL 16 IS 7 BP 916 EP 926 DI 10.1038/gt.2009.61 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 468HB UT WOS:000267806600010 PM 19458650 ER PT J AU Liu, QR Pan, CH Hishimoto, A Li, CY Xi, ZX Llorente-Berzal, A Viveros, MP Ishiguro, H Arinami, T Onaivi, ES Uhl, GR AF Liu, Q. -R. Pan, C. -H. Hishimoto, A. Li, C. -Y. Xi, Z. -X. Llorente-Berzal, A. Viveros, M. -P. Ishiguro, H. Arinami, T. Onaivi, E. S. Uhl, G. R. TI Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Brain; CB2 cannabinoid receptors; CB2A; CB2B; spleen; testis ID MOLECULAR CHARACTERIZATION; ENDOCANNABINOID SYSTEM; HUMAN GENOME; RAT-BRAIN; MICE; CLONING; PAIN; LOCALIZATION; ANANDAMIDE; SEQUENCE AB Cannabinoids, endocannabinoids and marijuana activate two well-characterized cannabinoid receptors (CB-Rs), CB1-Rs and CB2-Rs. The expression of CB1-Rs in the brain and periphery has been well studied, but neuronal CB2-Rs have received much less attention than CB1-Rs. Many studies have now identified and characterized functional glial and neuronal CB2-Rs in the central nervous system. However, many features of CB2-R gene structure, regulation and variation remain poorly characterized in comparison with the CB1-R. In this study, we report on the discovery of a novel human CB2 gene promoter transcribing testis (CB2A) isoform with starting exon located ca 45 kb upstream from the previously identified promoter transcribing the spleen isoform (CB2B). The 5' exons of both CB2 isoforms are untranslated 5'UTRs and alternatively spliced to the major protein coding exon of the CB2 gene. CB2A is expressed higher in testis and brain than CB2B that is expressed higher in other peripheral tissues than CB2A. Species comparison found that the CB2 gene of human, rat and mouse genomes deviated in their gene structures and isoform expression patterns. mCB2A expression was increased significantly in the cerebellum of mice treated with the CB-R mixed agonist, WIN55212-2. These results provide much improved information about CB2 gene structure and its human and rodent variants that should be considered in developing CB2-R-based therapeutic agents. C1 [Onaivi, E. S.] William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. [Liu, Q. -R.; Pan, C. -H.; Hishimoto, A.; Li, C. -Y.; Ishiguro, H.; Onaivi, E. S.; Uhl, G. R.] NIDA, Mol Neurobiol Branch, IRP, NIH, Baltimore, MD USA. [Xi, Z. -X.] NIDA, Chem Biol Res Branch, IRP, NIH, Baltimore, MD USA. [Llorente-Berzal, A.; Viveros, M. -P.] Univ Complutense Madrid, Madrid, Spain. [Ishiguro, H.; Arinami, T.] Univ Tsukuba, Tsukuba, Ibaraki, Japan. [Pan, C. -H.] Taipei City Hosp, Dept Psychiat, Taipei, Taiwan. [Pan, C. -H.] Taipei City Psychiat Ctr, Taipei, Taiwan. RP Onaivi, ES (reprint author), William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. EM OnaiviE@wpunj.edu RI Liu, Qing-Rong/A-3059-2012; Viveros, Maria-Paz/S-6855-2016 OI Liu, Qing-Rong/0000-0001-8477-6452; FU NIDA/IRP; William Paterson University Center for Research, Biology department; Dean's ( Dr De Young) student worker fund,; Red de Trastornos Adictivos [RD06/0001/1013] FX This work was supported in part by NIDA/IRP and ESO acknowledges the technical assistance and financial support from William Paterson University Center for Research, Biology department, the Dean's ( Dr De Young) student worker fund, and the Provost office for assigned release time. The CB2 knockout and their wild- type control mice were developed by Buckley et al. ( 2000), and obtained from NIAAA through Dr Kunos. Part of human brain tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, Maryland. The authors would also like to acknowledge the technical assistance of Dr Xia Li from Chemical Biology Research Branch and English editing by Dr Mary Pfeiffer, Editor and Writer NIDA, IRP. ALB and MPV acknowledges Red de Trastornos Adictivos (RD06/0001/1013). We thank Dr John McPartland for his excellent and in-depth review of the manuscript and for his suggestions. NR 44 TC 63 Z9 68 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2009 VL 8 IS 5 BP 519 EP 530 DI 10.1111/j.1601-183X.2009.00498.x PG 12 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 470IG UT WOS:000267967800005 PM 19496827 ER PT J AU Macbeth, AH Lee, HJ Edds, J Young, WS AF Macbeth, A. H. Lee, H. -J. Edds, J. Young, W. S., III TI Oxytocin and the oxytocin receptor underlie intrastrain, but not interstrain, social recognition SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Affiliation; knockout mice; conditional knockout mice; cre recombinase; forebrain; memory ID KNOCKOUT MOUSE; MICE; ODORS; RATS; DISCRIMINATION; ALPHA; PARTURITION; RESPONSES; DEFICITS; BRAIN AB We studied three lines of oxytocin (Oxt) and oxytocin receptor (Oxtr) knockout (KO) male mice [Oxt(-/-), total Oxtr(-/-) and partial forebrain Oxtr (Oxtr(FB/FB))] with established deficits in social recognition to further refine our understanding of their deficits with regard to stimulus female's strain. We used a modified social discrimination paradigm in which subjects are singly housed only for the duration of the test. Additionally, stimulus females are singly housed throughout testing and are presented within corrals for rapid comparison of investigation by subject males. Wild-type (WT) males from all three lines discriminated between familiar and novel females of three different strains (C57BL/6, BALB/c and Swiss-Webster). No KO males discriminated between familiar and novel BALB/c or C57BL/6 females. Male Oxt(-/-) and Oxtr(-/-) mice, but not Oxtr(FB/FB) mice, discriminated between familiar and novel Swiss-Webster females. As this might indicate a global deficit in individual recognition for Oxtr(FB/FB) males, we examined their ability to discriminate between females from different strains and compared performance with Oxtr(-/-) males. WT and KO males from both lines were able to distinguish between familiar and novel females from different strains, indicating the social recognition deficit is not universal. Instead, we hypothesize that the Oxtr is involved in 'fine' intrastrain recognition, but is less important in 'broad' interstrain recognition. We also present the novel finding of decreased investigation across tests, which is likely an artifact of repeated testing and not because of stimulus female's strain or age of subject males. C1 [Macbeth, A. H.; Lee, H. -J.; Edds, J.; Young, W. S., III] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Young, WS (reprint author), NIMH, Sect Neural Gene Express, NIH, DHHS, 9000 Rockville Pike,Bldg 49,Room 5A60, Bethesda, MD 20892 USA. EM wsy@mail.nih.gov RI Young, W Scott/A-9333-2009; OI Young, W Scott/0000-0001-6614-5112; , Heon-Jin/0000-0002-1911-5014 FU NIMH [Z01-MH-002498-20]; Division of Intramural Research; National Institute of Mental Health; National Institutes of Health; DHHS FX We thank the NEI/NIMH Animal Facilities staff in Building 49 for their exceptional animal care and daily assistance, Particularly Ana Carderas and Darwin Romero. Drs Scott Wersinger, Heather Caldwell and Jerome Pagani provided excellent comments on early versions of this manuscript. We also thank Jim Heath and Emily Shepard for their technical assistance. This research was supported by NIMH (Z01-MH-002498-20) from the Division of Intramural Research, National Institute of Mental Health, National Institutes of Health, DHHS. NR 31 TC 44 Z9 44 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD JUL PY 2009 VL 8 IS 5 BP 558 EP 567 DI 10.1111/j.1601-183X.2009.00506.x PG 10 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 470IG UT WOS:000267967800009 PM 19531157 ER PT J AU Li, QZ Wacholder, S Hunter, DJ Hoover, RN Chanock, S Thomas, G Yu, K AF Li, Qizhai Wacholder, Sholom Hunter, David J. Hoover, Robert N. Chanock, Stephen Thomas, Gilles Yu, Kai TI Genetic Background Comparison Using Distance-Based Regression, with Applications in Population Stratification Evaluation and Adjustment SO GENETIC EPIDEMIOLOGY LA English DT Article DE population stratification; pseudo F statistic; distance-based regression ID GENOME-WIDE ASSOCIATION; PROSTATE-CANCER; RISK AB Population stratification (PS) can lead to an inflated rate of false-positive findings in genome-wide association studies (GWAS). The commonly used approach of adjustment for a fixed number of principal components (PCs) could have a deleterious impact on power when selected PCs are equally distributed in cases and controls, or the adjustment of certain covariates, such as self-identified ethnicity or recruitment center, already included in the association analyses, correctly maps to major axes of genetic heterogeneity. We propose a computationally efficient procedure, PC-Finder, to identify a minimal set of PCs while permitting an effective correction for PS. A general pseudo F statistic, derived from a non-parametric multivariate regression model, can be used to assess whether PS exists or has been adequately corrected by a set of selected PCs. Empirical data from two GWAS conducted as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project demonstrate the application of the procedure. Furthermore, simulation studies show the power advantage of the proposed procedure in GWAS over currently used PS correction strategies, particularly when the PCs with substantial genetic variation are distributed similarly in cases and controls and therefore do not induce PS. Genet. Epidemiol. 33:432-441, 2009. Published 2009 Wiley-Liss, Inc. C1 [Li, Qizhai; Wacholder, Sholom; Hunter, David J.; Hoover, Robert N.; Chanock, Stephen; Thomas, Gilles; Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing, Peoples R China. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. RP Yu, K (reprint author), 6120 Execut Blvd,EPS 8040, Bethesda, MD 20892 USA. EM yuka@mail.nih.gov FU Intramural NIH HHS [Z01 CP010181-05] NR 19 TC 9 Z9 10 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD JUL PY 2009 VL 33 IS 5 BP 432 EP 441 DI 10.1002/gepi.20396 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 465RX UT WOS:000267605700007 PM 19140130 ER PT J AU Haag, T Santos, AS De Angelo, C Srbek-Araujo, AC Sana, DA Morato, RG Salzano, FM Eizirik, E AF Haag, Taiana Santos, Anelisie S. De Angelo, Carlos Srbek-Araujo, Ana Carolina Sana, Denis A. Morato, Ronaldo G. Salzano, Francisco M. Eizirik, Eduardo TI Development and testing of an optimized method for DNA-based identification of jaguar (Panthera onca) and puma (Puma concolor) faecal samples for use in ecological and genetic studies SO GENETICA LA English DT Article DE Faecal DNA; Mitochondrial DNA; Panthera onca; Puma concolor; Species identification ID POPULATION-SIZE; FECES; CARNIVORES; HYBRIDIZATION; TIGRIS; SCATS; SITES; SEX AB The elusive nature and endangered status of most carnivore species imply that efficient approaches for their non-invasive sampling are required to allow for genetic and ecological studies. Faecal samples are a major potential source of information, and reliable approaches are needed to foster their application in this field, particularly in areas where few studies have been conducted. A major obstacle to the reliable use of faecal samples is their uncertain species-level identification in the field, an issue that can be addressed with DNA-based assays. In this study we describe a sequence-based approach that efficiently distinguishes jaguar versus puma scats, and that presents several desirable properties: (1) considerably high amplification and sequencing rates; (2) multiple diagnostic sites reliably differentiating the two focal species; (3) high information content that allows for future application in other carnivores; (4) no evidence of amplification of prey DNA; and (5) no evidence of amplification of a nuclear mitochondrial DNA insertion known to occur in the jaguar. We demonstrate the reliability and usefulness of this approach by evaluating 55 field-collected samples from four locations in the highly fragmented Atlantic Forest biome of Brazil and Argentina, and document the presence of one or both of these endangered felids in each of these areas. C1 [Haag, Taiana; Santos, Anelisie S.; Eizirik, Eduardo] Univ Catolica Rio Grande Do Sul, Fac Biociencias, Lab Biol Genom & Mol, BR-90619900 Porto Alegre, RS, Brazil. [Haag, Taiana] Univ Fed Rio Grande do Sul, Programa Posgrad Genet & Biol Mol, Porto Alegre, RS, Brazil. [De Angelo, Carlos] CeIBA, Natl Res Council Argentina CONICET & Asociac Civi, Buenos Aires, DF, Argentina. [Srbek-Araujo, Ana Carolina] Inst Ambiental Vale, Vitoria, Espirito, Spain. [Sana, Denis A.; Morato, Ronaldo G.; Eizirik, Eduardo] Inst Procarnivoros, Sao Paulo, Brazil. [Morato, Ronaldo G.] CENAP ICMBio, Sao Paulo, Brazil. [Salzano, Francisco M.] Univ Fed Rio Grande do Sul, Dept Genet, Porto Alegre, RS, Brazil. [Eizirik, Eduardo] NCI, Lab Genom Div, Frederick, MD 21701 USA. RP Eizirik, E (reprint author), Univ Catolica Rio Grande Do Sul, Fac Biociencias, Lab Biol Genom & Mol, Av Ipiranga 6681, BR-90619900 Porto Alegre, RS, Brazil. EM eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012; Srbek-Araujo, Ana Carolina/I-1436-2015; Salzano, Francisco/L-7916-2015; OI Eizirik, Eduardo/0000-0002-9658-0999; Srbek-Araujo, Ana Carolina/0000-0003-1154-0072; De Angelo, Carlos/0000-0002-7759-3321 FU Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil FX We would like to thank all the institutions and people who helped with collection of biological samples used in this study, including those mentioned in Table 1, as well as Warren E. Johnson, Stephen J. O'Brien, Peter G. Crawshaw Jr., Laury Cullen Jr., Alessandra Nava, Leonardo R. Viana, Adriano G. Chiarello, Cristian Corio, Esteban Hasson, Agustin Paviolo and Mario Di Bitteti. We especially thank Paulo B. Chaves for technical assistance and suggestions, as well as access to unpublished data on ocelot ATP6 sequences. We are also grateful to the Centro Nacional de Pesquisas para a Conservacao de Predadores Naturais (CENAP/ICMBio), Instituto Pro-Carnivoros, Companhia Energetica de Sao Paulo ( CESP) and Instituto Ambiental Vale for having supported this project, and the Laboratorio de Evolucion, Departamento de Ecologia, Genetica y Evolucion, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, for help in the analysis of scat samples from Argentina. T. Haag is supported by a fellowship from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), Brazil. NR 35 TC 26 Z9 26 U1 1 U2 29 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0016-6707 J9 GENETICA JI Genetica PD JUL PY 2009 VL 136 IS 3 BP 505 EP 512 DI 10.1007/s10709-008-9347-6 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 451DP UT WOS:000266451200013 PM 19137401 ER PT J AU Khoury, MJ Feero, WG Reyes, M Citrin, T Freedman, A Leonard, D Burke, W Coates, R Croyle, RT Edwards, K Kardia, S McBride, C Manolio, T Randhawa, G Rasooly, R Pierre, JS Terry, S AF Khoury, Muin J. Feero, W. Gregory Reyes, Michele Citrin, Toby Freedman, Andrew Leonard, Debra Burke, Wylie Coates, Ralph Croyle, Robert T. Edwards, Karen Kardia, Sharon McBride, Colleen Manolio, Teri Randhawa, Gurvaneet Rasooly, Rebekah Pierre, Jeannette St. Terry, Sharon CA GAPPNet Planning Grp TI The Genomic Applications in Practice and Prevention Network SO GENETICS IN MEDICINE LA English DT Review DE decision support; genomics; information; medicine; network; public health ID EGAPP WORKING GROUP; OVARIAN-CANCER; UNITED-STATES; HEALTH-CARE; PROPHYLACTIC SURGERY; BREAST; RECOMMENDATIONS; WOMEN; SUSCEPTIBILITY; MORBIDITY AB The authors describe the rationale and initial development of a new collaborative initiative, the Genomic Applications in Practice and Prevention Network. The network convened by the Centers for Disease Control and Prevention and the National Institutes of Health includes multiple stakeholders from academia, government, health care, public health, industry and consumers. The premise of Genomic Applications in Practice and Prevention Network is that there is an unaddressed chasm between gene discoveries and demonstration of their clinical validity and utility. This chasm is due to the lack of readily accessible information about the utility of most genomic applications and the lack of necessary knowledge by consumers and providers to implement what is known. The mission of Genomic Applications in Practice and Prevention Network is to accelerate and streamline the effective integration of validated genomic knowledge into the practice of medicine and public health, by empowering and sponsoring research, evaluating research findings, and disseminating high quality information on candidate genomic applications in practice and prevention. Genomic Applications in Practice and Prevention Network will develop a process that links ongoing collection of information on candidate genomic applications to four crucial domains: (1) knowledge synthesis and dissemination for new and existing technologies, and the identification of knowledge gaps, (2) a robust evidence-based recommendation development process, (3) translation research to evaluate validity, utility and impact in the real world and how to disseminate and implement recommended genomic applications, and (4) programs to enhance practice, education, and surveillance. Genet Med 2009:11(7):488-494. C1 [Khoury, Muin J.; Reyes, Michele; Coates, Ralph; Pierre, Jeannette St.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. [Feero, W. Gregory; Kardia, Sharon; McBride, Colleen; Manolio, Teri] Natl Human Genome Res Inst, NIH, Bethesda, MD USA. [Citrin, Toby; Croyle, Robert T.] Univ Michigan, Ctr Community & Publ Hlth Genom, Ann Arbor, MI 48109 USA. [Freedman, Andrew] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [Leonard, Debra] Cornell Univ, Dept Pathol & Lab Med, New York, NY 10021 USA. [Burke, Wylie] Univ Washington, Ctr Genom & Healthcare Equal, Seattle, WA 98195 USA. [Edwards, Karen] Univ Washington, Ctr Genom & Publ Hlth, Seattle, WA 98195 USA. [Randhawa, Gurvaneet] Agcy Healthcare Res Qual, Rockville, MD USA. [Rasooly, Rebekah] NIDDK, NIH, Bethesda, MD USA. [Terry, Sharon] Genet Alliance, Washington, DC USA. RP Khoury, MJ (reprint author), Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA 30333 USA. EM mkhoury@cdc.gov OI Rasooly, Rebekah/0000-0002-6357-5528 NR 31 TC 37 Z9 39 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD JUL PY 2009 VL 11 IS 7 BP 488 EP 494 DI 10.1097/GIM.0b013e3181a551cc PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 472WA UT WOS:000268162200002 PM 19471162 ER PT J AU Pruitt, KD Harrow, J Harte, RA Wallin, C Diekhans, M Maglott, DR Searle, S Farrell, CM Loveland, JE Ruef, BJ Hart, E Suner, MM Landrum, MJ Aken, B Ayling, S Baertsch, R Fernandez-Banet, J Cherry, JL Curwen, V DiCuccio, M Kellis, M Lee, J Lin, MF Schuster, M Shkeda, A Amid, C Brown, G Dukhanina, O Frankish, A Hart, J Maidak, BL Mudge, J Murphy, MR Murphy, T Rajan, J Rajput, B Riddick, LD Snow, C Steward, C Webb, D Weber, JA Wilming, L Wu, WY Birney, E Haussler, D Hubbard, T Ostell, J Durbin, R Lipman, D AF Pruitt, Kim D. Harrow, Jennifer Harte, Rachel A. Wallin, Craig Diekhans, Mark Maglott, Donna R. Searle, Steve Farrell, Catherine M. Loveland, Jane E. Ruef, Barbara J. Hart, Elizabeth Suner, Marie-Marthe Landrum, Melissa J. Aken, Bronwen Ayling, Sarah Baertsch, Robert Fernandez-Banet, Julio Cherry, Joshua L. Curwen, Val DiCuccio, Michael Kellis, Manolis Lee, Jennifer Lin, Michael F. Schuster, Michael Shkeda, Andrew Amid, Clara Brown, Garth Dukhanina, Oksana Frankish, Adam Hart, Jennifer Maidak, Bonnie L. Mudge, Jonathan Murphy, Michael R. Murphy, Terence Rajan, Jeena Rajput, Bhanu Riddick, Lillian D. Snow, Catherine Steward, Charles Webb, David Weber, Janet A. Wilming, Laurens Wu, Wenyu Birney, Ewan Haussler, David Hubbard, Tim Ostell, James Durbin, Richard Lipman, David TI The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes SO GENOME RESEARCH LA English DT Article ID BIOTECHNOLOGY INFORMATION; DATABASE RESOURCES; NATIONAL CENTER; NCBI; IDENTIFICATION; ANNOTATION; ELEMENTS; ENSEMBL; ENCODE; SRCAP AB Effective use of the human and mouse genomes requires reliable identification of genes and their products. Although multiple public resources provide annotation, different methods are used that can result in similar but not identical representation of genes, transcripts, and proteins. The collaborative consensus coding sequence (CCDS) project tracks identical protein annotations on the reference mouse and human genomes with a stable identifier (CCDS ID), and ensures that they are consistently represented on the NCBI, Ensembl, and UCSC Genome Browsers. Importantly, the project coordinates on manually reviewing inconsistent protein annotations between sites, as well as annotations for which new evidence suggests a revision is needed, to progressively converge on a complete protein-coding set for the human and mouse reference genomes, while maintaining a high standard of reliability and biological accuracy. To date, the project has identified 20,159 human and 17,707 mouse consensus coding regions from 17,052 human and 16,893 mouse genes. Three evaluation methods indicate that the entries in the CCDS set are highly likely to represent real proteins, more so than annotations from contributing groups not included in CCDS. The CCDS database thus centralizes the function of identifying well-supported, identically-annotated, protein-coding regions. C1 [Pruitt, Kim D.; Wallin, Craig; Maglott, Donna R.; Farrell, Catherine M.; Landrum, Melissa J.; Cherry, Joshua L.; DiCuccio, Michael; Lee, Jennifer; Shkeda, Andrew; Brown, Garth; Dukhanina, Oksana; Hart, Jennifer; Maidak, Bonnie L.; Murphy, Michael R.; Murphy, Terence; Rajput, Bhanu; Riddick, Lillian D.; Webb, David; Weber, Janet A.; Wu, Wenyu; Ostell, James; Lipman, David] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Harrow, Jennifer; Searle, Steve; Loveland, Jane E.; Hart, Elizabeth; Suner, Marie-Marthe; Aken, Bronwen; Fernandez-Banet, Julio; Curwen, Val; Frankish, Adam; Mudge, Jonathan; Rajan, Jeena; Snow, Catherine; Steward, Charles; Wilming, Laurens; Hubbard, Tim; Durbin, Richard] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Harte, Rachel A.; Diekhans, Mark; Baertsch, Robert; Haussler, David] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Ruef, Barbara J.; Amid, Clara] Univ Oregon, Zebrafish Informat Network, Eugene, OR 97403 USA. [Ayling, Sarah] Univ Manchester, Fac Life Sci, Manchester Interdisciplinary Bioctr, Manchester M1 7DN, Lancs, England. [Kellis, Manolis; Lin, Michael F.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Kellis, Manolis; Lin, Michael F.] MIT, Broad Inst, Cambridge, MA 02141 USA. [Kellis, Manolis; Lin, Michael F.] Harvard Univ, Cambridge, MA 02141 USA. [Schuster, Michael; Birney, Ewan] European Bioinformat Inst, Cambridge CB10 1SD, England. RP Pruitt, KD (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM Pruitt@ncbi.nlm.nih.gov RI Frankish, Adam/G-6545-2011; Hubbard, Tim/C-2567-2008; OI Hubbard, Tim/0000-0002-1767-9318; Ruef, Barbara/0000-0001-8690-979X; Wilming, Laurens/0000-0002-4154-7358; Snow, Catherine/0000-0002-1672-3532; Birney, Ewan/0000-0001-8314-8497; Schuster, Michael/0000-0003-2975-8969; Amid, Clara/0000-0001-6534-7425; Aken, Bronwen/0000-0002-3032-4095; Durbin, Richard/0000-0002-9130-1006; Fernandez Banet, Julio/0000-0003-0901-1286 FU NHGRI [1U54HG004555-01]; Wellcome Trust [WT062023, WT077198]; NIH FX We thank the programmer, database, and curation staff at Ensembl, NCBI, WTSI, and UCSC for their contribution to the CCDS analysis, maintenance, and continuing curation efforts. We thank the UniProt Consortium, the HGNC, and MGI for many useful discussions that improve protein representation in all data sets. UCSC thanks the UCSC Genome Browser team for their tools, data, and assistance, and Michele Clamp ( Broad Institute) for providing controls for conservation analysis. NCBI thanks Zev Hochberg for his contributions toward the initial CCDS database schema and CCDS build analysis. UCSC was funded for this work from subcontract no. 0244-03 from NHGRI grant no. 1U54HG004555-01 to the Wellcome Trust Sanger Institute. Work at the Wellcome Trust Sanger Institute was supported by the Wellcome Trust (grant nos. WT062023, WT077198) and by NHGRI grant no. 1U54HG004555-01. Work at NCBI was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 28 TC 259 Z9 265 U1 1 U2 7 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD JUL PY 2009 VL 19 IS 7 BP 1316 EP 1323 DI 10.1101/gr.080531.108 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 468AY UT WOS:000267786900019 PM 19498102 ER PT J AU Liu, J Malavya, S Wang, XQ Saavedra, JE Keefer, LK Tokar, E Qu, W Waalkes, MP Shami, PJ AF Liu, Jie Malavya, Swati Wang, Xueqian Saavedra, Joseph E. Keefer, Larry K. Tokar, Erik Qu, Wei Waalkes, Michael P. Shami, Paul J. TI Gene expression profiling for nitric oxide prodrug JS-K to kill HL-60 myeloid leukemia cells SO GENOMICS LA English DT Article DE JS-K; Nitric oxide donor; HL-60 cells; Gene expression; Confocal analysis ID GLUTATHIONE-S-TRANSFERASE; IN-VITRO; KINASE PATHWAYS; DIFFERENTIATION; GROWTH; VIVO; THROMBOSPONDIN-1; ANGIOGENESIS; MODULATION; ACTIVATION AB The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THIRS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metal loprotemases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug. Published by Elsevier Inc. C1 [Liu, Jie; Tokar, Erik; Qu, Wei; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Malavya, Swati; Shami, Paul J.] Univ Utah, Dept Internal Med, Div Med Oncol, Salt Lake City, UT 84112 USA. [Wang, Xueqian] NIEHS, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Saavedra, Joseph E.] SAIC, Basic Sci Program, Frederick, MD USA. [Keefer, Larry K.] NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. RP Liu, J (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, POB 12233, Res Triangle Pk, NC 27709 USA. EM Liu6@niehs.nih.gov; paul.shami@utah.edu RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute; National Institutes of Health [NO1-CO12400]; Leukemia and Lymphoma Society; NCI [R01CA84496] FX The authors thank Drs. Chikara Kojima and jean-Francois Coppin for their review of this manuscript. Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Centre for Cancer Research, the Federal funds from the National Cancer Institute, and the National Institutes of Health, under contract No. NO1-CO12400. Research Was also Supported by a Translational Research Award from the Leukemia and Lymphoma Society and NCI grant R01CA84496 (PJS). NR 28 TC 7 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD JUL PY 2009 VL 94 IS 1 BP 32 EP 38 DI 10.1016/j.ygeno.2009.03.005 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 461BH UT WOS:000267238600004 PM 19348908 ER PT J AU Lamba, S Ravichandran, V Major, EO AF Lamba, Shivani Ravichandran, Veerasamy Major, Eugene O. TI Glial Cell Type-Specific Subcellular Localization of 14-3-3 Zeta: An Implication for JCV Tropism SO GLIA LA English DT Article DE JC virus; 14-3-3 zeta; subcellular localization ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; VIRUS MULTIPLICATION; PROGENITOR CELLS; NERVOUS-SYSTEM; IN-VIVO; PROTEINS; PATHWAY; DISEASE; EXPRESSION; INCREASES AB 14-3-3 Isoforms are shown to be upregulated or accumnlated in the glial cells of autopsied patient brains affected with progressive multifocal leukoencephalopathy (PML), a demylinating disease caused by JC virus (JCV). The possible involvement of 14-3-3 in JCV tropism, however, has never been examined. To investigate a potential relationship between 14-3-3 isoforms and JCV in vitro, we examined the localization of six 14-3-3 isoforms in human neural progenitors and progenitor-derived astrocytes (PDAs) in cells without JCV exposure. The 14-3-3 zeta isoform was initially localized in the progenitor cytoplasm. When differentiation of progenitors into PDAs was induced, the zeta isoform was translocated into the nucleus. However, upon JCV infection, progenitor cells exhibited an uncharacteristic 14-3-3 zeta nuclear presence in the few cells that became infected. JCV-treated PDAs showed elevated levels of 14-3-3 zeta compared with noninfected PDAs. Treatment with TGF-beta 1, a known stimulant of JCV multi plication, increased the overall number of infected cells and the otherwise absent nuclear presence of 14-3-3 zeta in progenitors. These results suggest that the nuclear presence of 14-3-3 zeta may play a role in JCV infection, and that the isoform may in part determine JCV susceptibility in these cell types. (C) 2008 Wilely-Liss, Inc. C1 [Lamba, Shivani; Ravichandran, Veerasamy; Major, Eugene O.] NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, 10 Ctr Dr,Bldg 10,Room 3B14,MSC 1296, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke; National Institutes of Health FX Grant sponsor Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 23 TC 10 Z9 10 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD JUL PY 2009 VL 57 IS 9 BP 971 EP 977 DI 10.1002/glia.20821 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 454IQ UT WOS:000266676000005 PM 19062179 ER PT J AU Chien, J Fan, JB Bell, DA April, C Klotzle, B Ota, T Lingle, WL Bosquet, JG Shridhar, V Hartmann, LC AF Chien, Jeremy Fan, Jian-Bing Bell, Debra A. April, Craig Klotzle, Brandy Ota, Takayo Lingle, Wilma L. Bosquet, Jesus Gonzalez Shridhar, Viji Hartmann, Lynn C. TI Analysis of gene expression in stage I serous tumors identifies critical pathways altered in ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Stage I serous carcinoma; Gene expression; Serous borderline tumor; p53; E2F ID DISTAL FALLOPIAN-TUBE; SURFACE EPITHELIUM; TISSUE BIOMARKER; PROSTATE-CANCER; BEAD ARRAYS; NEW-MODEL; CARCINOMA; CELL; CARCINOGENESIS; RNA AB Objective. Despite recent advances in the conceptual understanding of the pathogenesis of ovarian cancer, it remains the foremost cause of death from gynecologic malignancies in developed countries. The main reason for such a high rate of mortality is the lack of sensitive and specific biomarkers and imaging techniques for early detection of ovarian cancer. Additional biological insights into early-stage ovarian carcinogenesis are needed to help speed the development of markers for early detection of ovarian cancer. The objective of this study was to characterize differentially expressed genes in high-grade stage I serous carcinoma of the ovary. Methods. We analyzed gene expression in macrodissected formalin-fixed, paraffin-embedded samples from 5 high-grade stage I serous carcinomas and 5 stage I borderline tumors of the ovary using the Illumina Whole Genome DASL assay (cDNA-mediated annealing, selection, extension, and ligation) corresponding to 24,000 genes. Significance Analysis of Microarrays was performed to determine differentially expressed genes in stage I serous carcinoma, and class prediction analysis was performed to determine the predictive value of differentially expressed gene sets to correctly classify serous carcinoma from borderline tumors in 3 independent data sets. Altered transcription factor pathways and biological pathways unique to stage I serous carcinoma were identified through class comparison of differentially expressed genes. Results. Unsupervised cluster analysis of gene expression correctly classified stage I serous carcinomas from serous borderline tumors. Supervised analysis identified several known, as well as novel, genes differentially expressed in stage I ovarian cancer. Using a differentially expressed gene set, class comparison prediction analysis correctly identified serous carcinomas from serous borderline tumors in 3 independent data sets at over 80% accuracy, sensitivity, and specificity. Pathway analysis demonstrated the significance of p53 and E2F pathways in serous carcinogenesis and significant involvements of cell cycle and immune response pathways in stage I serous epithelial ovarian cancer. Conclusion. We have identified differentially expressed genes associated with the carcinogenesis of high-grade stage 1 serous EOC. Furthermore, integrative analysis of biological and transcription pathway data contributed to the confirmation of important biological pathways and discovery of additional unique genes and pathways that may have potential importance in ovarian pathogenesis and biomarker development. (C) 2009 Elsevier Inc. All rights reserved. C1 [Chien, Jeremy; Ota, Takayo; Lingle, Wilma L.; Shridhar, Viji] Mayo Clin, Coll Med, Div Expt Pathol, Rochester, MN 55905 USA. [Bell, Debra A.] Mayo Clin, Coll Med, Div Anat Pathol, Rochester, MN 55905 USA. [Hartmann, Lynn C.] Mayo Clin, Coll Med, Div Med Oncol, Rochester, MN 55905 USA. [Bosquet, Jesus Gonzalez] NCI, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. [Fan, Jian-Bing; April, Craig; Klotzle, Brandy] Illumina Inc, San Diego, CA USA. RP Chien, J (reprint author), Mayo Clin, Coll Med, Div Expt Pathol, Rochester, MN 55905 USA. EM chien.jeremy@mayo.edu OI Ota, Takayo/0000-0003-1630-8301; Chien, Jeremy/0000-0003-4744-8374 FU Ovarian Cancer Research Fund Liz Tilberis Scholars; Wallace and Evelyn Simmers Career Development award; Andersen Foundation FX This work was funded by the Ovarian Cancer Research Fund Liz Tilberis Scholars (J.C.), the Wallace and Evelyn Simmers Career Development award (J.C.), and Andersen Foundation Program Project award (L.C.H.). We acknowledged statistical assistance from Ann Oberg and bioinformatics assistance from Yan Asmann. NR 44 TC 31 Z9 34 U1 2 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUL PY 2009 VL 114 IS 1 BP 3 EP 11 DI 10.1016/j.ygyno.2009.04.002 PG 9 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 457TX UT WOS:000266957700002 PM 19410283 ER PT J AU Kottilil, S Yan, MY Reitano, KN Zhang, X Lempicki, R Roby, G Daucher, M Yang, J Cortez, KJ Ghany, M Polis, MA Fauci, AS AF Kottilil, Shyam Yan, Michael Y. Reitano, Kristin N. Zhang, Xiaozhen Lempicki, Richard Roby, Gregg Daucher, Marybeth Yang, Jun Cortez, Karoll J. Ghany, Marc Polis, Michael A. Fauci, Anthony S. TI Human Immunodeficiency Virus and Hepatitis C Infections Induce Distinct Immunologic Imprints in Peripheral Mononuclear Cells SO HEPATOLOGY LA English DT Article ID ANTI-HCV THERAPY; GENE-EXPRESSION; IMMUNE ACTIVATION; HIV-1 INFECTION; PLUS RIBAVIRIN; LIVER FIBROSIS; UNITED-STATES; HLA-DR; DISEASE; INTERFERON-ALPHA-2B AB Coinfection with hepatitis C virus (HCV) is present in one-third of all human immunodeficiency virus (HIV)-infected individuals in the United States and is associated with rapid progression of liver fibrosis and poor response to pegylated interferon (IFN) and ribavirin. In this study we examined gene expression profiles in peripheral blood mononuclear cells (PBMCs) from different groups of individuals who are monoinfected or coinfected with HIV and HCV. Data showed that HIV and HCV viremia up-regulate genes associated with immune activation and immunoregulatory pathways. HCV viremia is also associated with abnormalities in all peripheral immune cells, suggesting a global effect of HCV on the immune system. Interferon-alpha-induced genes were expressed at a higher level in PBMCs from HIV-infected individuals. HCV and HIV infections leave distinct profiles or gene expression of immune activation in PBMCs. HIV viremia induces an immune activated state; by comparison, HCV infection induces immunoregulatory and proinflammatory pathways that may contribute to progression of liver fibrosis. Conclusion: An aberrant type-I IFN response seen exclusively in HIV-infected individuals could be responsible for the poor therapeutic response experienced by HIV/HCV coinfected individuals receiving interferon-alpha-based current standard of care. (HEPATOLOGY 2009;50:34-45.) C1 [Kottilil, Shyam] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Cortez, Karoll J.] NCI, NIH, DHHS, Bethesda, MD 20892 USA. [Lempicki, Richard; Yang, Jun] SAIC Frederick, Frederick, MD USA. [Cortez, Karoll J.] NIH, Dept Crit Care Med, NIH Clin Ctr, DHHS, Bethesda, MD 20892 USA. [Ghany, Marc] NIDDK, NIH, DHHS, Bethesda, MD USA. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH,Dept Hlth & Human Serv, Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268 FU NIH (NIAID and NIDDK) FX Supported in whole by the Intramural Research Program of the NIH (NIAID and NIDDK). NR 46 TC 31 Z9 32 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2009 VL 50 IS 1 BP 34 EP 45 DI 10.1002/hep.23055 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 465RW UT WOS:000267605500006 PM 19551908 ER PT J AU Seeff, LB Ghany, MG Strader, DB Thomas, DL AF Seeff, Leonard B. Ghany, Marc G. Strader, Doris B. Thomas, David L. TI Comment on the Updated AASLD Practice Guidelines for the Diagnosis, Management, and Treatment of Hepatitis C: Treating Active Drug Users Reply SO HEPATOLOGY LA English DT Letter ID VIRUS; GENOTYPE-2; RIBAVIRIN C1 [Seeff, Leonard B.] NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. [Strader, Doris B.] Univ Vermont, Coll Med, Burlington, VT USA. [Thomas, David L.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Seeff, LB (reprint author), NIDDK, Liver Dis Res Branch, NIH, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD JUL PY 2009 VL 50 IS 1 BP 324 EP 325 DI 10.1002/hep.23084 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 465RW UT WOS:000267605500041 ER PT J AU Fox, PT Bullmore, ET Bandettini, PA Lancaster, JL AF Fox, Peter T. Bullmore, Edward T. Bandettini, Peter A. Lancaster, Jack L. TI Untitled Reply SO HUMAN BRAIN MAPPING LA English DT Letter C1 [Fox, Peter T.; Lancaster, Jack L.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, San Antonio, TX 78229 USA. [Bullmore, Edward T.] Univ Cambridge, Dept Psychiat, Cambridge, England. [Bandettini, Peter A.] Natl Inst Hlth, Funct MRI Facil, Bethesda, MD USA. RP Fox, PT (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Ctr, San Antonio, TX 78229 USA. RI Lancaster, Jack/F-2994-2010; Fox, Peter/B-4725-2010; Bullmore, Edward/C-1706-2012 OI Fox, Peter/0000-0002-0465-2028; Bullmore, Edward/0000-0002-8955-8283 NR 3 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 EI 1097-0193 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2009 VL 30 IS 7 BP 1936 EP 1937 DI 10.1002/hbm.20808 PG 2 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 466VQ UT WOS:000267691900002 ER PT J AU Wolf, RC Plichta, MM Sambataro, F Fallgatter, AJ Jacob, C Lesch, KP Herrmann, MJ Schonfeldt-Lecuona, C Connemann, BJ Gron, G Vasic, N AF Wolf, Robert C. Plichta, Michael M. Sambataro, Fabio Fallgatter, Andreas J. Jacob, Christian Lesch, Klaus-Peter Herrmann, Martin J. Schoenfeldt-Lecuona, Carlos Connemann, Bernhard J. Groen, Georg Vasic, Nenad TI Regional Brain Activation Changes and Abnormal Functional Connectivity of the Ventrolateral Prefrontal Cortex During Working Memory Processing in Adults With Attention-Deficit/Hyperactivity Disorder SO HUMAN BRAIN MAPPING LA English DT Article DE working memory; prefrontal cortex; cerebellum; independent component analysis; functional connectivity; functional magnetic resonance imaging ID DEFICIT-HYPERACTIVITY DISORDER; EVENT-RELATED FMRI; ANTERIOR CINGULATE CORTEX; INDEPENDENT COMPONENT ANALYSIS; REPORT SCALE ASRS; MAGNETIC-RESONANCE; DEFAULT-MODE; FRONTAL-CORTEX; RESPONSE-INHIBITION; EXECUTIVE FUNCTION AB Previous Studies on working memory (WM) function in adults with attention-deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this Study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp 30:2252-2266, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Wolf, Robert C.; Schoenfeldt-Lecuona, Carlos; Connemann, Bernhard J.; Groen, Georg; Vasic, Nenad] Univ Ulm, Dept Psychiat & Psychotherapy 3, D-89075 Ulm, Germany. [Herrmann, Martin J.] Univ Wurzburg, Dept Psychiat, Genom Imaging Unit, D-97070 Wurzburg, Germany. [Sambataro, Fabio] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Wolf, RC (reprint author), Univ Ulm, Dept Psychiat & Psychotherapy 3, Leimgrubenweg 12-14, D-89075 Ulm, Germany. EM christian.wolf@uni-ulm.de RI Herrmann, Martin/C-9904-2009; Sambataro, Fabio/E-3426-2010; Lesch, Klaus-Peter/J-4906-2013 OI Herrmann, Martin/0000-0001-9970-2122; Sambataro, Fabio/0000-0003-2102-416X; Lesch, Klaus-Peter/0000-0001-8348-153X FU Deutsche Forschungsgemeinschaft [KFO 125/1-1] FX Contract grant sponsor: Deutsche Forschungsgemeinschaft Contract grant number: KFO 125/1-1. NR 87 TC 72 Z9 72 U1 5 U2 20 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD JUL PY 2009 VL 30 IS 7 BP 2252 EP 2266 DI 10.1002/hbm.20665 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 466VQ UT WOS:000267691900029 PM 19107748 ER PT J AU Blake, PW Toro, JR AF Blake, Patrick W. Toro, Jorge R. TI Update of Cylindromatosis Gene (CYLD) Mutations in Brooke-Spiegler Syndrome: Novel Insights Into the Role of Deubiquitination in Cell Signaling SO HUMAN MUTATION LA English DT Review DE CYLD; Brooke-Spiegler; familial cylindromatosis; cylindroma; trichoepithelioma; spiradenoma ID MULTIPLE FAMILIAL TRICHOEPITHELIOMA; NF-KAPPA-B; TUMOR-SUPPRESSOR CYLD; NONTYPABLE HAEMOPHILUS-INFLUENZAE; MALIGNANT ECCRINE SPIRADENOMA; SKIN ADNEXAL NEOPLASMS; ENZYME CYLD; NEGATIVE REGULATOR; MISSENSE MUTATION; HEPATOCELLULAR CARCINOMAS AB Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51. mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappa B and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation. Hum Mutat 30:1025-1036, 2009. Published 2009 Wiley-Liss, Inc. C1 [Blake, Patrick W.; Toro, Jorge R.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20892 USA. [Blake, Patrick W.] Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20817 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Execut Plaza S,Room 7012, Rockville, MD 20892 USA. EM toroj@mail.nih.gov FU NIH; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX We thank the BSS families for their participation in this research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, the Division of Cancer Epidemiology and Genetics. P.B. is a Howard Hughes Medical Institute Research Scholar. NR 121 TC 50 Z9 51 U1 0 U2 11 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD JUL PY 2009 VL 30 IS 7 BP 1025 EP 1036 DI 10.1002/humu.21024 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 468CQ UT WOS:000267791700001 PM 19462465 ER PT J AU Bradac, J Dieffenbach, CW AF Bradac, James Dieffenbach, Carl W. TI HIV vaccine development: Lessons from the past, informing the future SO IDRUGS LA English DT Review DE ELISPOT; HIV; HIV vaccine; neutralizing antibody; nonhuman primate model; simian immuno-deficiency virus; SIV; T-cell vaccine AB In September 2007, a clinical trial (STEP trial) evaluating the candidate HIV vaccine MRK Ad5 HIV-1 gag/pol/nef from Merck & Co Inc was halted at the first interim analysis because the vaccine demonstrated no positive impact on virus acquisition or virus load following infection. Additionally, there was an increased rate of HIV infection in vaccinees who had prior immunity to adenovirus type 5 (Ad5) and/or were circumcised. This failure of the vaccine, as well as the apparent harm caused to some study participants, generated a massive pessimism regarding HIV vaccine development. Concerns regarding the future of HIV vaccine research led to a summit convened by the NIAID in March 2008 to provide new directions in HIV vaccine research. A shift in emphasis focused on three areas: discovery research, animal models and clinical research. In each of these areas, notable new activities have occurred: a wealth of information has emerged from the STEP trial, promising results have been reported on assay development for markers of vaccine-induced immune function, and evaluations of promising new experimental vaccines have occurred in nonhuman primates. Overall, the progress in the field of HIV vaccine research since September 2007 has reinforced the need for a balanced approach between basic vaccine discovery and development, as well as the importance of addressing questions in nonhuman primate studies and clinical trials. This article discusses how past product failures have invigorated the field of HIV vaccine research by addressing critical questions and suggesting additional possible approaches to follow. As a result of the insight gained, a new sense of optimism exists in the field of HIV vaccine research. C1 [Bradac, James; Dieffenbach, Carl W.] NIAID, NIH, Bethesda, MD 20892 USA. RP Dieffenbach, CW (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM CDieffenba@niaid.nih.gov NR 5 TC 8 Z9 8 U1 0 U2 10 PU THOMSON REUTERS (SCIENTIFIC) LTD PI LONDON PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND SN 1369-7056 J9 IDRUGS JI IDrugs PD JUL PY 2009 VL 12 IS 7 BP 435 EP 439 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 464OQ UT WOS:000267515200011 PM 19579164 ER PT J AU Motakis, E Ivshina, AV Kuznetsov, VA AF Motakis, Efthimios Ivshina, Anna V. Kuznetsov, Vladimir A. TI Data-Driven Approach to Predict Survival of Cancer Patients Estimation of Microarray Genes' Prediction Significance by Cox Proportional Hazard Regression Model SO IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE LA English DT Article ID BREAST-CANCER; VITAMIN-D; CELLS C1 [Motakis, Efthimios; Kuznetsov, Vladimir A.] ASTAR, BioInformat Inst, Singapore, Singapore. [Ivshina, Anna V.] Genome Inst Singapore, Lab Microarrays & Express Genom, Singapore, Singapore. [Ivshina, Anna V.; Kuznetsov, Vladimir A.] US FDA, Rockville, MD 20857 USA. [Kuznetsov, Vladimir A.] Russian Acad Sci, Inst Chem Phys, Lab Math Immunobiophys, Moscow 117901, Russia. [Kuznetsov, Vladimir A.] NCI, NICHD, NIH, Bethesda, MD 20892 USA. [Kuznetsov, Vladimir A.] ASTAR, Genome Inst Singapore, Lab Computat Genom & Syst Biol, Singapore, Singapore. RP Kuznetsov, VA (reprint author), ASTAR, BioInformat Inst, Singapore, Singapore. EM vladimirk@bii.a-star.edu.sg NR 23 TC 20 Z9 21 U1 1 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0739-5175 J9 IEEE ENG MED BIOL JI IEEE Eng. Med. Biol. Mag. PD JUL-AUG PY 2009 VL 28 IS 4 BP 58 EP 66 DI 10.1109/MEMB.2009.932937 PG 9 WC Engineering, Biomedical; Medical Informatics SC Engineering; Medical Informatics GA 474KJ UT WOS:000268281900015 PM 19622426 ER PT J AU Tamer, GG Luh, WM Talavage, TM AF Tamer, Gregory G., Jr. Luh, Wen-Ming Talavage, Thomas M. TI Characterizing Response to Elemental Unit of Acoustic Imaging Noise: An fMRI Study SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Acoustic noise; auditory system; biomedical image processing; magnetic resonance imaging; modeling ID HUMAN AUDITORY-CORTEX; EVENT-RELATED FMRI; SENSORY STIMULATION; SCANNER NOISE; BRAIN ACTIVATION; BOLD RESPONSE; TIME-COURSE; BLOOD-FLOW; VOLUME; OXYGENATION AB Acoustic imaging noise produced during functional magnetic resonance imaging (fMRI) studies can hinder auditory fMRI research analysis by altering the properties of the acquired time-series data. Acoustic imaging noise can be especially confounding when estimating the time course of the hemodynamic response (HDR) in auditory event-related fMRI (IMRI) experiments. This study is motivated by the desire to establish a baseline function that can serve not only as a comparison to other quantities of acoustic imaging noise for determining how detrimental is one's experimental noise, but also as a foundation for a model that compensates for the response to acoustic imaging noise. Therefore, the amplitude and spatial extent of the HDR to the elemental unit of acoustic imaging noise (i.e., a single ping) associated with echoplanar acquisition were characterized and modeled. Results from this fMRI study at 1.5 T indicate that the group-averaged HIM in left and right auditory cortex to acoustic imaging noise (duration of 46 ms) has an estimated peak magnitude of 0.29% (right) to 0.48% (left) signal change from baseline, peaks between 3 and 5 s after stimulus presentation, and returns to baseline and remains within the noise range approximately 8 s after stimulus presentation. C1 [Tamer, Gregory G., Jr.; Talavage, Thomas M.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. [Luh, Wen-Ming] NIMH, NIH, Funct MRI Facil, Bethesda, MD 20892 USA. [Talavage, Thomas M.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. RP Tamer, GG (reprint author), Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47907 USA. EM gtamer@purdue.edu; luhw@mail.nih.gov; tmt@purdue.edu FU Purdue Research Foundation, from the National Institute of Biomedical Imaging and Bioengineering [R01 EB003990]; National Institute of Mental Health Training [T32 MH19554]; National Institute of Mental Health FX The work of G. Tamer, Jr., was supported by the Purdue Research Foundation under Grant R01 EB003990 from the National Institute of Biomedical Imaging and Bioengineering, and by the National Institute of Mental Health Training under Grant T32 MH19554. The work of W.-M. Luh was supported by the Intramural Research Program of the National Institute of Mental Health. NR 46 TC 4 Z9 4 U1 0 U2 1 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUL PY 2009 VL 56 IS 7 BP 1919 EP 1928 DI 10.1109/TBME.2009.2016573 PG 10 WC Engineering, Biomedical SC Engineering GA 462TI UT WOS:000267379100016 PM 19304477 ER PT J AU Le Floc'h, S Ohayon, J Tracqui, P Finet, G Gharib, AM Maurice, RL Cloutier, G Pettigrew, RI AF Le Floc'h, Simon Ohayon, Jacques Tracqui, Philippe Finet, Gerard Gharib, Ahmed M. Maurice, Roch L. Cloutier, Guy Pettigrew, Roderic I. TI Vulnerable Atherosclerotic Plaque Elasticity Reconstruction Based on a Segmentation-Driven Optimization Procedure Using Strain Measurements: Theoretical Framework SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Coronary arteries; elastography; inverse problem; linear elasticity; modulography; vulnerable plaques ID OPTICAL COHERENCE TOMOGRAPHY; MATERIAL PROPERTY ALTERATIONS; SUDDEN CORONARY DEATH; INTRAVASCULAR ULTRASOUND; IN-VIVO; ENDOVASCULAR ELASTOGRAPHY; MODULUS DISTRIBUTION; MECHANICAL ANALYSIS; BLOOD-PRESSURE; CAP THICKNESS AB It is now recognized that prediction of the vulnerable coronary plaque rupture requires not only an accurate quantification of fibrous cap thickness and necrotic core morphology but also a precise knowledge of the mechanical properties of plaque components. Indeed, such knowledge would allow a precise evaluation of the peak cap-stress amplitude, which is known to be a good biomechanical predictor of plaque rupture. Several studies have been performed to reconstruct a Young's modulus map from strain elastograms. It seems that the main issue for improving such methods does not rely on the optimization algorithm itself, but rather on preconditioning requiring the best estimation of the plaque components' contours. The present theoretical study was therefore designed to develop: 1) a preconditioning model to extract the plaque morphology in order to initiate the optimization process, and 2) an approach combining a dynamic segmentation method with an optimization procedure to highlight the modulogram of the atherosclerotic plaque. This methodology, based on the continuum mechanics theory prescribing the strain field, was successfully applied to seven intravascular ultrasound coronary lesion morphologies. The re-constructed cap thickness, necrotic core area, calcium area, and the Young's moduli of the calcium, necrotic core, and fibrosis were obtained with mean relative errors of 12%, 4% and 1%, 43%, 32%, and 2%, respectively. C1 [Le Floc'h, Simon; Ohayon, Jacques] In3S, CNRS, UMR 5525, Lab TIMC,DynaCell, F-38706 Grenoble, France. [Ohayon, Jacques; Gharib, Ahmed M.; Pettigrew, Roderic I.] NIDDK, NIH, Bethesda, MD 20892 USA. [Finet, Gerard] Hosp Civils Lyon, Dept Hemodynam & Intervent Cardiol, F-69394 Lyon, France. [Finet, Gerard] Univ Lyon 1, INSERM, U886, F-69394 Lyon, France. [Cloutier, Guy] Univ Montreal Hosp CRCHUM, Lab Biorheol & Med Ultrason, Res Ctr, Montreal, PQ H2L 2W5, Canada. [Maurice, Roch L.] Univ Montreal, Dept Radiol Radiooncol & Nucl Med, Montreal, PQ H2L 2W5, Canada. [Maurice, Roch L.] Univ Montreal, Inst Biomed Engn, Montreal, PQ H2L 2W5, Canada. RP Ohayon, J (reprint author), In3S, CNRS, UMR 5525, Lab TIMC,DynaCell, F-38706 Grenoble, France. EM ohayonj2@mail.nih.gov; guy.cloutier@umontreal.ca; rpettig@mail.nih.gov RI Ohayon, Jacques/M-6576-2014; Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X FU Agence National de la Recherche, France [ANR 2006-2009]; Rhone-Alpes (France) FX Manuscript received November 19, 2008: revised December 26, 2008. First published January 19, 2009; current version published June 24. 2009. This work was supported in part by an appointment (J. Ohayon) to the Senior Fellow Program at the National Institutes of Health (NIH). This program is administered by Oak Ridge Institute for Science and Education through an interagency agreement between the NIH and the U.S. Department of Energy. The work of (J. Ohayon), P. Tracqui, G. Finet, and S. Le Floc'h was supported by grants from the Agence National de la Recherche, France (ANR 2006-2009, ATHEBIOMEC), the Rhone-Alpes (France) research cluster (I3M: Medical Images and Multiscale Models), Emergence 2005 and Explora'Doc 2006, Rhone-Alpes Region (France). Asterisk indicates corresponding author. NR 73 TC 40 Z9 41 U1 2 U2 8 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 EI 1558-254X J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD JUL PY 2009 VL 28 IS 7 BP 1126 EP 1137 DI 10.1109/TMI.2009.2012852 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 466XI UT WOS:000267698100015 PM 19164080 ER PT J AU Chang, JH Sun, L Yen, JT Shung, KK AF Chang, Jin Ho Sun, Lei Yen, Jesse T. Shung, K. Kirk TI Low-Cost, High-Speed Back-End Processing System for High-Frequency Ultrasound B-Mode Imaging SO IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL LA English DT Article ID HIGH-FRAME RATE; SCAN CONVERSION; MICE; MHZ AB For real-time visualization of the mouse heart (6 to 13 beats per second), a back-end processing system involving high-speed signal processing functions to form and display images has been developed. This back-end system was designed with new signal processing algorithms to achieve a frame rate of more than 400 images per second. These algorithms were implemented in a simple and cost-effective manner with a single field-programmable gate array (FPGA) and software programs written in C++. The operating speed of the back-end system was investigated by recording the time required for transferring an image to a personal computer. Experimental results showed that the back-end system is capable of producing 433 images per second. To evaluate the imaging performance of the back-end system, a complete imaging system was built. This imaging system, which consisted of a recently reported highspeed mechanical sector scanner assembled with the back-end system, was tested by imaging a wire phantom, a pig eye (in vitro), and a mouse heart (in vivo). It was shown that this system is capable of providing high spatial resolution images with fast temporal resolution. C1 [Chang, Jin Ho; Yen, Jesse T.; Shung, K. Kirk] Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Sun, Lei] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Kowloon, Hong Kong, Peoples R China. RP Chang, JH (reprint author), Univ So Calif, NIH, Resource Ctr Med Ultrason Transducer Technol, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM jhchang@ieee.org RI SUN, Lei/G-3350-2014 OI SUN, Lei/0000-0001-7047-9529 FU NHLBI NIH HHS [R01-HL079976, R01 HL079976]; NIBIB NIH HHS [P41 EB002182, P41 EB002182-12, P41-EB2182] NR 18 TC 9 Z9 9 U1 2 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0885-3010 J9 IEEE T ULTRASON FERR JI IEEE Trans. Ultrason. Ferroelectr. Freq. Control PD JUL PY 2009 VL 56 IS 7 BP 1490 EP 1497 DI 10.1109/TUFFC.2009.1205 PG 8 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 460WN UT WOS:000267222400026 PM 19574160 ER PT J AU Davis, BR Candotti, F AF Davis, Brian R. Candotti, Fabio TI Revertant somatic mosaicism in the Wiskott-Aldrich syndrome SO IMMUNOLOGIC RESEARCH LA English DT Article DE Wiskott-Aldrich syndrome; Reversion; Mutation; Mutation rate; DNA polymerase; Selective advantage; Immunodeficiency; Lymphocytes ID IN-VIVO REVERSION; SEVERE COMBINED IMMUNODEFICIENCY; T-CELL; 2ND-SITE MUTATIONS; INHERITED MUTATION; SYNDROME PROTEIN; GENETIC-DEFECT; PATIENT; LYMPHOCYTES; SIBLINGS AB Up to 11% of patients affected with Wiskott-Aldrich syndrome (WAS) have presented with somatic mosaicism due to spontaneous in vivo reversion to normal of the original mutation or second-site compensatory mutations that restored production of the WAS gene product. The reasons underlying the high prevalence of this phenomenon in WAS are unclear and may include strong selective advantage of revertant cells over mutated populations, abnormally high general mutation rate and/or increased susceptibility of specific WAS gene sequences to DNA polymerase errors. Additional studies in human samples and in vitro/in vivo models of the disease will likely yield further insights into the mechanisms responsible for the occurrence of revertant mosaicism in WAS and elucidate additional biological characteristics of the WAS gene and protein. C1 [Candotti, Fabio] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Davis, Brian R.] Univ Texas Hlth Sci Ctr Houston, Ctr Stem Cell Res, Brown Fdn Inst Mol Med Prevent Human Dis, Houston, TX USA. RP Candotti, F (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM fabio@mail.nih.gov NR 23 TC 27 Z9 28 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0257-277X J9 IMMUNOL RES JI Immunol. Res. PD JUL PY 2009 VL 44 IS 1-3 BP 127 EP 131 DI 10.1007/s12026-008-8091-4 PG 5 WC Immunology SC Immunology GA 453AR UT WOS:000266582800014 PM 19129986 ER PT J AU Holcomb, VB Keck, VA Barrett, JC Hong, J Libutti, SK Nunez, NP AF Holcomb, Valerie B. Keck, Victoria A. Barrett, J. Carl Hong, Jina Libutti, Steven K. Nunez, Nomeli P. TI Obesity Impairs Wound Healing in Ovariectomized Female Mice SO IN VIVO LA English DT Article DE Obesity; wound healing; ovariectomy; caloric restriction ID BONE-MINERAL DENSITY; CANCER; OVERWEIGHT; GROWTH; RISK AB Obesity is increasing worldwide. Estrogen protects female mice front gaining weight in contrast to ovariectomy. Excess weight can inhibit wound healing. We. determine the effects a obesity on wound healing in the presence and absence of estrogen. For this purpose, we generated (ovariectomized (OVX) and non-ovariectomized (NOVX)) lean mice by feeding a 30% calorie-restricted diet (CR), overweight mice a low-fat (LF) diet and obese mice a high-fat (HF) diet. CR mice had the lowest, LF an intermediate, and HF mice the highest body, weights. OVX exacerbated weight gain in female mice. Wounds healed fastest in CR mice regardless of estrogen status. Contrastingly,, wound healing in OVX obese female mice was delayed. In sum, OVX increased the propensity of gaining weight, CR mice healed wounds more rapidly than obese mice irrespective of estrogen status, and obesity it? the absence of estrogen impaired wound healing. C1 [Nunez, Nomeli P.] Univ Texas Austin, Coll Nat Sci, Sch Human Ecol, Dept Nutr Sci, Austin, TX 78712 USA. [Keck, Victoria A.] NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Barrett, J. Carl] Novartis Inst Biomed Res Inc, Cambridge, MA 02139 USA. [Libutti, Steven K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Surg, Bronx, NY 10467 USA. RP Nunez, NP (reprint author), Univ Texas Austin, Coll Nat Sci, Sch Human Ecol, Dept Nutr Sci, 1 Univ Stn A2703,PAI 5-14, Austin, TX 78712 USA. EM nomeli@mail.utexas.edu FU ACS RSG [CNE-113703]; NCI [1K22CA127519-01A1]; NIEHS National Institutes of Health [ES09145]; National Institute of Environmental Health Sciences Center [ES007784] FX This work was supported by grants ACS RSG CNE-113703 (NPN), NCI 1K22CA127519-01A1 (NPN), NIEHS National Institutes of Health ES09145, and National Institute of Environmental Health Sciences Center ES007784. NR 15 TC 7 Z9 7 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0258-851X J9 IN VIVO JI In Vivo PD JUL-AUG PY 2009 VL 23 IS 4 BP 515 EP 518 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 471SK UT WOS:000268078400002 PM 19567384 ER PT J AU De Angel, RE Berrigan, D Nunez, NP Hursting, SD Perkins, SN AF De Angel, Rebecca E. Berrigan, David Nunez, Nomeli P. Hursting, Stephen D. Perkins, Susan N. TI Dietary Calcium Source Influences Body Composition, Glucose Metabolism and Hormone Levels in a Mouse Model of Postmenopausal Obesity SO IN VIVO LA English DT Article DE Dairy; calcium supplement; DXA; ovariectomy; C57BL/6 mice ID INSULIN-RESISTANCE SYNDROME; BONE-MINERAL DENSITY; VITAMIN-D; DAIRY; WOMEN; MICE; SUPPLEMENTATION; CONSUMPTION; WEIGHT; GROWTH AB Background: The prevalence of obesity has risen dramatically, with postmenopausal women particularly prone to increased adiposity. Epidemiologic data suggest that dietary calcium, particularly from dairy products, can decrease weight gain. The aim of this study was to evaluate effects of different calcium sources in a mouse model of postmenopausal obesity. Materials and Methods: Ovariectomized C57BL/6 mice were randomized to either low-fat (LF) or high-fat (HF) diets containing either calcium phosphate from non-fat dried milk and whey mineral concentrate (dairy) or calcium carbonate (supplement). Results: Dairy, but not supplement, decreased weight gain and percent body fat in HF mice, with no effect on food consumption. Dairy improved insulin resistance and glucose tolerance, while supplement increased bone mineral density in LF mice. Dairy had no effect oil bone. Conclusion: The beneficial effects of dietary calcium on body weight and bone health after menopause may be significantly influenced by other dietary components. C1 [De Angel, Rebecca E.; Nunez, Nomeli P.; Hursting, Stephen D.; Perkins, Susan N.] Univ Texas Austin, Dept Nutr Sci, Austin, TX 78712 USA. [Berrigan, David] NCI, Bethesda, MD 20892 USA. [Hursting, Stephen D.] UT MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. RP Perkins, SN (reprint author), Univ Texas Austin, Dept Nutr Sci, 1 Univ Stn A2703, Austin, TX 78712 USA. EM perkinss@mail.utexas.edu FU Breast Cancer Research Foundation; US Department of Defense Congressionally Directed Breast Cancer Research Program [BC 053292] FX The authors would like to thank Nicole Smith and Mariam J. Ahmed for technical assistance. This work was funded in part by grants to Dr. Stephen Hursting from the Breast Cancer Research Foundation and from the US Department of Defense Congressionally Directed Breast Cancer Research Program (BC 053292). NR 38 TC 10 Z9 10 U1 0 U2 3 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0258-851X J9 IN VIVO JI In Vivo PD JUL-AUG PY 2009 VL 23 IS 4 BP 527 EP 535 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 471SK UT WOS:000268078400004 PM 19567386 ER PT J AU Tilly, K Bestor, A Dulebohn, DP Rosa, PA AF Tilly, Kit Bestor, Aaron Dulebohn, Daniel P. Rosa, Patricia A. TI OspC-Independent Infection and Dissemination by Host-Adapted Borrelia burgdorferi SO INFECTION AND IMMUNITY LA English DT Article ID OUTER-SURFACE PROTEIN; LYME-DISEASE SPIROCHETE; CRYSTAL-STRUCTURE; IMMUNE EVASION; ANTIBODY-RESPONSE; MAMMALIAN HOST; EXPRESSION; MICE; TICKS; VLSE AB Borrelia burgdorferi OspC is required for the spirochete to establish infection in a mammal by tick transmission or needle inoculation. After a brief essential period, the protein no longer is required and the gene can be shut off. Using a system in which spirochetes contain only an unstable wild-type copy of the ospC gene, we can obtain mice persistently infected with bacteria lacking OspC. We implanted pieces of infected mouse skin subcutaneously in naive mice, using donors carrying wild-type or ospC mutant spirochetes, and found that both could infect mice by this method, with similar numbers of wild-type or ospC mutant spirochetes disseminated throughout the tissues of recipient mice. Recipient mouse immune responses to tissue transfer-mediated infection with wild-type or ospC mutant spirochetes were similar. These experiments demonstrate that mammalian host-adapted spirochetes can infect and disseminate in mice in the absence of OspC, thereby circumventing this hallmark of tick-derived or in vitro-grown spirochetes. We propose a model in which OspC is one of a succession of functionally equivalent, essential proteins that are synthesized at different stages of mammalian infection. In this model, another protein uniquely present on host-adapted spirochetes performs the same essential function initially fulfilled by OspC. The strict temporal control of B. burgdorferi outer surface protein gene expression may reflect immunological constraints rather than distinct functions. C1 [Tilly, Kit; Bestor, Aaron; Dulebohn, Daniel P.; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Tilly, K (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM ktilly@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases; NIH FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 59 TC 23 Z9 23 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2009 VL 77 IS 7 BP 2672 EP 2682 DI 10.1128/IAI.01193-08 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 460XV UT WOS:000267227000009 PM 19398538 ER PT J AU Matsuura, G Morinaga, N Yahiro, K Komine, R Moss, J Yoshida, H Noda, M AF Matsuura, Gen Morinaga, Naoko Yahiro, Kinnosuke Komine, Reiko Moss, Joel Yoshida, Hideo Noda, Masatoshi TI Novel Subtilase Cytotoxin Produced by Shiga-Toxigenic Escherichia coli Induces Apoptosis in Vero Cells via Mitochondrial Membrane Damage SO INFECTION AND IMMUNITY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; DEATH DECISIONS; CHAPERONE BIP; CASPASE-12; TOXIN; ACTIVATION; PATHWAYS; FAMILY; MECHANISM; COMPLEX AB Subtilase cytotoxin (SubAB) is an AB5 cytotoxin produced by some strains of Shiga-toxigenic Escherichia coli. The A subunit is a subtilase-like serine protease and cleaves an endoplasmic reticulum chaperone, BiP, leading to transient inhibition of protein synthesis and cell cycle arrest at G(1) phase. Here we show that SubAB, but not the catalytically inactive mutant SubAB(S272A), induced apoptosis in Vero cells, as detected by DNA fragmentation and annexin V binding. SubAB induced activation of caspase-3, -7, and -8. Caspase-3 appeared earlier than caspase-8, and by use of specific caspase inhibitors, it was determined that caspase-3 may be upstream of caspase-8. A general caspase inhibitor blocked SubAB-induced apoptosis, detected by annexin V binding. SubAB also stimulated cytochrome c release from mitochondria, which was not suppressed by caspase inhibitors. In HeLa cells, Apaf-1 small interfering RNA inhibited caspase-3 activation, suggesting that cytochrome c might form an apoptosome, leading to activation of caspase-3. These data suggested that SubAB induced caspase-dependent apoptosis in Vero cells through mitochondrial membrane damage. C1 [Matsuura, Gen; Morinaga, Naoko; Yahiro, Kinnosuke; Komine, Reiko; Noda, Masatoshi] Chiba Univ, Grad Sch Med, Dept Mol Infectiol, Chiba, Japan. [Matsuura, Gen; Yoshida, Hideo] Chiba Univ, Grad Sch Med, Dept Pediat Surg, Chiba, Japan. [Yahiro, Kinnosuke; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Morinaga, N (reprint author), 1-8-1 Inohana,Chuo Ku, Chiba 2608670, Japan. EM nmorinaga@faculty.chiba-u.jp FU Intramural Research Program; NIH; NHLBI FX This work was supported by Grants-in-Aid of Scientific Research from the Ministry of Education, Science and Culture of Japan. J. Moss was supported by the Intramural Research Program, NIH, NHLBI. NR 33 TC 15 Z9 16 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUL PY 2009 VL 77 IS 7 BP 2919 EP 2924 DI 10.1128/IAI.01510-08 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 460XV UT WOS:000267227000034 PM 19380466 ER PT J AU Lombardo, F Ronca, R Rizzo, C Mestres-Simon, M Lanfrancotti, A Curra, C Fiorentino, G Bourgouin, C Ribeiro, JMC Petrarca, V Ponzi, M Coluzzi, M Arca, B AF Lombardo, Fabrizio Ronca, Raffaele Rizzo, Cinzia Mestres-Simon, Montserrat Lanfrancotti, Alessandra Curra, Chiara Fiorentino, Gabriella Bourgouin, Catherine Ribeiro, Jose M. C. Petrarca, Vincenzo Ponzi, Marta Coluzzi, Mario Arca, Bruno TI The Anopheles gambiae salivary protein gSG6: An anopheline-specific protein with a blood-feeding role SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE Anopheles gambiae; gSG6; Salivary glands; Saliva; Blood feeding ID ADULT FEMALE MOSQUITO; AEDES-AEGYPTI; GLAND TRANSCRIPTOME; ANTIBODY-RESPONSE; ARTHROPOD SALIVA; MALARIA; SIALOME; ANTIGENS; CATALOG; INSIGHT AB The Anopheles gambiae salivary gland protein 6 (gSG6) is a small protein specifically found in the salivary glands of adult female mosquitoes. We report here the expression of a recombinant form of the protein and we show that in vivo gSG6 is expressed in distal-lateral lobes and is secreted with the saliva while the female mosquito probes for feeding. Injection of gSG6 dsRNA into adult A. gambiae females results in decreased gSG6 protein levels, increased probing time and reduced blood feeding ability. gSG6 orthologs have been found so far only in the salivary glands of Anopheles stephensi and Anopheles funestus, both members of the Cellia subgenus. We report here the gSG6 sequence from five additional anophelines, four species of the A. gambiae complex and Anopheles freeborni, a member of the subgenus Anopheles. We conclude that gSG6 plays some essential blood feeding role and was recruited in the anopheline subfamily most probably after the separation of the lineage which gave origin to Cellia and Anopheles subgenera. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Ronca, Raffaele; Fiorentino, Gabriella; Arca, Bruno] Univ Naples Federico II, Dipartimento Biol Strutturale & Funz, I-80126 Naples, Italy. [Lombardo, Fabrizio; Rizzo, Cinzia; Mestres-Simon, Montserrat; Lanfrancotti, Alessandra; Coluzzi, Mario; Arca, Bruno] Univ Roma La Sapienza, Sez Parassitol, Dipartimento Sci Sanita Pubbl, I-00185 Rome, Italy. [Curra, Chiara; Ponzi, Marta] Ist Super Sanita, Dipartimento Malattie Infett Parassitarie & Immun, I-00161 Rome, Italy. [Bourgouin, Catherine] Inst Pasteur, Ctr Prod & Infect Anopheles, F-75724 Paris, France. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Petrarca, Vincenzo] Univ Roma La Sapienza, Dipartimento Genet & Biol Mol, I-00185 Rome, Italy. RP Arca, B (reprint author), Univ Naples Federico II, Dipartimento Biol Strutturale & Funz, Complesso Univ Monte S Angelo,Via Cinthia, I-80126 Naples, Italy. EM bruno.arca@unina.it RI Rizzo, Caterina/H-4092-2012; Bourgouin, Catherine/F-1253-2014; Lombardo, Fabrizio/J-8511-2014; Fiorentino, Gabriella/E-2843-2017; OI Rizzo, Caterina/0000-0002-5583-7508; Lombardo, Fabrizio/0000-0002-8563-0612; Fiorentino, Gabriella/0000-0002-4089-3822; Arca, Bruno/0000-0002-4029-0984; Ronca, Raffaele/0000-0003-2217-3378; Curra, Chiara/0000-0001-7851-1087; Ribeiro, Jose/0000-0002-9107-0818 FU BioMalPar European Network of Excellence [LSHP-CT-2004-503578] FX We wish to thank R. De Cristofaro (Catholic University, Rome), I. Francischetti (NIAID-NIH, Rockville MD), E. Ricca (University Federico II, Naples) and V. Barnaba (La Sapienza University, Rome) for their help with the functional assays; M. Ruzzi (La Tuscia University, Viterbo) and D. Soldati (imperial College, London) for the initial help with the Pichia pastoris expression system; G. Lycett (Liverpool School of Tropical Medicine, Liverpool) for kindly providing the pLL10 plasmid; A. della Torre (La Sapienza University, Rome) for making available genomic DNA from A. arabiensis, A. bwambae, A. melas and A. quadriannulatus A. FL was in part supported by the Fondazione "Istituto Pasteur-Cenci Bolognetti". RR was supported by Fondazione "Compagnia di San Paolo" (Torino) through the Italian Malaria Network. This work is part of the activities of the BioMalPar European Network of Excellence supported by a European grant (LSHP-CT-2004-503578) from the Priority 1 "Life Sciences, Genomics and Biotechnology for Health" in the 6th Framework Programme. NR 54 TC 32 Z9 33 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 EI 1879-0240 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD JUL PY 2009 VL 39 IS 7 BP 457 EP 466 DI 10.1016/j.ibmb.2009.04.006 PG 10 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 468CH UT WOS:000267790700005 PM 19442731 ER PT J AU Lee, JY Tuleuova, N Jones, CN Ramanculov, E Zern, MA Revzin, A AF Lee, Ji Youn Tuleuova, Nazgul Jones, Caroline N. Ramanculov, Erlan Zern, Mark A. Revzin, Alexander TI Directing hepatic differentiation of embryonic stem cells with protein microarray-based co-cultures SO INTEGRATIVE BIOLOGY LA English DT Article ID HEPATOCYTE-LIKE CELLS; IN-VITRO; PHOTOLITHOGRAPHY; SPECIFICATION; FIBROBLASTS; MODULATION; ATTACHMENT; EXPRESSION; ENDODERM; CULTURES AB Embryonic stem cells hold considerable promise in tissue engineering and regenerative medicine as a source of tissue-specific cells. However, realizing this promise requires novel methods for guiding lineage-specific differentiation of stem cells. In this study, we developed a micropatterned co-culture platform for stimulating hepatic differentiation of mouse embryonic stem cells (mESCs). Studies of mESC and hepatic cell adhesion preferences revealed that mESCs required fibronectin for attachment, while hepatic cells (HepG2) preferred collagen (1) substrate and did not adhere to fibronectin. Printing columns of collagen (1) and fibronectin spots (300 pin diameter), followed by sequential seeding of the two cell types, allowed the positioning of clusters of mESCs adjacent to groups of hepatic cells within the same microarray. These micropatterned co-cultures were maintained for up to two weeks in hepatic differentiation media supplemented. To examine the differentiation, mESCs were selectively extracted from the co-culture using laser microdissection and analyzed using real-time reverse transcriptase (RT)-polymerase chain reaction (PCR). These analyses revealed that mESCs co-cultured with HepG2 cells showed a decrease in pluripotency gene expression concomitant with up-regulation of endodermal genes. In addition, the co-culture format induced a significant increase in the expression of liver genes compared to mESCs cultured alone. In conclusion, micropatterned co-cultures of mESCs and hepatic cells showed a significant promise in driving stem cell differentiation towards hepatic phenotype. In the future, this cell culture platform will be further enhanced to enable efficient conversion of mouse and human ESCs to hepatocytes. C1 [Lee, Ji Youn; Tuleuova, Nazgul; Jones, Caroline N.; Revzin, Alexander] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. [Zern, Mark A.] Univ Calif Davis, Internal Med & Transplant Res Inst, Med Ctr, Davis, CA 95616 USA. RP Lee, JY (reprint author), Univ Calif Davis, Dept Biomed Engn, 451 E Hlth Sci St 2619, Davis, CA 95616 USA. EM arevzin@ucdavis.edu FU National Center for Biotechnology, Republic of Kazakhstan; NIH [DK073901] FX NT was supported by a fellowship from the National Center for Biotechnology, Republic of Kazakhstan. Financial support for this work was provided by NIH grant DK073901 awarded to AR. NR 34 TC 11 Z9 13 U1 2 U2 7 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1757-9694 J9 INTEGR BIOL JI Integr. Biol. PD JUL PY 2009 VL 1 IS 7 BP 460 EP 468 DI 10.1039/b905757a PG 9 WC Cell Biology SC Cell Biology GA 478CF UT WOS:000268564700004 PM 20023756 ER PT J AU Grigg, ME Sundar, N AF Grigg, Michael E. Sundar, Natarajan TI Sexual recombination punctuated by outbreaks and clonal expansions predicts Toxoplasma gondii population genetics SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Review DE Toxoplasma gondii; Population genetics; Virulence; Outbreaks; Sexual recombination; Clonality ID ENHYDRA-LUTRIS-NEREIS; FREE-RANGE CHICKENS; OCULAR TOXOPLASMOSIS; SEA OTTERS; WATERBORNE TOXOPLASMOSIS; DIFFERENT STRAINS; DRINKING-WATER; UNITED-STATES; GLOBAL REASSESSMENT; ORAL-TRANSMISSION AB The cosmopolitan parasitic pathogen Toxoplasma gondii is capable of infecting essentially any warm-blooded vertebrate worldwide, including most birds and mammals, and establishes chronic infections in one-third of the globe's human population. The success of this highly prevalent zoonosis is largely the result of its ability to propagate both sexually and clonally. Frequent genetic exchanges via sexual recombination among extant parasite lineages that mix in the definitive felid host produces new lines that emerge to expand the parasite's host range and cause outbreaks. Highly successful lines spread clonally via carnivorism and in some cases sweep to pandemic levels. The extent to which sexual reproduction versus clonal expansion shapes Toxoplasma's current, global population genetic structure is the central question this review will attempt to answer. Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. C1 [Grigg, Michael E.; Sundar, Natarajan] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20815 USA. RP Grigg, ME (reprint author), NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20815 USA. EM griggm@niaid.nih.gov FU National Science Foundation; NIH; NIAID FX I thank John Boothroyd, Patrick Keeling, Gary Holland, Jeff Jones, Melissa Miller, Pat Conrad, Bill Bowie, JP Dubey, David Roos and members of the Grigg laboratory for many helpful discussions; and David Sibley for access to intron sequencing data at www.toxohapmap.wustl.edu. This work was supported by the National Science Foundation and the Intramural Research Program of the NIH and NIAID. MEG is a scholar of the Canadian Institute for Advanced Research (CIFAR) Program for Integrated Microbial Biodiversity. NR 107 TC 64 Z9 66 U1 4 U2 13 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD JUL 1 PY 2009 VL 39 IS 8 BP 925 EP 933 DI 10.1016/j.ijpara.2009.02.005 PG 9 WC Parasitology SC Parasitology GA 458DH UT WOS:000266993800011 PM 19217909 ER PT J AU Mendoza, M Khanna, C AF Mendoza, Martin Khanna, Chand TI Revisiting the seed and soil in cancer metastasis SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Review DE Metastasis; Microenvironment; Stress; Seed; Soil ID ENDOTHELIAL GROWTH-FACTOR; LYMPH-NODE METASTASIS; SQUAMOUS-CELL CARCINOMA; CHEMOKINE RECEPTOR CCR7; NITRIC-OXIDE SYNTHASE; CHLORIDE CHANNEL PROTEIN; NECROSIS-FACTOR-ALPHA; INTERCELLULAR-ADHESION MOLECULE-1; EPITHELIAL-MESENCHYMAL TRANSITION; EXPERIMENTAL PULMONARY METASTASIS AB Metastasis remains the overwhelming cause of death for cancer patients. During metastasis, cancer cells will leave the primary tumor, intravasate into the bloodstream, arrest at a distant organ, and eventually develop into gross lesions at the secondary sites. This intricate process is influenced by innumerable factors and complex cellular interactions described in 1889 by Stephen Paget as the seed and soil hypothesis. In this review, we revisit this seed and soil hypothesis with an emerging understanding of the cancer cell (i.e. seed) and its microenvironment (i.e. soil). We will provide background to suggest that a critical outcome of the seed-soil interaction is resistance of the stresses that would otherwise impede metastasis. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Mendoza, Martin; Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, 37 Convent Dr,Room 2144, Bethesda, MD 20892 USA. EM KhannaC@mail.nih.gov NR 247 TC 67 Z9 70 U1 0 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD JUL PY 2009 VL 41 IS 7 BP 1452 EP 1462 DI 10.1016/j.biocel.2009.01.015 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 441KP UT WOS:000265768000002 PM 19401145 ER PT J AU Gao, Y Goldstein, AM Consonni, D Pesatori, AC Wacholder, S Tucker, MA Caporaso, NE Goldin, L Landi, MT AF Gao, Ying Goldstein, Alisa M. Consonni, Dario Pesatori, Angela C. Wacholder, Sholom Tucker, Margaret A. Caporaso, Neil E. Goldin, Lynn Landi, Maria Teresa TI Family history of cancer and nonmalignant lung diseases as risk factors for lung cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE family history; lung cancer; smoking; chronic bronchitis; pneumonia ID OBSTRUCTIVE PULMONARY-DISEASE; NONSMOKING CHINESE WOMEN; NEVER-SMOKERS; SUSCEPTIBILITY LOCUS; RESPIRATORY-DISEASE; CIGARETTE-SMOKING; HISTOLOGIC TYPES; GENE-EXPRESSION; UNITED-STATES; RELATIVES AB Family history (FH) of lung cancer is an established risk factor for lung cancer, but the modifying effect of smoking in relatives has been rarely examined. Also, the role of FH of nonmalignant lung diseases l lung cancer risk is not well known. We examined the role of FH of cancer and nonmalignant lung diseases in lung cancer risk overall, and by personal smoking, FH of smoking and histology in 1,946 cases and 2,116 population-based controls within the Environment And Genetics in Lung cancer Etiology (EAGLE) study. Odds ratios (ORs) and 95% CI from logistic regression were calculated adjusting for age, gender, residence, education and cigarette smoking. FH of lung cancer in any family member was associated with increased lung cancer risk (OR = 1.57, 95% CI = 1.25-1.98). The odds associated with fathers', mothers' and siblings' history of lung cancer were 1.41, 2.14 and 1.53, respectively. The associations were generally stronger in never smokers, younger subjects and for the adenocarinoma and squamous cell carcinoma subtypes. FH of chronic bronchitis and pneumonia was associated with increased (OR = 1.49, 95% CI = 1.21-1.80) and decreased (OR = 0.73, 95% CI = 0.61-0.87) lung cancer risk, respectively. FH of lung cancer and nonmalignant lung diseases affected lung cancer risk independently, and did not appear to be modified by FH of smoking. (C) 2007 UICC C1 [Gao, Ying; Goldstein, Alisa M.; Tucker, Margaret A.; Caporaso, Neil E.; Goldin, Lynn; Landi, Maria Teresa] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Consonni, Dario; Pesatori, Angela C.] Univ Milan, Epidemiol Res Ctr, EPOCA, I-20122 Milan, Italy. [Consonni, Dario; Pesatori, Angela C.] Osped Maggiore Policlin, Fdn IRCCS, Milan, Italy. [Wacholder, Sholom] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS 7114, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Tucker, Margaret/B-4297-2015; OI pesatori, angela/0000-0002-0261-3252 FU National Institutes of Health FX National Institutes of Health. NR 67 TC 22 Z9 23 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2009 VL 125 IS 1 BP 146 EP 152 DI 10.1002/ijc.24283 PG 7 WC Oncology SC Oncology GA 452VL UT WOS:000266569200018 PM 19350630 ER PT J AU Carman, S Kamangar, F Freedman, ND Wright, ME Dawsey, SM Dixon, LB Subar, A Schatzkin, A Abnet, CC AF Carman, Sarah Kamangar, Farin Freedman, Neal D. Wright, Margaret E. Dawsey, Sanford M. Dixon, L. Beth Subar, Amy Schatzkin, Arthur Abnet, Christian C. TI Vitamin E intake and risk of esophageal and gastric cancers in the NIH-AARP Diet and Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE esophageal cancer; gastric cancer; vitamin E; cohort; tocopherol ID RETIRED-PERSONS DIET; NUTRIENT INTAKE; AMERICAN-ASSOCIATION; NATIONAL-INSTITUTES; ANTIOXIDANT INTAKE; UNITED-STATES; MALE SMOKERS; CARDIA; SUPPLEMENTATION; POPULATION AB We investigated the association of dietary alpha-tocopherol, gamma-tocopherol and supplemental vitamin E intake with the risk of esophageal squamous cell carcinoma (n = 158), esophageal adenocarcinoma (n = 382), gastric cardia adenocarcinoma to = 320) and gastric noncardia adenocarcinoma (GNCA; n = 327) in the NIH-AARP Diet and Health Study, a cohort (of approximately 500,000 people. Data (in dietary and supplemental vitamin E intake were collected using a validated questionnaire at baseline and were analyzed using Cox regression models. Intakes were analyzed as continuous variables and as quartiles. For dietary alpha-tocopherol, we found some evidence of association with decreased esophageal squamous cell carcinoma and increased esophageal adenocarcinoma risk in the continuous analyses, with adjusted hazard ratios and 95% confidence intervals of 0.90 (0.81-0.99) and 1.05 (1.00-1.11), respectively, per 1.17 mg (half the interquartile range) increased intake. However, in quartile analyses, the p value for trend was nonsignificant for both these cancers. There was no association between dietary alpha-tocopherol and gastric cardia adenocarcinoma or GNCA. We observed no statistically significant associations with gamma-tocopherol. For supplemental vitamin E, the results were mainly null, except for a significantly lower risk of GNCA with higher doses of supplemental vitamin E. An increase of 71 mg/day (half the interquartile range) in supplemental vitamin E had an hazard ratio (95% confidence interval) of 0.92) (0.85-1.00) and the p value for trend in file quartile analysis was 0.015. (C) 2009 UICC C1 [Kamangar, Farin] NCI, Div Canc Epidemiol & Genet, NEB DCEG, Bethesda, MD 20892 USA. [Wright, Margaret E.] Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. [Dixon, L. Beth] NYU, Dept Nutr Food Stuides & Publ Hlth, New York, NY USA. [Subar, Amy] NCI, RFMMB DCCPS, Bethesda, MD 20892 USA. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, NEB DCEG, 6120 Execut Blvd,Room 3034, Bethesda, MD 20892 USA. EM kamangaf@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Intramural NIH HHS [Z01 CP010196-01] NR 36 TC 15 Z9 15 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2009 VL 125 IS 1 BP 165 EP 170 DI 10.1002/ijc.24342 PG 6 WC Oncology SC Oncology GA 452VL UT WOS:000266569200021 PM 19326432 ER PT J AU Mirabello, L Troisi, RJ Savage, SA AF Mirabello, Lisa Troisi, Rebecca J. Savage, Sharon A. TI International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE osteosarcoma; bone cancer; epidemiology; incidence ID CHILDHOOD-CANCER SURVIVAL; VITAMIN-D INSUFFICIENCY; PAGETS-DISEASE; BONE-TUMORS; OSTEOGENIC SARCOMA; EWINGS-SARCOMA; D DEFICIENCY; EUROPE; EPIDEMIOLOGY; SEX AB Osteosarcoma incidence rates in the United States peak in adolescence and in the elderly. The international patterns of osteosarcoma incidence in children have been described, whereas those for young, middle age or elderly adults have not. Using the Cancer Incidence in Five Continents, International Agency for Cancer Research database we compared incidence rates for children and adolescents (age 0-24 years, the middle age group (25-59 years) and elderly (>= 60 years) persons by world regions and individual countries. Overall, worldwide osteosarcoma incidence rates were quite similar in the younger age groups. The greatest variation in incidence rates was observed in the elderly. Published 2009 UICC. C1 [Mirabello, Lisa; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Troisi, Rebecca J.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca J.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7018, Rockville, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX Intramural Research Program of the National Institutes of Health. National Cancer Institute. Division of Cancer Epidemiology and Genetics. NR 44 TC 113 Z9 126 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUL 1 PY 2009 VL 125 IS 1 BP 229 EP 234 DI 10.1002/ijc.24320 PG 6 WC Oncology SC Oncology GA 452VL UT WOS:000266569200028 PM 19330840 ER PT J AU Nichols, L Tchounwou, PB Mena, L Sarpong, D AF Nichols, Lucersia Tchounwou, Paul B. Mena, Leandro Sarpong, Daniel TI The Effects of Environmental Factors on Persons Living with HIV/AIDS SO INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH LA English DT Article DE Human Immunodeficiency Virus (HIV); Acquired Immunodeficiency Syndrome (AIDS); Sexually Transmitted Disease (STD) patients; environmental barriers; quality of life AB In recent years, environmental awareness has received a great deal of public attention. However, little emphasis has been put on the influence of environmental factors (weather, personal attitudes, policies, physical structures, transportation, etc.) on the quality of life of persons infected with HIV/AIDS. The goal of this study was to assess the effect of selected environmental factors on the quality of life of persons affected by HIV/AIDS. To achieve this goal, the Craig Hospital Inventory of Environmental Factors (CHIEF) subscales including Policies, Physical Structure, Work/School, Attitudes/Support, and Service/Assistance were evaluated in patients selected from a STD/HIV clinic in Jackson, MS. They were chosen based on previously diagnosed HIV/AIDS status and age (16-95). Written consents, demographics sheets and self-administered questionnaires were obtained. Data were analyzed using Excel and SPSS software. Interviews started in July 2007 and ended in August, 2007. One hundred and thirteen patients responded. Participants were 72.6% (82) male, 26.5% (30) female and 0.9% (1) transgender. The median age of participants was 38.8 (18-63). Over 50% (65) had some college or higher education, and 35.4% reported annual incomes less than $10,000. Multivariate analysis showed marginal significance between disease diagnosis and gender (p < 0.10), and statistical significance between disease diagnosis and income (p = 0.03). Also, age (p = 0.01) and education (p = 0.03) were significant predictors in one of the subscales. The CHIEF subscales that showed the greatest significance among AIDS respondents were Attitudes and Support, and Government Policies with mean sensitivity scores of 1.39 and 1.42, respectively. The element with the least effect on AIDS patients was the Work/School subscale, with a mean score of 0.74. In general AIDS patients were disproportionately affected in all but one of the five subscales observed. Conversely those with HIV were more affected in the Work/School subscale with a mean score of 1.70. This proved to be the only subscale responsible for causing the greatest degree of perceived barriers for the HIV population. With a mean score of 0.75, Physical/Structural subscale showed the least negative impact on those infected HIV without AIDS. It is therefore recommended that the environmental barriers identified in this study be addressed in order to eliminate/minimize their negative effect and improve the quality of life of HIV/AIDS patients. C1 [Nichols, Lucersia; Tchounwou, Paul B.] Jackson State Univ, NIH, RCMI, Ctr Environm Hlth, Jackson, MS USA. [Mena, Leandro] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Sarpong, Daniel] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. RP Nichols, L (reprint author), Jackson State Univ, NIH, RCMI, Ctr Environm Hlth, Jackson, MS USA. EM Lucersia.Nichols@msdh.state.ms.us; paul.b.tchounwou@jsums.edu; Lmena@medicine.umsmed.edu; daniel.f.sarpong@jsums.edu FU National Institutes of Health RCMI-Center for Environmental Health FX The support of the National Institutes of Health RCMI-Center for Environmental Health at Jackson State University, and the Mississippi Department of Health, is gracefully acknowledged. NR 16 TC 1 Z9 1 U1 0 U2 4 PU MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI PI BASEL PA KANDERERSTRASSE 25, CH-4057 BASEL, SWITZERLAND SN 1660-4601 J9 INT J ENV RES PUB HE JI Int. J. Environ. Res. Public Health PD JUL PY 2009 VL 6 IS 7 BP 2041 EP 2054 DI 10.3390/ijerph6072041 PG 14 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 474XD UT WOS:000268317200008 PM 19742170 ER PT J AU Ye, XB Qian, HJ Xu, PC Zhu, L Longnecker, MP Fu, H AF Ye, Xibiao Qian, Haojun Xu, Peicheng Zhu, Lin Longnecker, Matthew P. Fu, Hua TI Nephrotoxicity, neurotoxicity, and mercury exposure among children with and without dental amalgam fillings SO INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH LA English DT Article DE Dental amalgam; Mercury; Nephrotoxicity; Neurotoxicity ID RANDOMIZED CLINICAL-TRIAL; ENVIRONMENTAL EXPOSURE; RESTORATIONS; EXCRETION AB Purpose: A scientific review panel for the US Food and Drug Administration (FDA) recently identified the need for more data on the health risk of mercury exposure from dental amalgam among susceptible populations. We evaluated impacts of low-level mercury exposure on renal function and neurobehavioral and neuropsychological performance among children. Methods: Dental histories for 403 children aged 7-11 years in five schools from Xuhui, Shanghai were checked by dentists. Of them, 198 with confirmed amalgam fillings were recruited (exposure group). Reference children (N = 205) were those who never had dental amalgam treatment. In May 2004, each child provided a urine sample for measurements of total mercury, N-acetyl-beta-D-glucosaminidase activity, microalbumin, and creatinine (Cr). The Child Behavior Checklist, Eysenck Personality Questionnaire, and an intelligence screening test were administered. Results: The geometric mean urinary mercury concentration was 1.6 mu g/g Cr for children with and 1.4 mu g/g Cr for children without amalgam fillings. No differences were found between children with and without fillings for either renal function biomarker, or on neurobehavioral, neuropsychological, or intelligence tests. Conclusions: Although urinary mercury concentration was slightly elevated among children with amalgam fillings, we found no evidence of adverse effects on the outcomes evaluated. These results agree with those from recent trials in developed countries. Published by Elsevier GmbH. C1 [Ye, Xibiao; Qian, Haojun; Fu, Hua] Fudan Univ, Dept Prevent Med, Sch Publ Hlth, Shanghai 20032, Peoples R China. [Ye, Xibiao; Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Xu, Peicheng; Zhu, Lin] Xuhui Dent Hosp, Shanghai 20032, Peoples R China. RP Ye, XB (reprint author), Fudan Univ, Dept Prevent Med, Sch Publ Hlth, POB 248,138 Yixueyuan Rd, Shanghai 20032, Peoples R China. EM yex2@niehs.nih.gov; hfu@fudan.edu.cn OI Longnecker, Matthew/0000-0001-6073-5322 FU Xuhui Department of Health, Shanghai [02123]; Intramural Research Program; National Institute of Environmental Health Sciences; National Institutes of Health FX This study was funded by Xuhui Department of Health, Shanghai (02123 to X.Y.). This study was supported in part by the Intramural Research Program, National Institute of Environmental Health Sciences, National Institutes of Health. NR 33 TC 13 Z9 16 U1 1 U2 4 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 1438-4639 J9 INT J HYG ENVIR HEAL JI Int. J. Hyg. Environ. Health. PD JUL PY 2009 VL 212 IS 4 BP 378 EP 386 DI 10.1016/j.ijheh.2008.09.004 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 451OB UT WOS:000266478400003 PM 18996050 ER PT J AU Hahn, Y Kim, DS Pastan, IH Lee, B AF Hahn, Yoonsoo Kim, Dong Seon Pastan, Ira H. Lee, Byungkook TI Anoctamin and transmembrane channel-like proteins are evolutionarily related SO INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE LA English DT Article DE anoctamin; transmembrane channel-like; ion channel; membrane topology ID GASTROINTESTINAL STROMAL TUMORS; TMC GENE FAMILY; MEMBRANE-PROTEIN; EPIDERMODYSPLASIA-VERRUCIFORMIS; TRANSCRIPTOME ANALYSIS; COMPLETE GENOMES; HEARING-LOSS; PROSTATE; TMEM16A; NGEP AB The anoctamin (ANO) family of proteins, consisting of 10 members in mammals, are transmembrane proteins that have Ca(2+)-activated Cl(-) channel activity. The transmembrane channel-like (TMC) family of proteins, consisting of 8 members in mammals, are also transmembrane proteins of which mutations are implicated in various human conditions, such as hearing loss and epidermodysplasia verruciformis. Here we show that ANO and TMC proteins share high sequence similarity and probably the same membrane topology, indicating that these proteins are evolutionarily related. We found many conserved amino acid residues between the two families of proteins, especially in regions spanning the transmembrane domains TM1, TM4-TM5, and TM6-TM7. These findings imply that these proteins form one large family, which we term ANO/TMC superfamily and that TMC proteins also function as channels for Cl- or other ions. The ANO/TMC superfamily proteins are present in almost all diverse groups of eukaryotic organisms, suggesting that the proteins function in important biological processes, such as ion homeostasis, in eukaryotic cells. C1 [Hahn, Yoonsoo; Kim, Dong Seon] Chung Ang Univ, Dept Life Sci, Seoul 156756, South Korea. [Pastan, Ira H.; Lee, Byungkook] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hahn, Y (reprint author), Chung Ang Univ, Dept Life Sci, 47 Heukseok Ro, Seoul 156756, South Korea. EM hahny@cau.ac.kr FU National Cancer Institute, National Institutes of Health; Chung-Ang University FX This research was partially supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health and partially by the Chung-Ang University Excellent Researcher Grant in 2009. NR 33 TC 8 Z9 8 U1 0 U2 6 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1107-3756 J9 INT J MOL MED JI Int. J. Mol. Med. PD JUL PY 2009 VL 24 IS 1 BP 51 EP 55 DI 10.3892/ijmm_00000205 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 460ZC UT WOS:000267230900008 PM 19513534 ER PT J AU Law, AJ Pei, Q Feldon, J Pryce, CR Harrison, PJ AF Law, Amanda J. Pei, Qi Feldon, Joram Pryce, Christopher R. Harrison, Paul J. TI Gene expression in the anterior cingulate cortex and amygdala of adolescent marmoset monkeys following parental separations in infancy SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Depression; mood disorder; sexual dimorphism; subgenual area; 5-HT(1A) receptor ID MAJOR-DEPRESSIVE-DISORDER; TREATMENT-RESISTANT DEPRESSION; MEDIAL PREFRONTAL CORTEX; DEEP BRAIN-STIMULATION; EARLY-LIFE STRESS; HIPPOCAMPAL-FORMATION; SEXUAL-DIMORPHISM; 5-HT1A RECEPTORS; DENDRITIC SPINES; MOOD DISORDERS AB Early life adversities are risk factors for later mood and emotional disorders. Repeated separation of infant marmosets from their parents provides a validated primate model of depression vulnerability, producing in-vivo biochemical and behavioural effects indicative of persistently altered stress reactivity and mild anhedonia. Here we report the long-term effect (in adolescence) of this intervention on the expression of synaptophysin, GAP-43, VGluT1, VGAT, MAP-2, spinophilin, and 5-HT(1A) and 5-HT(2A) receptors, in the anterior cingulate cortex (ACC; supragenual and subgenual areas) and amygdala (lateral, basal and central nuclei). These genes and regions are implicated in the response to stress or in mood disorder. The profile of 5-HT(1A) receptor binding in ACC was affected by early deprivation, notably in the subgenual region, with a decrease in deep laminae but an increase in superficial laminae. Following early deprivation, spinophilin mRNA was reduced in subgenual ACC. In the amygdala, no significant effects of the manipulation were seen, but expression of several transcripts was sexually dimorphic. There were correlations between expression of some transcripts and in-vivo measurements. The results show that early deprivation in a non-human primate has a selective long-term effect on expression of genes in the ACC, particularly the subgenual area. The results differ from those reported in the hippocampus of the same animals, indicating the presence of limbic region-specific long-term molecular responses to early life stress. C1 [Law, Amanda J.; Pei, Qi; Harrison, Paul J.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. [Law, Amanda J.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. [Feldon, Joram; Pryce, Christopher R.] Swiss Fed Inst Technol, Lab Behav Neurobiol, Schwerzenbach, Switzerland. [Pryce, Christopher R.] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland. RP Harrison, PJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. EM paul.harrison@psych.ox.ac.uk RI Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU Wellcome Trust; National Science Foundation, Switzerland [3167791.02]; National Center for Competence in Research: Swiss Etiological Study of Adjustment and Mental Health [51A240-104890] FX The study was funded by the Wellcome Trust, with additional support from the National Science Foundation, Switzerland (Project grant 3167791.02) and National Center for Competence in Research: Swiss Etiological Study of Adjustment and Mental Health (grant no. 51A240-104890). We thank Phil Burnet, Andrea Dettling, Helen Gordon-Andrews and Mary Walker for their expert contributions. NR 84 TC 22 Z9 23 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2009 VL 12 IS 6 BP 761 EP 772 DI 10.1017/S1461145708009723 PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 467FH UT WOS:000267722800005 PM 19102816 ER PT J AU Bachmann, RF Wang, Y Yuan, PX Zhou, RL Li, XX Alesci, S Du, J Manji, HK AF Bachmann, Rosilla F. Wang, Yun Yuan, Peixiong Zhou, Rulun Li, Xiaoxia Alesci, Salvatore Du, Jing Manji, Husseini K. TI Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bcl-2; lithium; methamphetamine; mitochondria; valproate ID INCREASES BCL-2 EXPRESSION; MOOD-STABILIZING AGENTS; CNS IN-VIVO; BIPOLAR DISORDER; OXIDATIVE-PHOSPHORYLATION; CYTOCHROME-C; PERMEABILITY TRANSITION; OXYGEN-CONSUMPTION; PREFRONTAL CORTEX; INDUCED APOPTOSIS AB Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrialty mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases ill mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia. C1 [Manji, Husseini K.] NIMH, NIH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, NIH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Bldg 35,1C912, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov RI Du, Jing/A-9023-2012 FU National Institute of Mental Health FX We acknowledge the support of the Intramural Research Program of the National Institute of Mental Health. We thank loline Henter and Holly Giesen for their invaluable editorial assistance. This work was undertaken under the auspices of the NIMH Intramural Program; Dr Manji is now at Johnson and Johnson Pharmaceutical Research and Development. NR 65 TC 62 Z9 66 U1 1 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2009 VL 12 IS 6 BP 805 EP 822 DI 10.1017/S1461145708009802 PG 18 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 467FH UT WOS:000267722800009 PM 19149911 ER PT J AU Rao, JS Rapoport, SI Kim, HW AF Rao, Jagadeesh S. Rapoport, Stanley I. Kim, Hyung-Wook TI Decreased GRK3 but not GRK2 expression in frontal cortex from bipolar disorder patients SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Bipolar disorder; brain; G-protein beta subunit; G-protein gamma subunit; GRK2; GRK3 ID COUPLED RECEPTOR KINASES; POSITRON-EMISSION-TOMOGRAPHY; BETA-GAMMA-SUBUNITS; ARACHIDONIC-ACID; MESSENGER-RNA; G-PROTEINS; RAT-BRAIN; UNANESTHETIZED RATS; SIGNAL-TRANSDUCTION; MOOD DISORDERS AB Overactivation of G-protein-mediated functions and altered G-protein regulation have been reported in bipolar disorder (BD) brain. Further, drugs effective in treating BD are reported to up-regulate expression of G-protein receptor kinase (GRK) 3 in rat frontal cortex. We therefore hypothesized that some G-protein subunits and GRK levels would be reduced in the brain of BD patients. We determined protein and mRNA levels of G-protein beta and gamma subunits, GRK2, and GRK3 in post-mortem frontal cortex from 10 BD patients and 10 age-matched controls by using immunoblots and real-time RT-PCR. There were statistically significant decreases in protein and mRNA levels of G-protein subunits beta and gamma and of GRK3 in BD brain but not a significant difference in the GRK2 level. Decreased expression of G-protein subunits and of GRK3 may alter neurotransmission, leading to disturbed cognition and behaviour in BD. C1 [Rao, Jagadeesh S.; Rapoport, Stanley I.; Kim, Hyung-Wook] NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, NIH, Brain Physiol & Metab Sect, 9000 Rockville Pike,Bldg 91S-126, Bethesda, MD 20892 USA. EM jrao@grc.nia.nih.gov RI Rao, Jagadeesh/C-1250-2009 FU National Institute on Aging, National Institutes of Health FX This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We thank Kathy Benjamin for critically reading the manuscript. NR 65 TC 13 Z9 15 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUL PY 2009 VL 12 IS 6 BP 851 EP 860 DI 10.1017/S146114570900025X PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 467FH UT WOS:000267722800013 PM 19400979 ER PT J AU Park, SK Kang, D Beane-Freeman, L Blair, A Hoppin, JA Sandler, DP Lynch, CF Knott, C Gwak, J Alavanja, M AF Park, Sue K. Kang, Daehee Beane-Freeman, Laura Blair, Aaron Hoppin, Jane A. Sandler, Dale P. Lynch, Charles F. Knott, Charles Gwak, Jin Alavanja, Michael TI Cancer Incidence Among Paraquat Exposed Applicators in the Agricultural Health Study Prospective Cohort Study SO INTERNATIONAL JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH LA English DT Article DE Paraquat; cancer incidence; non-Hodgkin's lymphoma; Agricultural Health Study ID NEUROBLASTOMA SH-SY5Y CELLS; NON-HODGKINS-LYMPHOMA; COSTA-RICA; PESTICIDE APPLICATORS; HERBICIDE PARAQUAT; INDUCED APOPTOSIS; TUMOR-CELLS; DNA-DAMAGE; II CELLS; RISK AB Paraquat (1,1'-dimethyl-4, 4'-bipyridinium dichloride) is a nonselective herbicide that is extremely toxic after acute exposure. It was once widely used in North America and is still used in some countries, including the United States. Although there is little firm evidence that paraquat is a carcinogen, previous Studies have suggested a potential relationship with some cancers. This prospective cohort Study was performed to evaluate the association between lifetime paraquat exposure and cancer incidence among licensed pesticide applicators with 9.1 years of median follow-up. The lifetime ever-use of paraquat was evaluated in 56,224 subjects at baseline and exposure-response relationship was evaluated in 24,667 subjects (44%) who provided detailed information on total life-time paraquat exposure in a second questionnaire. Among the total subjects, the risk for non-Hodgkin's lymphoma (NHL) in the exposed group was marginally elevated (Relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) compared to the non-exposed group. However, among the 24,667 applicators who Supplied total life-time exposure days, the highest tertile of lifetime exposure-days (LE) and intensity-weighted lifetime exposure-days (IWLE) was not significantly associated with NHL risk (RR, 1.57; 95%CI, 0.57-4.23 for LE; RR, 1.42; 95%CI, 0.40-4.71 for IWLE, respectively) and there was no significant exposure-response trend (p-trend > 0.1). There was Some suggestion of a possible link between paraquat exposure and NHL risk in humans, but die inconsistency in exposure level trend suggests that this could be a chance finding. C1 [Park, Sue K.; Beane-Freeman, Laura; Blair, Aaron; Alavanja, Michael] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Park, Sue K.; Kang, Daehee; Gwak, Jin] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Knott, Charles] Battelle Ctr Publ Hlth Res & Evaluat, Durham, NC USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. RP Alavanja, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8000, Bethesda, MD 20892 USA. EM suepark@snu.ac.kr; alavanjm@mail.nih.gov RI Kang, Dae Hee/E-8631-2012; Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health (Division of Cancer Epidemiology and Genetics of the National Cancer Institute and the National Institute of Environmental Health Sciences) FX Received from Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea (SKP, DK, JG); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA (SKP, LB-F, AB, MA); Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, North Carolina, USA (JAH, DPS); Department of Epidemiology, University of Iowa, Iowa, USA (CFL); Battelle/Centers for Public Health Research and Evaluation, Durham, North Carolina, USA (CK). This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (Division of Cancer Epidemiology and Genetics of the National Cancer Institute and the National Institute of Environmental Health Sciences). Send correspondence to: Michael Alavanja Ph.D., Division of Cancer, Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd., EPS 8000 Bethesda, MD 20892-7234; email: alavanjm@mail.nih.gov; Sue K. Park, M.D., Ph.D., Department of Preventive Medicine, Seoul National University College of Medicine, 28 Dachak-Ro, Jongro-Gu, Seoul 110-799, Republic of Korea; email: suepark@snu.ac.kr. NR 42 TC 1 Z9 1 U1 1 U2 4 PU ABEL PUBLICATION SERVICES PI BURLINGTON PA 1611 AQUINAS COURT, BURLINGTON, NC 27215 USA SN 1077-3525 J9 INT J OCCUP ENV HEAL JI Int. J. Occup. Environ. Health PD JUL-SEP PY 2009 VL 15 IS 3 BP 274 EP 281 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 475MC UT WOS:000268362600006 PM 19650582 ER PT J AU Douglas, PS Taylor, A Bild, D Bonow, R Greenland, P Lauer, M Peacock, F Udelson, J AF Douglas, Pamela S. Taylor, Allen Bild, Diane Bonow, Robert Greenland, Philip Lauer, Michael Peacock, Frank Udelson, James TI Outcomes Research in Cardiovascular Imaging Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE cardiovascular imaging; chest pain diagnosis; clinical trials ID CORONARY-ARTERY-DISEASE; ABDOMINAL AORTIC-ANEURYSM; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ISCHEMIC MITRAL REGURGITATION; INCREMENTAL PROGNOSTIC VALUE; RANDOMIZED CONTROLLED TRIAL; ACUTE MYOCARDIAL-INFARCTION; ASSOCIATION TASK-FORCE; INTIMA-MEDIA THICKNESS; ACUTE CARDIAC ISCHEMIA AB In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation. C1 [Douglas, Pamela S.] Duke Univ, Med Ctr, Div Cardiovasc Med, Durham, NC USA. [Taylor, Allen] Washington Hosp Ctr, Cardiovasc Res Inst, Dept Med, Washington, DC 20010 USA. [Bild, Diane] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Lauer, Michael] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Bonow, Robert; Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Peacock, Frank] Cleveland Clin, Cleveland, OH 44106 USA. [Udelson, James] Tufts Med Ctr, Div Cardiol, Boston, MA USA. RP Douglas, PS (reprint author), 7022 N Pavil DUMC,POB 17969, Durham, NC 27715 USA. EM pamela.douglas@duke.edu FU Abbott Labs; Abbott; BAS; Biosite; Brahms; Heartscape; Inovise; Inverness; EKR; Medicines Company; American College of Radiology Imaging Network (ACRIN); Lantheus Medical Imaging and Molecular Insight Pharmaceuticals FX Dr. Taylor has received research grant support (without salary compensation) and educational honoraria from Abbott Labs for the topic of HDL cholesterol and prevention. Dr. Greenland served as a consultant to GE and Toshiba, and received a small honorarium from Pfizer for a role on a Visiting Professor Selection Committee. Dr. Peacock is on the Scientific Advisory Board, or is a consultant or speaker for Abbott, Beckman Coulter, Biosite, Heartscape, Inovise, Inverness, Ortho Clinical Diagnostics, and The Medicines Company. He has received research grants from Abbott, BAS, Biosite, Brahms, Heartscape, Inovise, Inverness, EKR, and The Medicines Company. Also, he has an ownership interest in Vital Sensors. Dr. Udelson is co-PI of the ROMICAT-2 trial, sponsored by the American College of Radiology Imaging Network (ACRIN). He has received research funding and has served as a consultant to Lantheus Medical Imaging and Molecular Insight Pharmaceuticals. Drs. Douglas and Taylor are co-first authors. NR 70 TC 28 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD JUL PY 2009 VL 2 IS 7 BP 897 EP 907 DI 10.1016/j.jcmg.2009.01.018 PG 11 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 725OG UT WOS:000287654400015 PM 19608141 ER PT J AU Fife, KH Wu, JW Squires, KE Watts, DH Andersen, JW Brown, DR AF Fife, Kenneth H. Wu, Julia W. Squires, Kathleen E. Watts, D. Heather Andersen, Janet W. Brown, Darron R. TI Prevalence and Persistence of Cervical Human Papillomavirus Infection in HIV-Positive Women Initiating Highly Active Antiretroviral Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 17th Meeting of the International-Society-for-Sexually-Transmitted-Diseases-Research CY JUL 29-AUG 01, 2007 CL Seattle, WA SP Int Soc Sexually Transmitted Dis Res DE antiretroviral therapy; cervical dysplasia; HIV; human papillomavirus ID HUMAN-IMMUNODEFICIENCY-VIRUS; SQUAMOUS INTRAEPITHELIAL LESIONS; RANDOMIZED CONTROLLED-TRIAL; YOUNG-WOMEN; SEROPOSITIVE WOMEN; PARTICLE VACCINE; NEGATIVE WOMEN; GENITAL-TRACT; RISK-FACTORS; TYPE-16 AB Objective: To determine the prevalence of human papillomavirus (HPV) DNA in cervical specimens from treatment-naive women initiating highly active antiretroviral therapy (HAART) and explore the longitudinal association of HPV DNA with CD4 count and HIV viral load (VL). Methods: Women enrolled before HAART were evaluated at baseline, weeks 24, 48, and 96 with CD4 count, VL, and cervical swab for HPV DNA. Results: The 146 subjects had a median CD4 count of 238 cells per microliter and VL of 13,894 copies per milliliter. Ninety-seven subjects (66%) had HPV DNA detected in the baseline specimen including 90 subjects (62%) positive for I or more high-risk HPV types. HPV DNA detection declined to 49% at week 96 and that of a high risk HPV type to 39%. The duration of follow-up was associated with decreased detection of HPV DNA of any type (P = 0.045) and of high-risk HPV types (P = 0.003). There was at most a marginal association between HAART response and loss of detection of cervical HPV DNA. Conclusions: Women initiating HAART had a high prevalence of cervical HPV DNA that declined over 96 weeks of HAART. The relationship of CD4 count and VL response to the decline of cervical HPV DNA was not strong. C1 [Fife, Kenneth H.; Brown, Darron R.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Wu, Julia W.; Andersen, Janet W.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Squires, Kathleen E.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Watts, D. Heather] Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD USA. RP Fife, KH (reprint author), Indiana Univ, Sch Med, Dept Med, 545 Barnhill Dr,Room 435, Indianapolis, IN 46202 USA. EM kfife@iupui.edu FU NCRR NIH HHS [M01 RR000032, M01 RR000043, M01 RR000044, M01 RR000046, M01 RR000096, M01 RR000750, M01 RR000750-250289, RR-00032, RR000043, RR00044, RR00046, RR000750, RR00096]; NIAID NIH HHS [UM1 AI069452, AI 069434, AI 69471, AI027767, AI060354, AI069439, AI069452-01, AI069470, AI069472, AI069477, AI069495, AI069501, AI069532, AI25859, AI27664, AI27673, AI34853, AI38558, AI38855, AI46370, AI46381, AI50410, AI68634, AI68636, AI69411, AI69423-01, AI69494, AI69684, F32 AI069684, P30 AI027767, P30 AI050410, P30 AI060354, U01 AI025859, U01 AI025859-18, U01 AI027664, U01 AI027673, U01 AI027673-18, U01 AI034853, U01 AI038855, U01 AI046370, U01 AI046381, U01 AI068634, U01 AI068634-03, U01 AI068636, U01 AI068636-03, U01 AI069411, U01 AI069423, U01 AI069434, U01 AI069439, U01 AI069452, U01 AI069470, U01 AI069471, U01 AI069472, U01 AI069477, U01 AI069494, U01 AI069495, U01 AI069501, U01 AI069532, UM1 AI068634, UM1 AI068636, UM1 AI069411, UM1 AI069423, UM1 AI069434, UM1 AI069439, UM1 AI069470, UM1 AI069471, UM1 AI069472, UM1 AI069477, UM1 AI069494, UM1 AI069495, UM1 AI069501, UM1 AI069532]; NICHD NIH HHS [HD33345, N01HD33345] NR 42 TC 32 Z9 33 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2009 VL 51 IS 3 BP 274 EP 282 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 462UV UT WOS:000267383300006 PM 19387354 ER PT J AU Read, JS Mwatha, A Richardson, B Valentine, M Emel, L Manji, K Hoffman, I Sharma, U Goldenberg, RL Taha, TE AF Read, Jennifer S. Mwatha, Anthony Richardson, Barbra Valentine, Megan Emel, Lynda Manji, Karim Hoffman, Irving Sharma, Usha Goldenberg, Robert L. Taha, Taha E. TI Primary HIV-1 Infection Among Infants in Sub-Saharan Africa: HPTN 024 SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 17th International AIDS Conference CY AUG 03-08, 2008 CL Mexico City, MEXICO DE HIV-1; infant; primary infection ID IMMUNODEFICIENCY-VIRUS TYPE-1; RISK-FACTORS; TRANSMISSION; DIAGNOSIS; CHILDREN; TRIAL AB Objectives: Our objectives were to assess clinical signs and diagnoses associated with primary HIV-1 infection among infants. Methods: We analyzed data from a clinical trial (HIV Prevention Trials Network Protocol 024) in sub-Saharan Africa. Study visits were conducted at birth, at 4-6 weeks, and at 3, 6, 9, and 12 months. The study population comprised live born, singleton, first-born infants of HIV-1-infected women with negative HIV-1 RNA assays who were still breastfeeding at 4-6 weeks. Results: Of 1317 HIV-1-exposed infants, 84 became HIV-1 infected after 4-6 weeks and 1233 remained uninfected. There were 102 primary and 5650 nonprimary infection visits. The most common signs were cough and diarrhea, and the most common diagnoses were malaria and pneumonia. Primary infection was associated with significantly increased odds of diarrhea [odds ratio (OR) = 2.4], pneumonia (OR = 3.5), otitis media (OR = 3.1), and oral thrush (OR = 2.9). For the clinical signs and diagnoses evaluated, sensitivity was low (1%-16.7%) and specificity was high (88.2%-99%). Positive predictive values ranged from 0.1%-1.4%. Negative predictive values ranged from 28.0%-51.1%. Conclusions: Certain clinical signs and diagnoses, although more common during primary HIV-1 infection, had low sensitivity and high specificity. Efforts to expand access to laboratory assays for the diagnosis of primary HIV-1 infection among infants of HIV-1-infected women should be emphasized. C1 [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Ctr Res Mothers & Children,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mwatha, Anthony; Richardson, Barbra; Emel, Lynda] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Richardson, Barbra] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Valentine, Megan] Family Hlth Int, Dept Facil Sci, Durham, NC USA. [Manji, Karim] Muhimbili Univ Hlth & Allied Sci, Dept Pediat, Dar Es Salaam, Tanzania. [Hoffman, Irving] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Sharma, Usha] NIAID, Div Aids, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Goldenberg, Robert L.] Drexel Coll Med, Dept Obstet & Gynecol, Philadelphia, PA USA. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Read, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Ctr Res Mothers & Children,Dept Hlth & Human Serv, Execut Bldg,Room 4B11C,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. EM jennifer_read@nih.gov FU NIAID NIH HHS [U01 AI047972-01, N01 AI035173, N01 AI045200, N01-AI-35173-117/412, U01 AI047972, U01 AI048005, U01 AI048005-01, U01 AI048006, U01 AI048006-01, U01-AI-47972, U01-AI-48005, U01-AI-48006] NR 24 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD JUL 1 PY 2009 VL 51 IS 3 BP 317 EP 322 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 462UV UT WOS:000267383300012 PM 19367174 ER PT J AU Short, PF Bradley, CJ Yabroff, KR AF Short, Pamela Farley Bradley, Cathy J. Yabroff, K. Robin TI Employment Status Among Cancer Survivors SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Short, Pamela Farley] Penn State Univ, Dept Hlth Policy & Adm, University Pk, PA 16802 USA. [Bradley, Cathy J.] Virginia Commonwealth Univ, Med Coll Virginia, Massey Canc Ctr, Richmond, VA 23298 USA. [Yabroff, K. Robin] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Short, PF (reprint author), Penn State Univ, Dept Hlth Policy & Adm, University Pk, PA 16802 USA. EM cjbradley@vcu.edu NR 3 TC 2 Z9 2 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 1 PY 2009 VL 302 IS 1 BP 33 EP 33 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 464GH UT WOS:000267492800015 ER PT J AU Schaefer, GO Emanuel, EJ Wertheimer, A AF Schaefer, G. Owen Emanuel, Ezekiel J. Wertheimer, Alan TI The Obligation to Participate in Biomedical Research SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RETHINKING RESEARCH ETHICS; 20-YEAR FOLLOW-UP; CLINICAL-RESEARCH; BREAST-CANCER; DUTY; TRIALS; MASTECTOMY AB The current prevailing view is that participation in biomedical research is above and beyond the call of duty. While some commentators have offered reasons against this, we propose a novel public goods argument for an obligation to participate in biomedical research. Biomedical knowledge is a public good, available to any individual even if that individual does not contribute to it. Participation in research is a critical way to support an important public good. Consequently, all have a duty to participate. The current social norm is that individuals participate only if they have a good reason to do so. The public goods argument implies that individuals should participate unless they have a good reason not to. Such a shift would be of great aid to the progress of biomedical research, eventually making society significantly healthier and longer lived. JAMA. 2009;302(1):67-72 C1 [Schaefer, G. Owen; Emanuel, Ezekiel J.; Wertheimer, Alan] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Wertheimer, A (reprint author), NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. EM wertheimera@cc.nih.gov OI Schaefer, Gerald Owen/0000-0002-6915-6148 FU Intramural NIH HHS [NIH0013833506]; PHS HHS [NIH0013833506] NR 50 TC 62 Z9 62 U1 2 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 1 PY 2009 VL 302 IS 1 BP 67 EP 72 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 464GH UT WOS:000267492800023 PM 19567441 ER PT J AU Ward, M Liang, MH Burns, T Singh, G AF Ward, Michael Liang, Matthew H. Burns, Thomas Singh, Gurkirpal TI RA treatment study group: Improvement in RA management SO JOINT BONE SPINE LA English DT Article; Proceedings Paper CT 1st Conference of the European-American-Rheumatology-Association-Immunotherapy-in-Rheumatic-Di seases -Science & Clinical Practice CY FEB 25-28, 2009 CL Sonoma, CA SP European Amer Rheumatol Assoc Immunotherapy Rheumat Dis DE Rheumatoid arthritis; Methotrexate; Anti-TNF drugs; Treatment strategy; Infections; Orthopedics ID ELECTIVE ORTHOPEDIC-SURGERY; RHEUMATOID-ARTHRITIS; DISEASE C1 [Ward, Michael] NIAMSD, Bethesda, MD 20892 USA. [Liang, Matthew H.] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Burns, Thomas] Permanente Med Grp No Calif Santa Clara, Dept Med, Santa Clara, CA USA. [Singh, Gurkirpal] Stanford Univ, Sch Med, Div Gastroenterol & Hepatol, Palo Alto, CA 94304 USA. RP Ward, M (reprint author), NIAMSD, Bldg 10 Clin Res Ctr,Room 4-1339,10 Ctr Dr,MSC 14, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-04] NR 6 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 1297-319X J9 JOINT BONE SPINE JI Joint Bone Spine PD JUL PY 2009 VL 76 IS 4 BP 435 EP 437 DI 10.1016/j.jbspin.2009.05.003 PG 3 WC Rheumatology SC Rheumatology GA 476TK UT WOS:000268468100026 PM 19541527 ER PT J AU Schvey, NA Tanofsky-Kraff, M Yanoff, LB Checchi, JM Shomaker, LB Brady, S Savastano, DM Ranzenhofer, LM Yanovski, SZ Reynolds, JC Yanovski, JA AF Schvey, Natasha A. Tanofsky-Kraff, Marian Yanoff, Lisa B. Checchi, Jenna M. Shomaker, Lauren B. Brady, Sheila Savastano, David M. Ranzenhofer, Lisa M. Yanovski, Susan Z. Reynolds, James C. Yanovski, Jack A. TI Disordered-Eating Attitudes in Relation to Bone Mineral Density and Markers of Bone Turnover in Overweight Adolescents SO JOURNAL OF ADOLESCENT HEALTH LA English DT Article DE Adolescents; Bone turnover; Bone mineral density; Disordered-eating attitudes; Overweight; Cortisol ID PREMENOPAUSAL WOMEN; DIETARY RESTRAINT; PUBERTAL CHANGES; LUMBAR SPINE; YOUNG-WOMEN; CHILDREN; OBESE; DEPRESSION; CORTISOL; BODY AB Purpose: To examine the relationships between cognitive eating restraint and both bone mineral density (BMD) and markers of bone turnover in overweight adolescents. Methods: One hundred thirty-seven overweight (BMI 39.1 +/- 6.8 kg/m(2)) African American and Caucasian adolescent (age = 14.4 +/- 1.4 years) girls (66.4%) and boys were administered the Eating Disorder Examination (EDE) interview and Eating Inventory (EI) questionnaire and underwent dual energy X-ray absorptiometry (DXA) to measure total lumbar spine BMD. Markers of bone formation (serum bone specific alkaline phosphatase and osteocalcin), bone resorption (24-hour urine N-telopeptides), and stress (urine free cortisol) were measured. Results: After accounting for the contribution of demographics, height, weight, serum 25-hydroxy-vitamin D, and depressive symptoms, adolescents' weight concern, as assessed by interview, was a significant contributor to the model of urine free cortisol (beta = .30, p < .05). Shape concern, as also assessed by interview, was significantly associated with lumbar spine bone mineral density (beta = -.15, p < .05). Dietary restraint was not a significant predictor in any of these models. Conclusions: These findings suggest that among severely overweight adolescents, dissatisfaction with shape and weight may be salient stressors. Future research is required to illuminate the relationship between bone health and disordered-eating attitudes in overweight adolescents. (c) 2009 Society for Adolescent Medicine. All rights reserved. C1 [Schvey, Natasha A.; Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Ranzenhofer, Lisa M.] Uniformed Serv Univ Hlth Sci, Washington, DC USA. [Schvey, Natasha A.; Tanofsky-Kraff, Marian; Yanoff, Lisa B.; Checchi, Jenna M.; Shomaker, Lauren B.; Brady, Sheila; Savastano, David M.; Ranzenhofer, Lisa M.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH,DHHS, Rockville, MD USA. [Checchi, Jenna M.; Ranzenhofer, Lisa M.; Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, DHHS, Rockville, MD USA. [Reynolds, James C.] NIH, Dept Nucl Med, Hatfield Clin Res Ctr, DHHS, Rockville, MD USA. RP Tanofsky-Kraff, M (reprint author), Uniformed Serv Univ Hlth Sci, MPS, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mtanofsky@usuhs.mil OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural Research Program of the NIH [Z01-HD-00641]; National Institute of Child Health and Human Development; National Center on Minority Health and Health Disparities, NIH FX J. Yanovski is a Commissioned Officer in the United States Public Health Service, DHHS. This research was supported by the Intramural Research Program of the NIH, Grant Z01-HD-00641, from the National Institute of Child Health and Human Development (to J.A.Y.) and the National Center on Minority Health and Health Disparities, NIH (to J.A.Y.). NR 40 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1054-139X J9 J ADOLESCENT HEALTH JI J. Adolesc. Health PD JUL PY 2009 VL 45 IS 1 BP 33 EP 39 DI 10.1016/j.jadohealth.2008.12.020 PG 7 WC Psychology, Developmental; Public, Environmental & Occupational Health; Pediatrics SC Psychology; Public, Environmental & Occupational Health; Pediatrics GA 468JQ UT WOS:000267814200007 PM 19541247 ER PT J AU Friend, JC Hilligoss, DM Marquesen, M Wrick, J Estwick, T Turner, ML Cowen, EW Anderson, V Holland, SM Malech, HL AF Friend, Julia C. Hilligoss, Dianne M. Marquesen, Martha Wrick, Jean Estwick, Tyra Turner, Maria L. Cowen, Edward W. Anderson, Victoria Holland, Steven M. Malech, Harry L. TI Skin ulcers and disseminated abscesses are characteristic of Serratia marcescens infection in older patients with chronic granulomatous disease SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID OSTEOMYELITIS; FEATURES C1 [Friend, Julia C.; Hilligoss, Dianne M.; Marquesen, Martha; Wrick, Jean; Estwick, Tyra; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Anderson, Victoria; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Turner, Maria L.; Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Malech, HL (reprint author), NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hmalech@nih.gov OI Malech, Harry/0000-0001-5874-5775 FU Intramural NIH HHS [Z01 AI000645-16, Z01 AI000645-17] NR 8 TC 8 Z9 9 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD JUL PY 2009 VL 124 IS 1 BP 164 EP 166 DI 10.1016/j.jaci.2009.04.009 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 469OR UT WOS:000267909700022 PM 19477489 ER PT J AU Cabrera, JE Cagliero, C Quan, S Squires, CL Jin, DJ AF Cabrera, Julio E. Cagliero, Cedric Quan, Selwyn Squires, Catherine L. Jin, Ding Jun TI Active Transcription of rRNA Operons Condenses the Nucleoid in Escherichia coli: Examining the Effect of Transcription on Nucleoid Structure in the Absence of Transertion SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CHROMOSOME SEGREGATION; BACTERIAL CHROMATIN; FOLDED CHROMOSOME; DNA; POLYMERASE; COMPACTION; ORGANIZATION; CHLORAMPHENICOL; TRANSLATION; PROTEINS AB In Escherichia coli the genome must be compacted similar to 1,000-fold to be contained in a cellular structure termed the nucleoid. It is proposed that the structure of the nucleoid is determined by a balance of multiple compaction forces and one major expansion force. The latter is mediated by transertion, a coupling of transcription, translation, and translocation of nascent membrane proteins and/or exported proteins. In supporting this notion, it has been shown consistently that inhibition of transertion by the translation inhibitor chloramphenicol results in nucleoid condensation due to the compaction forces that remain active in the cell. Our previous study showed that during optimal growth, RNA polymerase is concentrated into transcription foci or "factories," analogous to the eukaryotic nucleolus, indicating that transcription and RNA polymerase distribution affect the nucleoid structure. However, the interpretation of the role of transcription in the structure of the nucleoid is complicated by the fact that transcription is implicated in both compacting forces and the expansion force. In this work, we used a new approach to further examine the effect of transcription, specifically from rRNA operons, on the structure of the nucleoid, when the major expansion force was eliminated. Our results showed that transcription is necessary for the chloramphenicol-induced nucleoid compaction. Further, an active transcription from multiple rRNA operons in chromosome is critical for the compaction of nucleoid induced by inhibition of translation. All together, our data demonstrated that transcription of rRNA operons is a key mechanism affecting genome compaction and nucleoid structure. C1 [Cabrera, Julio E.; Cagliero, Cedric; Jin, Ding Jun] Natl Canc Inst Frederick, Gene Regulat & Chromosome Biol Lab, Transcript Control Sect, NIH, Ft Detrick, MD 21702 USA. [Quan, Selwyn; Squires, Catherine L.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Jin, DJ (reprint author), Natl Canc Inst Frederick, Gene Regulat & Chromosome Biol Lab, Transcript Control Sect, NIH, 1050 Boyles St, Ft Detrick, MD 21702 USA. EM djjin@helix.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research and National Institutes of Health [GM24751] FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and National Institutes of Health grant GM24751 to C. L. S. NR 53 TC 55 Z9 56 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL 1 PY 2009 VL 191 IS 13 BP 4180 EP 4185 DI 10.1128/JB.01707-08 PG 6 WC Microbiology SC Microbiology GA 458JT UT WOS:000267015000014 PM 19395497 ER PT J AU Voth, DE Howe, D Beare, PA Vogel, JP Unsworth, N Samuel, JE Heinzen, RA AF Voth, Daniel E. Howe, Dale Beare, Paul A. Vogel, Joseph P. Unsworth, Nathan Samuel, James E. Heinzen, Robert A. TI The Coxiella burnetii Ankyrin Repeat Domain-Containing Protein Family Is Heterogeneous, with C-Terminal Truncations That Influence Dot/Icm-Mediated Secretion SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ANAPLASMA-PHAGOCYTOPHILUM ANKA; LEGIONELLA-PNEUMOPHILA DOTA; Q-FEVER; HOST-CELL; HUMAN MACROPHAGES; EFFECTOR PROTEINS; SYSTEM; TRANSLOCATION; INFECTION; GENES AB Coxiella burnetii is an obligate intracellular bacterium that directs biogenesis of a parasitophorous vacuole (PV) for replication. Effectors of PV maturation are likely translocated into the host cytosol by a type IV secretion system (T4SS) with homology to the Dot/Icm apparatus of Legionella pneumophila. Since secreted bacterial virulence factors often functionally mimic the activities of host proteins, prokaryotic proteins with eukaryotic features are considered candidate T4SS substrates. Genes encoding proteins with eukaryotic-type ankyrin repeat domains (Anks) were identified upon genome sequencing of the C. burnetii Nine Mile reference isolate, which is associated with a case of human acute Q fever. Interestingly, recent genome sequencing of the G and K isolates, derived from human chronic endocarditis patients, and of the Dugway rodent isolate revealed remarkable heterogeneity in the Ank gene family, with the Dugway isolate harboring the largest number of full-length Ank genes. Using L. pneumophila as a surrogate host, we identified 10 Dugway Anks and 1 Ank specific to the G and K endocarditis isolates translocated into the host cytosol in a Dot/Icm-dependent fashion. A 10-amino-acid C-terminal region appeared to be necessary for translocation, with some Anks also requiring the chaperone IcmS for secretion. Ectopically expressed Anks localized to a variety of subcellular regions in mammalian cells, including microtubules, mitochondria, and the PV membrane. Collectively, these data suggest that C. burnetii isolates translocate distinct subsets of the Ank protein family into the host cytosol, where they modulate diverse functions, some of which may be unique to C. burnetii pathotypes. C1 [Voth, Daniel E.; Howe, Dale; Beare, Paul A.; Heinzen, Robert A.] NIAID, Rocky Mt Labs, Coxiella Pathogenesis Sect, Intracellular Parasites Lab,NIH, Hamilton, MT 59840 USA. [Vogel, Joseph P.] Washington Univ, Dept Mol Microbiol, St Louis, MO 63110 USA. [Unsworth, Nathan; Samuel, James E.] Texas A&M Univ Syst Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. RP Heinzen, RA (reprint author), NIAID, Rocky Mt Labs, Coxiella Pathogenesis Sect, Intracellular Parasites Lab,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health National Institute of Allergy and Infectious Diseases. NR 58 TC 95 Z9 96 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL 1 PY 2009 VL 191 IS 13 BP 4232 EP 4242 DI 10.1128/JB.01656-08 PG 11 WC Microbiology SC Microbiology GA 458JT UT WOS:000267015000019 PM 19411324 ER PT J AU Gutierrez-Lugo, MT Baker, H Shiloach, J Boshoff, H Bewley, CA AF Gutierrez-Lugo, Maria-Teresa Baker, Heather Shiloach, Joseph Boshoff, Helena Bewley, Carole A. TI Dequalinium, a New Inhibitor of Mycobacterium tuberculosis Mycothiol Ligase Identified by High-Throughput Screening SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE competitive inhibitor; luminescent assay; mycothiol biosynthesis; screening; small molecular weight thiol ID 2-AMINO-2-DEOXY-ALPHA-D-GLUCOPYRANOSIDE LIGASE; L-CYSTEINE; GROWTH; ASSAY; SMEGMATIS; PROTEINS; ANALOGS; STRESS; FUSION; GENES AB Mycothiol ligase (Mshc) is a key enzyme in the biosynthesis of mycothiol, a small molecular weight thiol that is unique to actinomycetes and whose primary role is to maintain intracellular redox balance and remove toxins. Mshc catalyzes the adenosine triphosphate (ATP)-dependent condensation of cysteine and glucosamine-inositol (GI) to produce cysteine-glucosamine-inositol (CGI). Mshc is essential to mycobacterium tuberculosis and therefore represents an attractive target for chemotherapeutic intervention. a screening protocol was developed to identify Mshc inhibitors based on quantification of residual ATP using a coupled luminescent assay. the protocol was used to screen a library of 3100 compounds in a 384- well plate format (Z' >= 0.65). Fifteen hits (0.48%) were identified from the screen, and 2 hits were confirmed in a secondary assay that measures production of CGI. the structures of both hits contain N-substituted quinolinium moieties, and the more potent of the 2-namely, dequalinium chloride-inhibits Mshc with an IC(50) value of 24 +/- 1 mu M. Further studies showed dequalinium to be an ATP-competitive inhibitor of Mshc, to bind MshC with a K(D) of 0.22 mu M, and to inhibit the growth of m. tuberculosis under aerobic and anaerobic conditions with minimum inhibitory and anaerobic bactericidal concentrations of 1.2 and 0.3 mu g/mL, respectively. the screening protocol described is robust and has enabled the identification of new Mshc inhibitors. (Journal of Biomolecular screening 2009:643-652) C1 [Gutierrez-Lugo, Maria-Teresa; Baker, Heather; Bewley, Carole A.] NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20817 USA. [Shiloach, Joseph] NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20817 USA. [Boshoff, Helena] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, NIH, Bioorgan Chem Lab, 9000 Rockville Pike, Bethesda, MD 20817 USA. EM caroleb@mail.nih.gov FU NIH FX We thank Girma Woldemichael of the National cancer institute for generous assistance and contributory discussions pertaining to assay development and Jessica Keffer for assistance with antimicrobial assays. this work was supported in part by the intramural research Program, NIH (National institute of Diabetes and Digestive and Kidney Diseases, National institute of allergy and infectious Diseases), and the intramural AIDs targeted antiviral Program of the office Director, NIH (CAB). NR 33 TC 20 Z9 21 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2009 VL 14 IS 6 BP 643 EP 652 DI 10.1177/1087057109335743 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 471ZV UT WOS:000268098200006 PM 19525487 ER PT J AU Waybright, TJ Britt, JR McCloud, TG AF Waybright, Timothy J. Britt, John R. McCloud, Thomas G. TI Overcoming Problems of Compound Storage in DMSO: Solvent and Process Alternatives SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article CT 47th Annual Meeting of the American-Society of Pharmacognosy CY AUG, 2006 CL Arlington, VA SP Amer Soc Pharmacognosy DE DMSO; precipitation; solubility; cosolvent ID HIV-1 NUCLEOCAPSID PROTEIN; DIMETHYL-SULFOXIDE; IDENTIFICATION; SIMULATIONS; PERMEABILITY; INHIBITION; SOLUBILITY; ACTIVATION; EXPRESSION; DYNAMICS AB The common practice of preparing storage libraries of compounds in 100% DMSO solution well in advance of bioassay brings with it difficulties that affect the accuracy of the data obtained. This publication presents a series of studies done on a subset of compounds that are difficult to bioassay because they precipitate from DMSO solution. These compounds are members of a frequently used, diverse compound library of the sort commonly used in the high-throughput screening (HTS) environment. Experiments were performed to determine the concentration of drug in solution above the precipitate, observe the time course and effect of various mixtures of solvents upon precipitation, measure the viscosity of cosolvents to determine compatibility with HTS, determine water absorption rates for various solvent combinations, and investigate resolubilization techniques to ensure proper drug solution for HTS. Recommendations are made on how to best maximize the probability that problem compounds will remain in solution, be accurately transferred during assay plate production, and, as a result, be accurately bioassayed at the specified molar concentration. (Journal of Biomolecular Screening 2009:708-715) C1 [Waybright, Timothy J.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Britt, John R.; McCloud, Thomas G.] SAIC Frederick Inc, Nat Prod Support Grp, Appl Dev Res Support Program, Frederick, MD USA. RP McCloud, TG (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, POB B,Bldg 431, Frederick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov NR 29 TC 12 Z9 13 U1 2 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD JUL PY 2009 VL 14 IS 6 BP 708 EP 715 DI 10.1177/1087057109335670 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 471ZV UT WOS:000268098200013 PM 19531665 ER PT J AU Yang, YZ Kozin, SH AF Yang, Yingzi Kozin, Scott H. TI Cell Signaling Regulation of Vertebrate Limb Growth and Patterning SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article; Proceedings Paper CT 6th Triennial Symposium on Science and the Surgery of Congenital Upper-Limb Malformations CY NOV 07-08, 2008 CL Minneapolis, MN ID APICAL ECTODERMAL RIDGE; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME; SONIC-HEDGEHOG; POLARIZING ACTIVITY; FEEDBACK LOOP; CHICK LIMB; MOUSE; BUD; GENE; GLI3 RP Yang, YZ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 49,Room 4A68,49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM Yingzi@mail.nih.gov; skozin@shrinenet.org NR 42 TC 3 Z9 3 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL PY 2009 VL 91A BP 76 EP 80 DI 10.2106/JBJS.I.00079 PG 5 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 466PG UT WOS:000267673900012 PM 19571072 ER PT J AU Wollert, T Yang, D Ren, XF Lee, HH Im, YJ Hurley, JH AF Wollert, Thomas Yang, Dong Ren, Xuefeng Lee, Hyung Ho Im, Young Jun Hurley, James H. TI The ESCRT machinery at a glance SO JOURNAL OF CELL SCIENCE LA English DT Article ID STRUCTURAL BASIS; III RECOGNITION; CELL-DIVISION; VPS4; COMPLEX; CYTOKINESIS; PROTEINS; MIDBODY; PATHWAY; BIOGENESIS C1 [Wollert, Thomas; Yang, Dong; Ren, Xuefeng; Lee, Hyung Ho; Im, Young Jun; Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Wollert, Thomas/0000-0001-9732-4789 FU Intramural NIH HHS NR 38 TC 50 Z9 52 U1 1 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL PY 2009 VL 122 IS 13 BP 2163 EP 2166 DI 10.1242/jcs.029884 PG 4 WC Cell Biology SC Cell Biology GA 459LX UT WOS:000267105100001 PM 19535731 ER PT J AU Langer, HF Chavakis, T AF Langer, Harald F. Chavakis, Triantafyllos TI Leukocyte-endothelial interactions in inflammation SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE endothelial cells; adhesion; leukocytes; platelets; inflammation ID JUNCTIONAL ADHESION MOLECULE; GLYCOPROTEIN IB-ALPHA; NEUTROPHIL TRANSENDOTHELIAL MIGRATION; ISCHEMIA-REPERFUSION INJURY; INTEGRIN MAC-1 CD11B/CD18; RECRUITMENT IN-VIVO; CELL-CELL CONTACTS; P-SELECTIN; COUNTER-RECEPTOR; VE-CADHERIN AB Introduction Adhesion molecules Leukocyte margination, capture and cell rolling Activation and adhesion of leukocytes Transmigration Endogenous inhibitors of leukocyte adhesion Platelet-leukocyte crosstalk Conclusions At sites of inflammation, infection or vascular injury local proinflammatory or pathogen-derived stimuli render the luminal vascular endothelial surface attractive for leukocytes. This innate immunity response consists of a well-defined and regulated multi-step cascade involving consecutive steps of adhesive interactions between the leukocytes and the endothelium. During the initial contact with the activated endothelium leukocytes roll along the endothelium via a loose bond which is mediated by selectins. Subsequently, leukocytes are activated by chemokines presented on the luminal endothelial surface, which results in the activation of leukocyte integrins and the firm leukocyte arrest on the endothelium. After their firm adhesion, leukocytes make use of two transmigration processes to pass the endothelial barrier, the transcellular route through the endothelial cell body or the paracellular route through the endothelial junctions. In addition, further circulating cells, such as platelets arrive early at sites of inflammation contributing to both coagulation and to the immune response in parts by facilitating leukocyte-endothelial interactions. Platelets have thereby been implicated in several inflammatory pathologies. This review summarizes the major mechanisms and molecules involved in leukocyte-endothelial and leukocyte-platelet interactions in inflammation. C1 [Langer, Harald F.; Chavakis, Triantafyllos] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Langer, HF (reprint author), 10 Ctr Dr,5B17, Bethesda, MD 20892 USA. EM langerh@mail.nih.gov; chavakist@mail.nih.gov FU National Cancer Institute; German Academy of Sciences (Leopoldina) FX The work was supported by the NIH Intramural Research Program, National Cancer Institute and the German Academy of Sciences (Leopoldina). NR 149 TC 120 Z9 124 U1 1 U2 22 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD JUL PY 2009 VL 13 IS 7 BP 1211 EP 1220 DI 10.1111/j.1582-4934.2009.00811.x PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 478LG UT WOS:000268589200003 PM 19538472 ER PT J AU Lozito, TP Taboas, JM Kuo, CK Tuan, RS AF Lozito, Thomas P. Taboas, Juan M. Kuo, Catherine K. Tuan, Rocky S. TI Mesenchymal Stem Cell Modification of Endothelial Matrix Regulates Their Vascular Differentiation SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE PERIVASCULAR NICHE; MESENCHYMAL STEM CELLS; ENDOTHELIAL CELLS; EXTRACELLULAR MATRIX; EXTRACELLULAR MATRIX MODIFICATIONS ID BONE MORPHOGENETIC PROTEIN; BASEMENT-MEMBRANE MATRIX; MARROW STROMAL CELLS; GROWTH-FACTOR-BETA; EXTRACELLULAR-MATRIX; CHONDROGENIC DIFFERENTIATION; IV COLLAGEN; ANGIOGENESIS; LAMININ-5; BINDING AB Mesenchymal stem cells (MSCs) respond to a variety of differentiation signal provided by their local environments. A large portion of these signals originate from the extracellular matrix (ECM). At the same time, MSCs secrete various matrix-altering agents, including proteases, that alter ECM-encoded differentiation signals. Here we investigated the interactions between MSC and ECM produced by endothelial cells (EC-matrix), focusing not only on the differentiation signals provided by EC-matrix, but also on MSC-alteration of these signals and the resultant affects on MSC differentiation. MSCs were cultured on EC-matrix modified in one of three distinct ways. First, MSCs cultured on native EC-matrix underwent endothelial cell (EC) differentiation early during the culture period and smooth muscle cell (SMC) differentiation at later time points. Second, MSCs cultured on crosslinked EC-matrix, which is resistant to MSC modification, differentiated towards an EC lineage only. Third, MSCs cultured on EC-matrix pre-modified by MSCs underwent SMC-differentiation only. These MSC-induced matrix alterations were found to deplete the factors responsible for EC-differentiation, yet activate the SMC-differentiation factors. In conclusion, our results demonstrate that the EC-matrix contains factors that support MSC differentiation into both ECs and SMCs, and that these factors are modified by MSC-secreted agents. By analyzing the framework by which EC-matrix regulates differentiation in MSCs, we have uncovered evidence of a feedback system in which MSCs are able to alter the very matrix signals acting upon them. J. Cell. Biochem. 107: 706-713, Published 2009 Wiley-Liss, Inc. C1 [Lozito, Thomas P.; Taboas, Juan M.; Kuo, Catherine K.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1140,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIAMS IRP [Z01AR41131] FX NIAMS IRP; Grant number: Z01AR41131. NR 47 TC 32 Z9 33 U1 3 U2 20 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL 1 PY 2009 VL 107 IS 4 BP 706 EP 713 DI 10.1002/jcb.22166 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 468JL UT WOS:000267813600016 PM 19415686 ER PT J AU Lozito, TP Kuo, CK Taboas, JM Tuan, RS AF Lozito, Thomas P. Kuo, Catherine K. Taboas, Juan M. Tuan, Rocky S. TI Human Mesenchymal Stem Cells Express Vascular Cell Phenotypes Upon Interaction With Endothelial Cell Matrix SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE PERIVASCULAR NICHE; MESENCHYMAL STEM CELLS; ENDOTHELIAL CELLS; EXTRACELLULAR MATRIX ID SMOOTH-MUSCLE-CELLS; HUMAN BONE-MARROW; GROWTH-FACTOR; IN-VITRO; STROMAL CELLS; DIFFERENTIATION; PERICYTES; VIVO; PROTEOGLYCANS; ADHESION AB Mesenchymal stem cells (MSCs) are thought to occupy a perivascular niche where they are exposed to signals originating from vascular cells. This study focused on the effects of endothelial cell (EC)-derived signals on MSC differentiation toward vascular cell lineages. Upon co-culture with two types of ECs, macrovascular (macro) ECs and microvascular (micro) ECs, the former caused MSCs to increase expression of both EC and smooth muscle cell (SMC) markers, while the latter induced expression of EC markers only. These marker changes in MSCs were linked to the extracellular matrixes secreted by the ECs (EC-matrix) rather than soluble EC-secreted factors. Beyond enhanced marker expression, EC-matrix also induced functional changes in MSCs indicative of development of a genuine vascular cell phenotype. These included enhanced incorporation into vessels and cytoskeletal localization of vascular SMC-specific contractile elements. The bioactivity of EC-matrix was sensitive to EDTA washes and required sulfated glycosaminoglycans. However, neither soluble VEGF nor substrate surfaces coated with fibronectin, collagen type IV, or laminin recreated the effects of EC-matrix on MSC vascular differentiation. In conclusion, these results identified EC-matrix as a critical regulator of vascular cell differentiation of MSCs. Elucidating these MSC-EC-matrix interactions and identifying the specific EC-matrix components involved will shed light on the perivascular signals seen by MSCs in vivo. J. Cell. Biochem. 107: 714-722, 2009. Published 2009 Wiley-Liss, Inc. C1 [Lozito, Thomas P.; Kuo, Catherine K.; Taboas, Juan M.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, Dept Hlth & Human Serv, NIH, Bldg 50,Room 1140,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIAMS IRP [ZO1AR41131] FX NIAMS IRP; Grant number: ZO1AR41131. NR 33 TC 63 Z9 65 U1 3 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL 1 PY 2009 VL 107 IS 4 BP 714 EP 722 DI 10.1002/jcb.22167 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 468JL UT WOS:000267813600017 PM 19415687 ER PT J AU Pandhare, J Donald, SP Cooper, SK Phang, JM AF Pandhare, Jui Donald, Steven P. Cooper, Sandra K. Phang, James M. TI Regulation and Function of Proline Oxidase Under Nutrient Stress SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE PROLINE OXIDASE; NUTRIENT STRESS; RAPAMYCIN; AMPK ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; CELL-SURVIVAL; CANCER-CELLS; APOPTOSIS; OXIDATION; OXYGEN; ACID; DELTA-1-PYRROLINE-5-CARBOXYLATE; INTERCONVERSIONS AB Under conditions of nutrient stress, cells switch to a survival mode catabolizing cellular and tissue constituents for energy. Proline metabolism is especially important in nutrient stress because proline is readily available from the breakdown of extracellular matrix (ECM), and the degradation of proline through the proline cycle initiated by proline oxidase (POX), a mitochondrial inner membrane enzyme, can generate ATP. This degradative pathway generates glutamate and a-ketoglutarate, products that can play an anaplerotic role for the TCA cycle. In addition the proline cycle is in a metabolic interlock with the pentose phosphate pathway providing another bioenergetic mechanism. Herein we have investigated the role of proline metabolism in conditions of nutrient stress in the RKO colorectal cancer cell line. The induction of stress either by glucose withdrawal or by treatment with rapamycin, stimulated degradation of proline and increased POX catalytic activity. Under these conditions POX was responsible, at least in part, for maintenance of ATP levels. Activation of AMP-activated protein kinase (AMPK), the cellular energy sensor, by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), also markedly upregulated POX and increased POX-dependent ATP levels, further supporting its role during stress. Glucose deprivation increased intracellular proline levels, and expression of POX activated the pentose phosphate pathway. Together, these results suggest that the induction of proline cycle under conditions of nutrient stress may be a mechanism by which cells switch to a catabolic mode for maintaining cellular energy levels. J. Cell. Biochem. 107: 759-768, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Pandhare, Jui; Donald, Steven P.; Phang, James M.] NCI, Metab & Canc Susceptibil Sect, Lab Comparat, Ctr Canc Res, Ft Detrick, MD 21702 USA. [Cooper, Sandra K.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Lab Comparat, Ctr Canc Res, Bldg 538,Room 144, Ft Detrick, MD 21702 USA. EM phang@ncifcrf.gov FU National Institutes of Health [N01-C0-12400]; National Institutes of Health, NCI, Center for Cancer Research (intramural Research Program) FX National Institutes of Health; Grant number: N01-C0-12400; Grant sponsor: National Institutes of Health, NCI, Center for Cancer Research (intramural Research Program). NR 30 TC 35 Z9 36 U1 1 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD JUL 1 PY 2009 VL 107 IS 4 BP 759 EP 768 DI 10.1002/jcb.22174 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 468JL UT WOS:000267813600022 PM 19415679 ER PT J AU Henning, EC Ruetzler, CA Gaudinski, MR Hu, TCC Latour, LL Hallenbeck, JM Warach, S AF Henning, Erica C. Ruetzler, Christl A. Gaudinski, Martin R. Hu, Tom C-C Latour, Lawrence L. Hallenbeck, John M. Warach, Steven TI Feridex preloading permits tracking of CNS-resident macrophages after transient middle cerebral artery occlusion SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article; Proceedings Paper CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA DE Feridex; inflammation; macrophages; MRI; stroke ID SUPERPARAMAGNETIC IRON-OXIDE; CENTRAL-NERVOUS-SYSTEM; BONE-MARROW; INFLAMMATORY RESPONSE; MONOCLONAL-ANTIBODIES; MULTIPLE-SCLEROSIS; BRAIN INFLAMMATION; MICROGLIAL CELLS; DENDRITIC CELLS; CONTRAST AGENTS AB At this time, the pathophysiology of macrophage involvement and their role in stroke progression are poorly understood. Recently, T(2)- and T(2)*-weighted magnetic resonance imaging (MRI), after intravenous administration of iron-oxide particles, have been used to understand the inflammatory cascade. Earlier studies report that image enhancement after stroke is from iron-laden macrophages; however, they do not account for potential blood-brain barrier disruption and nonspecific contrast enhancement. In this study, spontaneously hypertensive rats were preloaded with Feridex 7 days before stroke, permitting the labeling of bone-marrow-derived macrophages. Three-dimensional gradient-echo imaging showed average signal decreases of 13% to 23% in preloaded animals, concentrated on the lesion periphery and reaching a maximum on days 2 to 4 after stroke. Immunohistochemistry showed ED-2(+), PB(+), MHC-II(+) and TNF-alpha(+) perivascular macrophages (PVM), meningeal macrophages (MM), and choroid plexus macrophages (CPM). ED-1(+) and IBA(+) tissue macrophages and/or activated microglia were located throughout the lesion, but were PB(-). These findings indicate the following: (1) Feridex preloading permits tracking of the central nervous system (CNS)-resident macrophages (PVM, MM, and CPM) and (2) CNS-resident macrophages likely play an integral role in the inflammatory cascade through antigen presentation and expression of proinflammatory cytokines. Further refinement of this method should permit noninvasive monitoring of inflammation and potential evaluation of antiinflammatory therapies in preclinical models of stroke. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1229-1239; doi: 10.1038/jcbfm.2009.48; published online 6 May 2009 C1 [Henning, Erica C.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bethesda, MD 20892 USA. [Ruetzler, Christl A.; Hallenbeck, John M.] Natl Inst Neurol Disorders & Stroke, Clin Invest Sect, NIH, Bethesda, MD 20892 USA. [Hu, Tom C-C] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Henning, EC (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bldg 10,Room B1D733,10 Ctr Dr,MSC 1063, Bethesda, MD 20892 USA. EM henninge@ninds.nih.gov RI Henning, Erica/E-8542-2010 FU Intramural NIH HHS [Z01 NS002924-12, Z01 NS003044-01, NIH0012172661] NR 37 TC 27 Z9 29 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2009 VL 29 IS 7 BP 1229 EP 1239 DI 10.1038/jcbfm.2009.48 PG 11 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 464DQ UT WOS:000267485800001 PM 19417758 ER PT J AU Tomasi, G Bertoldo, A Bishu, S Unterman, A Smith, CB Schmidt, KC AF Tomasi, Giampaolo Bertoldo, Alessandra Bishu, Shrinivas Unterman, Aaron Smith, Carolyn Beebe Schmidt, Kathleen C. TI Voxel-based estimation of kinetic model parameters of the L-[1-(11)C]leucine PET method for determination of regional rates of cerebral protein synthesis: validation and comparison with region-of-interest-based methods SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE brain; leucine; parametric imaging; positron emission tomography; protein synthesis ID POSITRON EMISSION TOMOGRAPHY; GLUCOSE-UTILIZATION; AMINO-ACIDS; TISSUE; BRAIN; MOUSE; TIME; PERFORMANCE AB We adapted and validated a basis function method (BFM) to estimate at the voxel level parameters of the kinetic model of the L-[1-(11)C] leucine positron emission tomography ( PET) method and regional rates of cerebral protein synthesis (rCPS). In simulation at noise levels typical of voxel data, BFM yielded low-bias estimates of rCPS; in measured data, BFM and nonlinear least-squares parameter estimates were in good agreement. We also examined whether there are advantages to using voxel-level estimates averaged over regions of interest (ROIs) in place of estimates obtained by directly fitting ROI time-activity curves (TACs). In both simulated and measured data, fits of ROI TACs were poor, likely because of tissue heterogeneity not taken into account in the kinetic model. In simulation, rCPS determined from fitting ROI TACs was substantially overestimated and BFM-estimated rCPS averaged over all voxels in an ROI was slightly underestimated. In measured data, rCPS determined by regional averaging of voxel estimates was lower than rCPS determined from ROI TACs, consistent with simulation. In both simulated and measured data, intersubject variability of BFM-estimated rCPS averaged over all voxels in a ROI was low. We conclude that voxelwise estimation is preferable to fitting ROI TACs using a homogeneous tissue model. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 1317-1331; doi: 10.1038/jcbfm.2009.52; published online 13 May 2009 C1 [Bishu, Shrinivas; Unterman, Aaron; Smith, Carolyn Beebe; Schmidt, Kathleen C.] NIMH, Sect Neuroadaptat & Prot Metab, Bethesda, MD 20892 USA. [Tomasi, Giampaolo] Yale Univ, Dept Diagnost Radiol, New Haven, CT 06510 USA. [Bertoldo, Alessandra] Univ Padua, Dept Informat Engn, Padua, Italy. RP Schmidt, KC (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, Bldg 10,Rm 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. EM schmidtk@intra.nimh.nih.gov OI Bertoldo, Alessandra/0000-0002-6262-6354 FU Intramural NIH HHS [ZIA MH000889-30] NR 34 TC 15 Z9 15 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2009 VL 29 IS 7 BP 1317 EP 1331 DI 10.1038/jcbfm.2009.52 PG 15 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 464DQ UT WOS:000267485800009 PM 19436319 ER PT J AU Zanuy, D Ballano, G Jimenez, AI Casanovas, J Haspel, N Cativiela, C Curco, D Nussinov, R Aleman, C AF Zanuy, David Ballano, Gema Jimenez, Ana I. Casanovas, Jordi Haspel, Nurit Cativiela, Carlos Curco, David Nussinov, Ruth Aleman, Carlos TI Protein Segments with Conformationally Restricted Amino Acids Can Control Supramolecular Organization at the Nanoscale SO JOURNAL OF CHEMICAL INFORMATION AND MODELING LA English DT Article ID BETA-HELIX PROTEINS; X-RAY-DIFFRACTION; SIDE-CHAIN; BUILDING-BLOCKS; C-ALPHA,ALPHA-DIALKYLATED GLYCINES; STRUCTURAL VERSATILITY; NANOSTRUCTURE DESIGN; CYCLOPROPANE ANALOG; MOLECULAR-DYNAMICS; 1-AMINOCYCLOPENTANE-1-CARBOXYLIC ACID C1 [Zanuy, David; Aleman, Carlos] Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. [Ballano, Gema; Jimenez, Ana I.; Cativiela, Carlos] Univ Zaragoza, Dept Quim Organ, Inst Ciencia Mat Aragon, CSIC, E-50009 Zaragoza, Spain. [Casanovas, Jordi] Univ Lleida, Dept Quim, Escola Politecn Super, E-25001 Lleida, Spain. [Haspel, Nurit] Rice Univ, Dept Comp Sci, Houston, TX 77005 USA. [Curco, David] Univ Barcelona, Dept Engn Quim, Fac Quim, E-08028 Barcelona, Spain. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Dept Human Genet Sackler, Sch Med, IL-69978 Tel Aviv, Israel. [Aleman, Carlos] Univ Politecn Cataluna, Ctr Res Nanoengn, E-08028 Barcelona, Spain. [Haspel, Nurit] Tel Aviv Univ, Dept Comp Sci, Tel Aviv, Israel. RP Zanuy, D (reprint author), Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, Diagonal 647, E-08028 Barcelona, Spain. EM david.zanuy@upc.edu; ruthnu@helix.nih.gov; carlos.aleman@upc.edu RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178; FU Ministerio de Educacion y Ciencia [CTQ2007-62245]; Gobierno de Aragon [E40]; Generalitat de Catalunya; National Cancer Institute, National Institutes of Health [NOI-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research FX Gratitude is expressed to the Centre de Supercomputacio de Catalunya (CESCA) and to the Barcelona Supercomputing Center (BSC) for computational facilities. We also acknowledge the National Cancer Institute for partial allocation of computing time and staff support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center. Classic calculations were partially formed by utilizing the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD ( http://biowulf.nih.gov). Financial support from the Ministerio de Educacion y Ciencia (project CTQ2007-62245, Ramon y Cajal contract for DZ) and Gobierno de Aragon (research group E40) is gratefully acknowledged. Support for the research of C.A. was received through the prize "ICREA Academia" for excellence in research funded by the Generalitat de Catalunya. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NOI-CO-12400. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 56 TC 9 Z9 9 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1549-9596 J9 J CHEM INF MODEL JI J. Chem Inf. Model. PD JUL PY 2009 VL 49 IS 7 BP 1623 EP 1629 DI 10.1021/ci9001487 PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Computer Science, Information Systems; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Chemistry; Computer Science GA 472NN UT WOS:000268138900001 PM 19548653 ER PT J AU Popat, VB Calis, KA Vanderhoof, VH Cizza, G Reynolds, JC Sebring, N Troendle, JF Nelson, LM AF Popat, Vaishali B. Calis, Karim A. Vanderhoof, Vien H. Cizza, Giovanni Reynolds, James C. Sebring, Nancy Troendle, James F. Nelson, Lawrence M. TI Bone Mineral Density in Estrogen-Deficient Young Women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PREMATURE OVARIAN FAILURE; DIETARY CALCIUM INTAKE; AFRICAN-AMERICAN; FRACTURE RISK; OSTEOPOROSIS; AMENORRHEA; HEALTH; PREVALENCE; ADULTS; WHITE AB Context: Osteoporosis primarily affects postmenopausal women. However, young women with estrogen deficiency also are at increased risk for low bone density. Objective: The aim of the study was to assess bone density and associated risk factors for reduced bone density in young, estrogen-deficient women using primary ovarian insufficiency (POI) as the disease model. Design and Setting: We conducted a cross-sectional study at a tertiary care research center. Participants: We studied women with POI (n = 442), concurrent controls (n = 70), and matched controls from NHANES III (n = 353). Primary Outcome Measure: We measured bone mineral density (BMD) using dual-energy x-ray absorptiometry. Results: Patients on average had 2-3% lower BMD at L1-L4, femoral neck, and total hip (P < 0.01 at all sites). The modifiable risk factors for BMD below the expected range for age (Z-score < - 2) were: more than 1-yr delay in diagnosis of estrogen deficiency (P = 0.018), low (< 32 ng/ml) vitamin D levels (P = 0.002), estrogen replacement nonadherence (P = 0.002), low calcium intake (P = 0.005), and lack of exercise (P = 0.005). As compared to Caucasians, African-American and Asian women with POI were 3.18 and 4.34 times more likely, respectively, to have Z-scores below - 2 (P = < 0.0001 for both). Race was an overall risk factor, but on regression modeling, not an independent predictor of low bone density. Conclusions: Women with POI have lower bone density compared to regularly menstruating women. Comparedto Caucasians, minority women with estrogen deficiency are more likely to have BMD below the expected range for age. This racial disparity appears to be related to a combined effect of several modifiable risk factors. Delay in diagnosis of POI also contributes to reduced bone density by delaying proper therapy.(J Clin Endocrinol Metab 94: 2277-2283, 2009) C1 [Popat, Vaishali B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Radiol, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Sebring, Nancy] NIH, Dept Nutr, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Cizza, Giovanni] Natl Inst Diabet & Digest Dis, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Troendle, James F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, NIH, Bethesda, MD 20892 USA. RP Popat, VB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Integrat Reprod Med Unit, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, Room 1-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM popatv@mail.nih.gov; Lawrence_Nelson@nih.gov FU National Institutes of Health; U.S. Public Health Service FX This work was supported by Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. V.H.V., N.G.S., and L.M.N. are Commissioned Officers in the U.S. Public Health Service. NR 29 TC 51 Z9 51 U1 2 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2277 EP 2283 DI 10.1210/jc.2008-1878 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500013 PM 19401379 ER PT J AU Mahabadi, V Amory, JK Swerdloff, RS Bremner, WJ Page, ST Sitruk-Ware, R Christensen, PD Kumar, N Tsong, YY Blithe, D Wang, C AF Mahabadi, Vahid Amory, John K. Swerdloff, Ronald S. Bremner, William J. Page, Stephanie T. Sitruk-Ware, Regine Christensen, Peter D. Kumar, Narender Tsong, Yun-Yen Blithe, Diana Wang, Christina TI Combined Transdermal Testosterone Gel and the Progestin Nestorone Suppresses Serum Gonadotropins in Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the Endocrine-Society CY JUN 15-18, 2008 CL San Francisco, CA SP Endocrine Soc ID MALE HORMONAL CONTRACEPTION; DEPOT MEDROXYPROGESTERONE ACETATE; NORETHISTERONE ENANTHATE; ORAL LEVONORGESTREL; HYPOGONADAL MEN; SEXUAL FUNCTION; CLINICAL-TRIAL; PHARMACOLOGICAL PROFILE; HUMAN SPERMATOGENESIS; INTEGRATED ANALYSIS AB Context: Testosterone (T) plus progestin combinations are the most promising hormonal male contraceptives. Nestorone (NES), a progestin without estrogenic or androgenic activity, when combined with T may be an excellent candidate for male contraception. Objective: Our objective was to determine the effect of transdermal NES gel alone or with T gel on gonadotropin suppression. Design and Setting: The randomized, unblinded clinical trial was conducted at two academic medical centers. Participants: A total of 140 healthy male volunteers participated. Interventions: One hundred subjects were randomized initially (20 per group) to apply NES gel 2 or 4 mg, T gel 10 g, or T gel 10 g plus NES gel 2 or 4 mg daily for 20 d. Because only about half of the subjects in T plus NES 4 mg group suppressed serum gonadotropins to 0.5 IU/liter or less (suboptimal suppression), two additional groups of 20 men were randomized to apply daily T gel 10 g plus NES gel 6 or 8 mg. Main Outcome Variable: Suppression of serum LH and FSH concentrations to 0.5 IU/liter or less after treatment was the main outcome variable. Results: A total of 119 subjects were compliant with gel applications with few study-related adverse events. NES alone reduced gonadotropins significantly but less than T gel alone. Combined T gel 10g plus NES gel 6 or 8 mg suppressed both serum gonadotropins to 0.5 IU/liter or less in significantly more men than either gel alone. Conclusion: Transdermal NES gel alone had gonadotropin suppression activity. Combined transdermal NES (6 or 8 mg) plus T gel demonstrated safe and effective suppression of gonadotropins, justifying a longer-term study of this combination for suppression of spermatogenesis. (J Clin Endocrinol Metab 94: 2313-2320, 2009) C1 [Mahabadi, Vahid; Swerdloff, Ronald S.; Christensen, Peter D.; Wang, Christina] Harbor UCLA Med Ctr, Dept Med, Div Endocrinol, Torrance, CA 90509 USA. Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Amory, John K.; Bremner, William J.; Page, Stephanie T.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Swerdloff, Ronald S.; Kumar, Narender; Tsong, Yun-Yen] Populat Council, Ctr Biomed Res, New York, NY 10021 USA. [Blithe, Diana] NICHHD, Contracept & Reprod Hlth Branch, NIH, Rockville, MD 20852 USA. RP Wang, C (reprint author), Gen Clin Res Ctr, 1000 W Carson St, Torrance, CA 90509 USA. EM wang@labiomed.org FU NCRR NIH HHS [M01 RR000425, M01 RR00425]; NIA NIH HHS [K23 AG027238, K23 AG027238-03]; PHS HHS [HHSN275200403370I, HHSN275200403369I] NR 45 TC 27 Z9 27 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2313 EP 2320 DI 10.1210/jc.2008-2604 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500018 PM 19366848 ER PT J AU Schwartz, AV Garnero, P Hillier, TA Sellmeyer, DE Strotmeyer, ES Feingold, KR Resnick, HE Tylavsky, FA Black, DM Cummings, SR Harris, TB Bauer, DC AF Schwartz, Ann V. Garnero, Patrick Hillier, Teresa A. Sellmeyer, Deborah E. Strotmeyer, Elsa S. Feingold, Kenneth R. Resnick, Helaine E. Tylavsky, Frances A. Black, Dennis M. Cummings, Steven R. Harris, Tamara B. Bauer, Douglas C. CA Hlth Aging Body Composition Study TI Pentosidine and Increased Fracture Risk in Older Adults with Type 2 Diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLYCATION END-PRODUCTS; COLLAGEN CROSS-LINKS; BONE-MINERAL DENSITY; VERTEBRAL FRACTURES; NONENZYMATIC GLYCATION; BODY-COMPOSITION; I COLLAGEN; WOMEN; MEN; GLYCOXIDATION AB Context: Type 2 diabetes is associated with higher fracture risk at a given bone mineral density. Advanced glycation endproducts (AGEs) accumulate in bone collagen with age and diabetes and may weaken bone. Objective: The aim was to determine whether urine pentosidine, an AGE, was associated with fractures in older adults with and without diabetes. Design: We performed an observational cohort study. Setting: We used data from the Health, Aging and Body Composition prospective study of white and black, well-functioning men and women ages 70-79 yr. Participants: Participants with(n = 501) and with out(n = 427) diabetes were matched on gender, race, and study site. Predictor: Urine pentosidine was assayed from frozen stored baseline specimens. Main Outcome Measures: Incident clinical fractures and baseline vertebral fractures were measured. Results: Despite higher bone mineral density, clinical fracture incidence (14.8 vs. 12.6%) and vertebral fracture prevalence (2.3 vs. 2.9%) were not lower in those with diabetes (P > 0.05). In multivariable models, pentosidine was associated with increased clinical fracture incidence in those with diabetes [relative hazard, 1.42; 95% confidence interval (CI), 1.10, 1.83, for 1 SD increase in log pentosidine] but not in those without diabetes (relative hazard, 1.08; 95% CI, 0.79, 1.49; P value for interaction = 0.030). In those with diabetes, pentosidine was associated with increased vertebral fracture prevalence (adjusted odds ratio, 5.93; 95% CI, 2.08, 16.94, for 1 SD increase in log pentosidine) but not in those without diabetes (adjusted odds ratio, 0.74; 95% CI, 0.30, 1.83; P value for interaction = 0.005). Conclusions: Higher pentosidine levels are a risk factor for fracture in older adults with diabetes and may account in part for reduced bone strength in type 2 diabetes. (J Clin Endocrinol Metab 94: 2380-2386, 2009) C1 [Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94107 USA. [Garnero, Patrick] Hop Edouard Herriot, F-69003 Lyon, France. [Garnero, Patrick] Ctr Clin & Basic Res Synarc, F-69003 Lyon, France. [Hillier, Teresa A.] Kaiser Permanente Ctr Hlth Res, Portland, OR 97227 USA. [Strotmeyer, Elsa S.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Resnick, Helaine E.] Amer Assoc Homes & Serv Aging, Washington, DC 20008 USA. [Tylavsky, Frances A.] Univ Tennessee, Hlth Sci Ctr, Memphis, TN 38163 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, San Francisco, CA 94115 USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. RP Schwartz, AV (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, 185 Berry St,Suite 5700, San Francisco, CA 94107 USA. EM Aschwartz@psg.ucsf.edu RI Strotmeyer, Elsa/F-3015-2014; OI Strotmeyer, Elsa/0000-0002-4093-6036 FU National Institutes of Health; National Institute on Aging (NIA) [NIA N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103, NIA R01 AG17482]; American Diabetes Association Junior Faculty Award; Alliance for Better Bone Health FX Disclosure Summary: T.A.H., D.E.S., E.S.S., K.R.F., H.E.R., F.A.T., D.M.B., S.R.C., T.B.H. and D.C.B. have nothing to declare. A.V.S. and P. G. received research grant support from the Alliance for Better Bone Health (Procter & Gamble and Aventis). NR 37 TC 94 Z9 97 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2380 EP 2386 DI 10.1210/jc.2008-2498 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500028 PM 19383780 ER PT J AU Louiset, E Stratakis, CA Perraudin, V Griffin, KJ Libe, R Cabrol, S Feve, B Young, J Groussin, L Bertherat, J Lefebvre, H AF Louiset, Estelle Stratakis, Constantine A. Perraudin, Veronique Griffin, Kurt J. Libe, Rossella Cabrol, Sylvie Feve, Bruno Young, Jacques Groussin, Lionel Bertherat, Jerome Lefebvre, Herve TI The Paradoxical Increase in Cortisol Secretion Induced by Dexamethasone in Primary Pigmented Nodular Adrenocortical Disease Involves a Glucocorticoid Receptor-Mediated Effect of Dexamethasone on Protein Kinase A Catalytic Subunits SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CARNEY COMPLEX; ADRENAL-HYPERPLASIA; CUSHINGS-SYNDROME; TUMORS; EXPRESSION; GENE; PHOSPHODIESTERASE; MUTATIONS; CLASSIFICATION; INDIVIDUALS AB Context: Primary pigmented nodular adrenocortical disease (PPNAD) results in most cases from mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene. Patients with PPNAD exhibit a paradoxical increase in cortisol secretion in response to dexamethasone. Objective: The aim was to investigate the mechanism of the action of dexamethasone on adrenocortical cells removed from patients with PPNAD and a transgenic model of PPNAD [Tg(tTA/X2AS) mice]. Design and Setting: We performed an in vitro study in an academic research laboratory. Patients: Eleven patients with histologically proven PPNAD were included in the study. Intervention: Cultured PPNAD cells were incubated with dexamethasone in the presence of various modulators of the cAMP/PKA pathway and the glucocorticoid receptor antagonist RU486. Main Outcome Measure: Cortisol and corticosterone were measured by radio immunological assays in cell culture supernatants. Results: Dexamethasone stimulated in vitro cortisol secretion from PPNAD tissues in six patients. The stimulatory effect of dexamethasone on cortisol release was not reduced by the adenylyl cyclase inhibitor SQ22536 or potentiated by the phosphodiesterase inhibitor IMBX and the cAMP analog 8Br-cAMP. Conversely, the PKA inhibitor H89 and RU486 inhibited the cortisol response to dexamethasone. Dexamethasone had no effect on cortisol production from normal human adrenocortical cells but stimulated corticosteroidogenesis in the presence of RU486. Similarly, dexamethasone failed to influence corticosterone release by adrenocortical cells removed from Tg(tTA/X2AS) mice but stimulated corticosteroidogenesis in the presence of RU 486. Conclusions: These results indicate that, in human PPNAD tissues, dexamethasone paradoxically stimulates cortisol release through a glucocorticoid receptor-mediated effect on PKA catalytic subunits. (J Clin Endocrinol Metab 94: 2406-2413, 2009) C1 [Louiset, Estelle; Perraudin, Veronique; Lefebvre, Herve] Univ Rouen, INSERM,U413,EA4310, Lab Differentiat & Neuronal & Neuroendocrine Comm, Inst Federatif Rech Multidisciplinaires Peptides, F-76821 Mont St Aignan, France. [Stratakis, Constantine A.; Griffin, Kurt J.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. [Libe, Rossella; Groussin, Lionel; Bertherat, Jerome] Univ Paris 05, Ctr Hosp Univ Cochin, Dept Endocrinol, F-75014 Paris, France. [Libe, Rossella; Groussin, Lionel; Bertherat, Jerome] Univ Paris 05, Inst Cochin, INSERM U567, CNRS,UMR 8104,Inst Federatif Rech 116, F-75014 Paris, France. [Cabrol, Sylvie] Univ Paris 06, Hosp Trousseau, Dept Pediat Endocrinol, F-75571 Paris, France. [Feve, Bruno; Young, Jacques] Univ Paris 11, Dept Endocrinol, Hosp Bicetre, F-94275 Le Kremlin Bicetre, France. [Lefebvre, Herve] Univ Rouen, Inst Biomed Res, Univ Hosp Rouen, Dept Endocrinol, F-76031 Rouen, France. RP Lefebvre, H (reprint author), Ctr Hosp Univ Rouen, Hosp Boisguilaume, Dept Endocrinol,INSERM,U413,EA4310, Inst Federatif Rech Multidisciplinaires Peptides, F-76031 Rouen, France. EM herve.lefebvre@chu-rouen.fr FU INSERMU [413/EA4310, IFRMP23]; Carney Complex Network; U.S. National Institutes of Health [Z01-HD-000642-04]; CHU de Rouen; Reseau COMETE; Assistance Publique-Hopitaux de Paris; Conseil Regional de Haute-Normandie FX This work was supported by INSERMU 413/EA4310, IFRMP23, the Carney Complex Network, the U.S. National Institutes of Health [National Institute of Child Health and Human Development Intramural Project Z01-HD-000642-04 (to C.A.S.)], the CHU de Rouen, the Reseau COMETE, the Assistance Publique-Hopitaux de Paris, and the Conseil Regional de Haute-Normandie. NR 24 TC 29 Z9 32 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUL PY 2009 VL 94 IS 7 BP 2406 EP 2413 DI 10.1210/jc.2009-0031 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467UB UT WOS:000267767500032 PM 19383776 ER PT J AU Rehermann, B AF Rehermann, Barbara TI Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution and coexistence SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID CD8(+) T-CELLS; ACUTE HCV INFECTION; NONSTRUCTURAL 5A PROTEIN; SINGLE-SOURCE OUTBREAK; PERIPHERAL-BLOOD; IN-VITRO; PD-1 EXPRESSION; DENDRITIC CELLS; NEUTRALIZING ANTIBODY; ENVELOPE PROTEIN AB Since the identification of the hepatitis C virus (HCV) 20 years ago, much progress has been made in our understanding of its life cycle and interaction with the host immune system. Much has been learned from HCV itself, which, via decades of coevolution, gained an intricate knowledge of host innate and adaptive immune responses and developed sophisticated ways to preempt, subvert, and antagonize them. This review discusses the clinical, virological, and immunological features of acute and chronic hepatitis C and the role of the immune response in spontaneous and treatment-induced HCV clearance. C1 NIDDK, Immunol Sect, Liver Dis Branch, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,US Dept HHS, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM rehermann@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases, NIH FX This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. NR 125 TC 314 Z9 321 U1 5 U2 39 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2009 VL 119 IS 7 BP 1745 EP 1754 DI 10.1172/JCI39133 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 466WI UT WOS:000267694300002 PM 19587449 ER PT J AU Goldfarb, LG Dalakas, MC AF Goldfarb, Lev G. Dalakas, Marinos C. TI Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID ALPHA-B-CRYSTALLIN; INCLUSION-BODY MYOSITIS; HELICAL COILED COILS; MICE LACKING DESMIN; INTERMEDIATE-FILAMENTS; MYOFIBRILLAR MYOPATHIES; RESTRICTIVE CARDIOMYOPATHY; FAMILIAL CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; ELECTRON-MICROSCOPY AB Muscle fiber deterioration resulting in progressive skeletal muscle weakness, heart failure, and respiratory distress occurs in more than 20 inherited myopathies. As discussed in this Review, one of the newly identified myopathies is desminopathy, a disease caused by dysfunctional mutations in desmin, a type III intermediate filament protein, or all-crystallin, a chaperone for desmin. The range of clinical manifestations in patients with desminopathy is wide and may overlap with those observed in individuals with other myopathies. Awareness of this disease needs to be heightened, diagnostic criteria reliably outlined, and molecular testing readily available; this would ensure prevention of sudden death from cardiac arrhythmias and other complications. C1 [Goldfarb, Lev G.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Dalakas, Marinos C.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Goldfarb, LG (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, 5625 Fishers Lane,Room 4S06, Bethesda, MD 20892 USA. EM goldfarbl@ninds.nih.gov; m.dalakas@imperial.ac.uk FU National Institute of Neurological Disorders and Stroke, NIH FX This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 84 TC 91 Z9 98 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2009 VL 119 IS 7 BP 1806 EP 1813 DI 10.1172/JCI38027 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 466WI UT WOS:000267694300008 PM 19587455 ER PT J AU Larochelle, A Choi, U Shou, Y Naumann, N Loktionova, NA Clevenger, JR Krouse, A Metzger, M Donahue, RE Kang, E Stewart, C Persons, D Malech, HL Dunbar, CE Sorrentino, BP AF Larochelle, Andre Choi, Uimook Shou, Yan Naumann, Nora Loktionova, Natalia A. Clevenger, Joshua R. Krouse, Allen Metzger, Mark Donahue, Robert E. Kang, Elizabeth Stewart, Clinton Persons, Derek Malech, Harry L. Dunbar, Cynthia E. Sorrentino, Brian P. TI In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID COLONY-STIMULATING FACTOR; MURINE BETA-THALASSEMIA; LARGE-ANIMAL MODEL; STEM-CELLS; BONE-MARROW; REPOPULATING CELLS; RETROVIRAL VECTOR; NONHUMAN-PRIMATES; PERIPHERAL-BLOOD; PLUS O-6-BENZYLGUANINE AB Major limitations to gene therapy using HSCs are low gene transfer efficiency and the inability of most therapeutic genes to confer a selective advantage on the gene-corrected cells. One approach to enrich for gene-modified cells in vivo is to include in the retroviral vector a drug resistance gene, such as the P140K mutant of the DNA repair enzyme O-6-methylguanine-DNA methyltransferase (MGMT*). We transplanted 5 rhesus macaques with CD34(+) cells transduced with lentiviral vectors encoding MGMT* and a fluorescent marker, with or without homeobox B4 (HOXB4), a potent stem cell self-renewal gene. Transgene expression and common integration sites in lymphoid and myeloid lineages several months after transplantation confirmed transduction of long-term repopulating HSCs. However, all animals showed only a transient increase in gene-marked lymphoid and myeloid cells after O-6-benzylguanine (BG) and temozolomide (TMZ) administration. In I animal, cells transduced with MGMT* lentiviral vectors were protected and expanded after multiple courses of BG/TMZ, providing a substantial increase in the maximum tolerated dose of TMZ. Additional cycles of chemotherapy using 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in similar increases in gene marking levels, but caused high levels of nonhematopoietic toxicity. Inclusion of HOXB4 in the MGMT* vectors resulted in no substantial increase in gene marking or HSC amplification after chemotherapy treatment. Our data therefore suggest that lentivirally mediated gene transfer in transplanted HSCs can provide in vivo chemoprotection of progenitor cells, although selection of long-term repopulating HSCs was not seen. C1 [Larochelle, Andre] NHLBI, NIH, Bethesda, MD 20892 USA. [Choi, Uimook; Naumann, Nora; Kang, Elizabeth; Malech, Harry L.] NIAID, NIH, Bethesda, MD 20892 USA. [Shou, Yan; Persons, Derek; Sorrentino, Brian P.] St Jude Childrens Res Hosp, Dept Hematol, Div Expt Hematol, Memphis, TN 38105 USA. [Loktionova, Natalia A.] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Stewart, Clinton] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. RP Larochelle, A (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 10CRC,Room 3E-5256, Bethesda, MD 20892 USA. EM larochea@nhlbi.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU NHLBI; NIAID; NIH; NHLBI [P01 HL 53749]; Cancer Center [P30 CA 21765]; Assisi Foundation of Memphis; American Lebanese Syrian Associated Charities FX We thank Arthur Nienhuis for scientific discussion. This work was supported in part by the intramural research program of NHLBI and NIAID, NIH; by NHLBI grant P01 HL 53749; by Cancer Center Support Grant P30 CA 21765; by the Assisi Foundation of Memphis; and by the American Lebanese Syrian Associated Charities. NR 63 TC 43 Z9 47 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 EI 1558-8238 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2009 VL 119 IS 7 BP 1952 EP 1963 DI 10.1172/JCI37506 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 466WI UT WOS:000267694300024 PM 19509470 ER PT J AU Zelazny, AM Root, JM Shea, YR Colombo, RE Shamputa, IC Stock, F Conlan, S McNulty, S Brown-Elliott, BA Wallace, RJ Olivier, KN Holland, SM Sampaio, EP AF Zelazny, Adrian M. Root, Jeremy M. Shea, Yvonne R. Colombo, Rhonda E. Shamputa, Isdore C. Stock, Frida Conlan, Sean McNulty, Steven Brown-Elliott, Barbara A. Wallace, Richard J., Jr. Olivier, Kenneth N. Holland, Steven M. Sampaio, Elizabeth P. TI Cohort Study of Molecular Identification and Typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID RAPIDLY GROWING MYCOBACTERIA; LENGTH POLYMORPHISM ANALYSIS; FIELD GEL-ELECTROPHORESIS; SEQUENCE-BASED PCR; NONTUBERCULOUS MYCOBACTERIA; CYSTIC-FIBROSIS; SP-NOV; GENE; STRAINS; INFECTION AB Mycobacterium abscessus is the most common cause of rapidly growing mycobacterial chronic lung disease. Recently, two new M. abscessus-related species, M. massiliense and M. bolletii, have been described. Health care-associated outbreaks have recently been investigated by the use of molecular identification and typing tools; however, very little is known about the natural epidemiology and pathogenicity of M. massiliense or M. bolletii outside of outbreak situations. The differentiation of these two species from M. abscessus is difficult and relies on the sequencing of one or more housekeeping genes. We performed extensive molecular identification and typing of 42 clinical isolates of M. abscessus, M. massiliense, and M. bolletii from patients monitored at the NIH between 1999 and 2007. The corresponding clinical data were also examined. Partial sequencing of rpoB, hsp65, and secA led to the unambiguous identification of 26 M. abscessus isolates, 7 M. massiliense isolates, and 2 M. bolletii isolates. The identification results for seven other isolates were ambiguous and warranted further sequencing and an integrated phylogenetic analysis. Strain relatedness was assessed by repetitive-sequence-based PCR (rep-PCR) and pulsed-field gel electrophoresis (PFGE), which showed the characteristic clonal groups for each species. Five isolates with ambiguous species identities as M. abscessus-M. massiliense by rpoB, hsp65, and secA sequencing clustered as a distinct group by rep-PCR and PFGE together with the M. massiliense type strain. Overall, the clinical manifestations of disease caused by each species were similar. In summary, a multilocus sequencing approach (not just rpoB partial sequencing) is required for division of M. abscessus and closely related species. Molecular typing complements sequence-based identification and provides information on prevalent clones with possible relevant clinical aspects. C1 [Zelazny, Adrian M.; Shea, Yvonne R.; Stock, Frida] NIAID, Microbiol Serv, Dept Lab Med, Ctr Clin,Lab Clin Infect Dis,NIH, Bethesda, MD 20892 USA. [Conlan, Sean] NHGRI, NIH, Bethesda, MD 20892 USA. [Zelazny, Adrian M.; Root, Jeremy M.; Colombo, Rhonda E.; Olivier, Kenneth N.; Holland, Steven M.; Sampaio, Elizabeth P.] NIAID, Lab Clin Infect Dis, Immunopathogenesis Sect, Bethesda, MD 20892 USA. [Shamputa, Isdore C.] NIAID, Lab Clin Infect Dis, TB Res Sect, Bethesda, MD 20892 USA. [McNulty, Steven; Brown-Elliott, Barbara A.; Wallace, Richard J., Jr.] Univ Texas Hlth Sci Ctr, Dept Microbiol, Tyler, TX USA. [Sampaio, Elizabeth P.] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21045900 Rio De Janeiro, Brazil. RP Zelazny, AM (reprint author), NIAID, Microbiol Serv, Dept Lab Med, Ctr Clin,Lab Clin Infect Dis,NIH, 10 Ctr Dr,Bldg 10-2C-385, Bethesda, MD 20892 USA. EM azelazny@mail.nih.gov RI Conlan, Sean/B-4401-2008 OI Conlan, Sean/0000-0001-6848-3465 FU NIH; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, the NIH Clinical Center, and the National Institute of Allergy and Infectious Diseases. NR 41 TC 113 Z9 116 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUL PY 2009 VL 47 IS 7 BP 1985 EP 1995 DI 10.1128/JCM.01688-08 PG 11 WC Microbiology SC Microbiology GA 467CC UT WOS:000267713000001 PM 19420162 ER PT J AU O'Connell, MJ AF O'Connell, Michael J. TI Oxaliplatin or Irinotecan As Adjuvant Therapy for Colon Cancer: The Results Are In SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID FLUOROURACIL PLUS LEUCOVORIN; ADVANCED COLORECTAL-CANCER; III RANDOMIZED-TRIAL; STAGE-II; FOLFIRI; FOLFOX C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP O'Connell, MJ (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 13 TC 24 Z9 26 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2009 VL 27 IS 19 BP 3082 EP 3084 DI 10.1200/JCO.2009.22.2919 PG 3 WC Oncology SC Oncology GA 463TD UT WOS:000267454100004 PM 19451420 ER PT J AU Visvanathan, K Chlebowski, RT Hurley, P Col, NF Ropka, M Collyar, D Morrow, M Runowicz, C Pritchard, KI Hagerty, K Arun, B Garber, J Vogel, VG Wade, JL Brown, P Cuzick, J Kramer, BS Lippman, SM AF Visvanathan, Kala Chlebowski, Rowan T. Hurley, Patricia Col, Nananda F. Ropka, Mary Collyar, Deborah Morrow, Monica Runowicz, Carolyn Pritchard, Kathleen I. Hagerty, Karen Arun, Banu Garber, Judy Vogel, Victor G. Wade, James L. Brown, Powel Cuzick, Jack Kramer, Barnett S. Lippman, Scott M. TI American Society of Clinical Oncology Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; CONTINUING OUTCOMES RELEVANT; ITALIAN RANDOMIZED-TRIAL; NEGATIVE MAMMARY-TUMORS; BONE-MINERAL DENSITY; LOW-DOSE TAMOXIFEN; QUALITY-OF-LIFE; POSTMENOPAUSAL WOMEN; PREVENTION TRIAL AB Purpose To update the 2002 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A literature search identified relevant randomized trials published since 2002. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. An expert panel reviewed the literature and developed updated consensus guidelines. Results Seventeen articles met inclusion criteria. In premenopausal women, tamoxifen for 5 years reduces the risk of BC for at least 10 years, particularly estrogen receptor (ER)-positive invasive tumors. Women <= 50 years of age experience fewer serious side effects. Vascular and vasomotor events do not persist post-treatment across all ages. In postmenopausal women, raloxifene and tamoxifen reduce the risk of ER-positive invasive BC with equal efficacy. Raloxifene is associated with a lower risk of thromboembolic disease, benign uterine conditions, and cataracts than tamoxifen in postmenopausal women. No evidence exists establishing whether a reduction in BC risk from either agent translates into reduced BC mortality. Recommendations In women at increased risk for BC, tamoxifen (20 mg/d for 5 years) may be offered to reduce the risk of invasive ER-positive BC, with benefits for at least 10 years. In postmenopausal women, raloxifene (60 mg/d for 5 years) may also be considered. Use of aromatase inhibitors, fenretinide, or other selective estrogen receptor modulators to lower BC risk is not recommended outside of a clinical trial. Discussion of risks and benefits of preventive agents by health providers is critical to patient decision making. J Clin Oncol 27: 3235-3258. (C) 2009 by American Society of Clinical Oncology C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Harbor UCLA Med Ctr, Los Angeles, CA USA. Patient Advocates Res, Danville, CA USA. [Visvanathan, Kala] Amer Soc Clin Oncol, Canc Policy & Clin Affairs, Alexandria, VA 22314 USA. Maine Med Ctr, Portland, ME 04102 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Neag Comprehens Canc Ctr, Farmington, CT USA. Univ Texas MD Anderson Canc Ctr, Baylor Coll Med, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Canc Soc, Atlanta, GA 30329 USA. Canc Care Specialists Cent Illinois, Decatur, GA USA. Canc Res UK, London, England. NIH, Bethesda, MD 20892 USA. RP Visvanathan, K (reprint author), Amer Soc Clin Oncol, Canc Policy & Clin Affairs, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org RI Pritchard, Kathleen/I-2184-2014 OI Pritchard, Kathleen/0000-0003-0758-9666 NR 127 TC 145 Z9 148 U1 2 U2 13 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 1 PY 2009 VL 27 IS 19 BP 3235 EP 3258 DI 10.1200/JCO.2008.20.5179 PG 24 WC Oncology SC Oncology GA 463TD UT WOS:000267454100027 PM 19470930 ER PT J AU Airavaara, M Shen, H Kuo, CC Peranen, J Saarma, M Hoffer, B Wang, Y AF Airavaara, Mikko Shen, Hui Kuo, Chi-Chung Peranen, Johan Saarma, Mart Hoffer, Barry Wang, Yun TI Mesencephalic Astrocyte-Derived Neurotrophic Factor Reduces Ischemic Brain Injury and Promotes Behavioral Recovery in Rats SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article; Proceedings Paper CT 15th Annual Meeting of the American-Society-for-Neural-Therapy-and-Repair CY MAY 01-03, 2008 CL Clearwater Beach, FL SP Amer Soc Neural Therapy & Repair DE ischemia; armet; stroke ID MIDDLE CEREBRAL-ARTERY; UNFOLDED PROTEIN RESPONSE; BONE MORPHOGENETIC PROTEIN-7; ARGININE-RICH PROTEIN; OSTEOGENIC PROTEIN-1; DOPAMINERGIC-NEURONS; TIME WINDOW; STROKE; EXPRESSION; OCCLUSION AB Mesencephalic astrocyte-derived neurotrophic factor (MANF), also known as arginine-rich, mutated in early stage of tumors (ARMET), is a secreted protein that reduces endoplasmic reticulum (ER) stress. Previous studies have shown that MANF mRNA expression and protein levels are increased in the cerebral cortex after brain ischemia, a condition that induces ER stress. The function of MANF during brain ischemia is still not known. The purpose of this study was to examine the protective effect of MAN F after ischemic brain injury. Recombinant human MANF was administrated locally to the cerebral cortex before a 60-min middle cerebral artery occlusion (MCAo) in adult rats. Triphenyltetrazolium chloride (TTC) staining indicated that pretreatment with MANF significantly reduced the volume of infarction at 2 days after MCAo. MANF also attenuated TUNEL labeling, a marker of cell necrosis/apoptosis, in the ischemic cortex. Animals receiving MANF pretreatment demonstrated a decrease in body asymmetry and neurological score as well as an increase in locomotor activity after MCAo. Taken together, these data suggest that MANF has neuroprotective effects against cerebral ischemia, possibly through the inhibition of cell necrosis/apoptosis in cerebral cortex. J. Comp. Neurol. 515:116-124, 2009. (C) Published 2009 Wiley-Liss, Inc. C1 [Airavaara, Mikko; Shen, Hui; Kuo, Chi-Chung; Hoffer, Barry; Wang, Yun] Natl Inst Drug Abuse, IRP, Baltimore, MD 21224 USA. [Peranen, Johan; Saarma, Mart] Univ Helsinki, Inst Biotechnol, Viikki Bioctr, FIN-00014 Helsinki, Finland. RP Hoffer, B (reprint author), Natl Inst Drug Abuse, IRP, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM bhoffer@intra.nida.nih.gov OI Airavaara, Mikko/0000-0002-2026-1609 FU Intramural NIH HHS [Z99 DA999999] NR 36 TC 40 Z9 42 U1 0 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUL 1 PY 2009 VL 515 IS 1 BP 116 EP 124 DI 10.1002/cne.22039 PG 9 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 446HW UT WOS:000266113700011 PM 19399876 ER PT J AU Vossen, JA Buijs, M Geschwind, JFH Liapi, E Ventura, VP Lee, KH Bluemke, DA Kamel, IR AF Vossen, Josephina A. Buijs, Manon Geschwind, Jean-Francois H. Liapi, Eleni Ventura, Veronica Prieto Lee, Kwang Hun Bluemke, David A. Kamel, Ihab R. TI Diffusion-Weighted and Gd-EOB-DTPA-Contrast-Enhanced Magnetic Resonance Imaging for Characterization of Tumor Necrosis in an Animal Model SO JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY LA English DT Article DE VX2; Gd-EOB-DTPA; diffusion-weighted MRI; tumor size; HCC; liver cancer; tumor necrosis ID UNRESECTABLE HEPATOCELLULAR-CARCINOMA; FOCAL LIVER-LESIONS; GADOXETIC ACID; RADIOFREQUENCY ABLATION; CLINICAL-EVALUATION; RABBIT MODEL; CHEMOEMBOLIZATION; MRI; SAFETY; AGENT AB Purpose: To evaluate the role of diffusion-weighted magnetic resonance imaging (MRI) in determining tumor necrosis and contrast-enhanced MRI using gadoxetic acid disodium (Gd-EOB-DTPA) in determining maximum tumor size measurement and tumor delineation compared with criterion-standard histologic measurements in the rabbit VX2 liver tumor model. Materials and Methods: VX2 tumors were implanted in the livers of 13 rabbits. Magnetic resonance imaging was performed using a 1.5-T MRI scanner and an extremity coil. The imaging protocol included T2-weighted fast spin-echo images, 3-dimensional T1-weighted spoiled gradient-echo with and without fat Suppression after administration of Gd-EOB-DTPA, and diffusion-weighted echo planar images. Rabbits were killed, and the tumor was harvested and sliced at 4-mm intervals in the axial plane. The MRI parameters evaluated were tumor size, tumor delineation, and tumor apparent diffusion coefficient (ADC) values. Histologic sections were evaluated to quantify tumor necrosis. Results: On contrast-enhanced MRI (obtained front 11 rabbits), the mean tumor sizes were 20, 19, and 20 mm in the arterial, portal venous, and delayed phases, respectively. Tumor delineation was most distinguishable in the delayed phase. On diffusion-weighted MRI (acquired in 13 rabbits), the mean turner ADC value was 1.84 x 10(-3) mm(2)/s. The mean tumor size at pathology was 16 mm. The mean percent necrosis at the tumors pathologic condition was 36%. The correlation between ADC value and percent necrosis showed an R value of 0.68. Conclusions: Contrast-enhanced MRI using Gd-EOB-DTPA may provide additional information about tumor outline in the liver. Moreover, we showed a remarkable correlation between ADC values and tumor necrosis. Thus, diffusion-weighted imaging may be useful to assess tumor necrosis; nevertheless, the search for new modalities remains important. C1 [Vossen, Josephina A.; Buijs, Manon; Geschwind, Jean-Francois H.; Liapi, Eleni; Ventura, Veronica Prieto; Lee, Kwang Hun; Kamel, Ihab R.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Bluemke, David A.] NIH, Bethesda, MD 20892 USA. RP Kamel, IR (reprint author), Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St,Room 100, Baltimore, MD 21287 USA. EM ikamel@jhmi.edu RI Liapi, Eleni/B-5195-2013; OI Liapi, Eleni/0000-0001-5864-4448; Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-01, ZIA EB000072-01]; NIBIB NIH HHS [T32 EB006351, T32 EB006351-03] NR 24 TC 17 Z9 20 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-8715 J9 J COMPUT ASSIST TOMO JI J. Comput. Assist. Tomogr. PD JUL-AUG PY 2009 VL 33 IS 4 BP 626 EP 630 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 480AF UT WOS:000268703000026 PM 19638862 ER PT J AU Sutin, AR Gillath, O AF Sutin, Angelina R. Gillath, Omri TI Autobiographical Memory Phenomenology and Content Mediate Attachment Style and Psychological Distress SO JOURNAL OF COUNSELING PSYCHOLOGY LA English DT Article DE adult attachment; autobiographical memory; depression; phenomenology; coherence ID SELF-DEFINING MEMORIES; ADULT ATTACHMENT; COLLEGE-STUDENTS; REPRESSIVE DEFENSIVENESS; NARRATIVE COHERENCE; PROCESSING BIASES; NEGATIVE MOOD; DEPRESSION; ANXIETY; SPECIFICITY AB In 2 studies, the present research tested the phenomenology and content of autobiographical memory as distinct mediators between attachment avoidance and anxiety and depressive symptoms. In Study 1, participants (N = 454) completed measures of attachment and depressive symptoms in 1 session and retrieved and rated 2 self-defining memories of romantic relationships in a separate session. In Study 2, participants (N = 534) were primed with attachment security, attachment insecurity, or a control prime and then retrieved and rated a self-defining relationship memory. Memory phenomenology, specifically memory coherence and emotional intensity, mediated the association between attachment avoidance and depressive symptoms, whereas the negative affective content of the memory mediated the association between attachment anxiety and depressive symptoms. Priming attachment security led to retrieval of a more coherent relationship memory, whereas insecurity led to the retrieval of a more incoherent relationship memory. Discussion focuses on the construction and recollection of memories as underlying mechanisms of adult attachment and psychological distress, the importance of memory coherence, and the implications for counseling research and practice. C1 [Sutin, Angelina R.] Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. [Gillath, Omri] Univ Kansas, Dept Psychol, Lawrence, KS 66045 USA. RP Sutin, AR (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sutina@mail.nih.gov OI Gillath, Omri/0000-0001-8791-227X FU Intramural NIH HHS [Z99 AG999999] NR 81 TC 20 Z9 20 U1 4 U2 27 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-0167 J9 J COUNS PSYCHOL JI J. Couns. Psychol. PD JUL PY 2009 VL 56 IS 3 BP 351 EP 364 DI 10.1037/a0014917 PG 14 WC Psychology, Educational; Psychology, Applied SC Psychology GA 482QP UT WOS:000268904100002 PM 20706555 ER PT J AU Kornhauser, A Wei, RR Yamaguchi, Y Coelho, SG Kaidbey, K Barton, C Takahashi, K Beer, JZ Miller, SA Hearing, VJ AF Kornhauser, Andrija Wei, Rong-Rong Yamaguchi, Yuji Coelho, Sergio G. Kaidbey, Kays Barton, Curtis Takahashi, Kaoruko Beer, Janusz Z. Miller, Sharon A. Hearing, Vincent J. TI The effects of topically applied glycolic acid and salicylic acid on ultraviolet radiation-induced erythema, DNA damage and sunburn cell formation in human skin SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Article DE Hydroxyacids; Glycolic acid; Salicylic acid; UV-damage; Erythema; DNA damage; Sunburn cells; Cosmetics ID ALPHA-HYDROXY ACIDS; SODIUM-SALICYLATE; XERODERMA-PIGMENTOSUM; PYRIMIDINE DIMER; UV-RADIATION; LIGHT; PIGMENTATION; MUTATIONS; SUNLIGHT; CANCER AB Background: alpha-Hydroxy acids (alpha HAs) are reported to reduce signs of aging in the skin and are widely used cosmetic ingredients. Several studies suggest that alpha HA can increase the sensitivity of skin to ultraviolet radiation. More recently, beta-hydroxy acids (beta HAs), or combinations of alpha HA and beta HA have also been incorporated into antiaging skin care products. Concerns have also arisen about increased sensitivity to ultraviolet radiation following use of skin care products containing beta-HA. Objective: To determine whether topical treatment with glycolic acid, a representative aHA, or with salicylic acid, a beta HA modifies the short-term effects of solar simulated radiation (SSR) in human skin. Methods: Fourteen subjects participated in this study. Three of the four test sites on the mid-back of each subject were treated daily Monday-Friday, for a total of 3.5 weeks, with glycolic acid (10%), salicylic acid (2%), or vehicle (control). The fourth site received no treatment. After the last treatment, each site was exposed to SSR, and shave biopsies from all four sites were obtained. The endpoints evaluated in this study were erythema (assessed visually and instrumentally), DNA damage and sunburn cell formation. Results: Treatment with glycolic acid resulted in increased sensitivity of human skin to SSR, measured as an increase in erythema, DNA damage and sunburn cell formation. Salicylic acid did not produce significant changes in any of these biomarkers. Conclusions: Short-term topical application of glycolic acid in a cosmetic formulation increased the sensitivity of human skin to SSR, while a comparable treatment with salicylic acid did not. Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology. C1 [Kornhauser, Andrija; Wei, Rong-Rong; Barton, Curtis] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Yamaguchi, Yuji; Coelho, Sergio G.; Takahashi, Kaoruko; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Kaidbey, Kays] KGL Inc, Ivy Labs, Broomall, PA 19008 USA. [Beer, Janusz Z.; Miller, Sharon A.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. RP Kornhauser, A (reprint author), US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. EM akornhause@aol.com FU U.S. FDA Office of Science and Health Coordination FX This research was supported by the U.S. FDA Office of Science and Health Coordination and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The authors wish to thank K. Korossy, MD and C. Tock, MD for the dermatological support and for obtaining biopsies from all subjects; J. Kniskern, RN for excellent handling of human subjects' records; W. Warner for useful input to the manuscript; D. Lowther for her skillful technical and editorial assistance in preparing this manuscript; J. Hubinger for analysis of test products. NR 44 TC 16 Z9 16 U1 4 U2 15 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD JUL PY 2009 VL 55 IS 1 BP 10 EP 17 DI 10.1016/j.jdermsci.2009.03.011 PG 8 WC Dermatology SC Dermatology GA 459FJ UT WOS:000267086100002 PM 19411163 ER PT J AU Kong, H Lee, Y Hong, S Han, J Choi, B Jung, Y Kim, YM AF Kong, Hyesik Lee, Younghyun Hong, Sungchae Han, Jeongoh Choi, Biom Jung, Yunjin Kim, Young Mi TI Sulfate-conjugated methylprednisolone as a colon-targeted methylprednisolone prodrug with improved therapeutic properties against rat colitis SO JOURNAL OF DRUG TARGETING LA English DT Article DE Colonic delivery; prodrug; sulfate conjugation; methylprednisolone; inflammatory bowel disease ID INFLAMMATORY-BOWEL-DISEASE; APPENDED ALPHA-CYCLODEXTRIN; IN-VITRO PROPERTIES; 21-SULFATE SODIUM; POTENTIAL PRODRUGS; ULCERATIVE-COLITIS; DRUG-DELIVERY; PREDNISOLONE; DEXAMETHASONE; PATHOGENESIS AB Methylprednisolone (MP) is one of the most widely used corticosteroids for the treatment of inflammatory bowel disease (IBD). However, systemic adverse effects of MP limit its availability for the disease. In present study, sulfate-conjugated methylprednisolone (MPS) was evaluated in vivo as a colon-targeted prodrug of MP and its therapeutic properties against 2,4,6-trinitrobenzenesulfonic acid-induced rat colitis were investigated. Upon oral administration, a large fraction of MPS reached the large intestine, where MPS was converted to MP implying that MPS would deliver MID effectively to the large intestine. The fecal recovery of MP (after MPS administration) was much greater than that after MP administration and the urinary recovery of MP (after MPS administration) was much less than that after MP administration, suggesting that MPS should exhibit enhanced therapeutic activity and reduced systemic adverse effects. Consistent with this notion, MPS was more effective than MP in ameliorating rat colitis. Moreover, the adverse effects of MPS on adrenal function and thymus were much lower than those of MP Taken together, MPS may be therapeutically superior to MP in IBD treatment. C1 [Lee, Younghyun; Hong, Sungchae; Han, Jeongoh; Choi, Biom; Jung, Yunjin; Kim, Young Mi] Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. [Kong, Hyesik] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Jung, Y (reprint author), Pusan Natl Univ, Coll Pharm, Lab Biomed Med Chem, Pusan 609735, South Korea. EM jungy@pusan.ac.kr NR 23 TC 10 Z9 12 U1 1 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1061-186X J9 J DRUG TARGET JI J. Drug Target. PD JUL PY 2009 VL 17 IS 6 BP 450 EP 458 DI 10.1080/10611860902974077 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 473WU UT WOS:000268243200005 PM 19527116 ER PT J AU Prineas, RJ Soliman, EZ Howard, G Howard, VJ Cushman, M Zhang, ZM Moy, CS AF Prineas, Ronald J. Soliman, Elsayed Z. Howard, George Howard, Virginia J. Cushman, Mary Zhang, Zhu-Ming Moy, Claudia S. TI The Sensitivity of the Method Used to Detect Atrial Fibrillation in Population Studies Affects Group-Specific Prevalence Estimates: Ethnic and Regional Distribution of Atrial Fibrillation in the REGARDS Study SO JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atrial fibrillation; race/ethnicity; REGARDS study ID RISK-FACTORS; ISCHEMIC-STROKE; RACIAL-DIFFERENCES; METABOLIC SYNDROME; IMPACT; REASONS AB Background: Among African-Americans, and in southern US states, the rates of stroke are high but the reported prevalences of atrial fibrillation (AF) are low. We hypothesized that the reported ethnic and regional distributions of AF are affected by the sensitivity of the methods that were used to detect AF in previous reports. Methods: A total of 18 833 black and white participants from the US national REasons For Geographic And Racial Differences In Stroke (REGARDS) study were included in this analysis. Levels of sensitivity to detect AF, from least to most sensitive, were created for combinations of self-report (SR) and ECG methods, as follows: (1) SR Plus ECG, (2) ECG alone, (3) SR alone, and (4) SR or ECG. Geographic regions were dichotomized as Stroke Belt (the southern US states) and non-Stroke Belt. Logistic regression analysis estimated the odd ratios of AF associated with the Stroke Belt and black ethnicity for each diagnostic combination. Results: Residence in the Stroke Belt was significantly associated with AF when diagnosed by SR plus ECG (multivariable-adjusted OR, 0.66; 95% Cl, 0.47 to 0.92), but not when diagnosed with SR or ECG (OR, 0.95; 95% CI, 0.85 to 1.06). Similarly, for the 4 methods used to detect AF, the strength of the association between black ethnicity and AF progressively decreased with increasing test sensitivity (ORs: 0.20, 0.40, 0.70, 0.71, respectively). Conclusions: The association of AF with residence in the Stroke Belt and black ethnicity was inversely related to the sensitivity of the method used to detect AF: as test sensitivity increased, the association became attenuated. This may partially explain the lower reported prevalence of AF in populations and regions with higher stroke rates. C1 [Prineas, Ronald J.] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr, Winston Salem, NC 27104 USA. [Howard, George] Univ Alabama, Sch Publ Hlth, Dept Biostat, Tuscaloosa, AL USA. [Howard, Virginia J.] Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Tuscaloosa, AL USA. [Cushman, Mary] Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. [Moy, Claudia S.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Prineas, RJ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Epidemiol Cardiol Res Ctr, 2000 W 1st St,Suite 505, Winston Salem, NC 27104 USA. EM rprineas@wfubmc.edu RI Soliman, Elsayed/D-8124-2011 OI Soliman, Elsayed/0000-0001-5632-8150 FU National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, United States of America [U01 NS041588] FX This work was supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, United States of America. NR 22 TC 18 Z9 18 U1 1 U2 1 PU JAPAN EPIDEMIOLOGICAL ASSOC PI TOCHIGI PA JICHI MEDICAL SCHOOL, DEPT PUBLIC HEALTH, 3311-1 YAKUSHIJI, MINAMIKAWACH, TOCHIGI, 329-0498, JAPAN SN 0917-5040 J9 J EPIDEMIOL JI J. Epidemiol. PD JUL PY 2009 VL 19 IS 4 BP 177 EP 181 DI 10.2188/jea.JE20081032 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 470RC UT WOS:000267995900003 PM 19561382 ER PT J AU Pronk, A Coble, J Stewart, PA AF Pronk, Anjoeka Coble, Joseph Stewart, Patricia A. TI Occupational exposure to diesel engine exhaust: A literature review SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Review DE diesel exhaust; occupational; review; determinant ID RAILROAD WORKERS; LUNG-CANCER; TRUCKING INDUSTRY; PARTICULATE MATTER; ELEMENTAL CARBON; NITROGEN-DIOXIDE; RISK-ASSESSMENT; COAL-MINERS; EMISSIONS; PARTICLES AB Diesel exhaust (DE) is classified as a probable human carcinogen. Aims were to describe the major occupational uses of diesel engines and give an overview of personal DE exposure levels and determinants of exposure as reported in the published literature. Measurements representative of personal DE exposure were abstracted from the literature for the following agents: elemental carbon (EC), particulate matter (PM), carbon monoxide (CO), nitrogen oxide (NO), and nitrogen dioxide (NO(2)). Information on determinants of exposure was abstracted. In total, 3528 EC, 4166 PM, 581 CO, 322 NO, and 1404 NO(2) measurements were abstracted. From the 10,001 measurements, 32% represented exposure from on-road vehicles and 68% from off-road vehicles (30% mining, 15% railroad, and 22% others). Highest levels were reported for enclosed underground work sites in which heavy equipment is used: mining, mine maintenance, and construction (EC: 27-658 mu g/m(3)). Intermediate exposure levels were generally reported for above-ground (semi-) enclosed areas in which smaller equipment was run: mechanics in a shop, emergency workers in. re stations, distribution workers at a dock, and workers loading/unloading inside a ferry (generally: EC < 50 mu g/m(3)). Lowest levels were reported for enclosed areas separated from the source, such as drivers and train crew, or outside, such as surface mining, parking attendants, vehicle testers, utility service workers, surface construction and airline ground personnel (EC < 25 mu g/m(3)). The other agents showed a similar pattern. Determinants of exposure reported for enclosed situations were ventilation and exhaust after treatment devices. Reported DE exposure levels were highest for underground mining and construction, intermediate for working in above-ground (semi-) enclosed areas and lowest for working outside or separated from the source. The presented data can be used as a basis for assessing occupational exposure in population-based epidemiological studies and guide future exposure assessment efforts for industrial hygiene and epidemiological studies. Journal of Exposure Science and Environmental Epidemiology (2009) 19, 443-457; doi: 10.1038/jes.2009.21; published online 11 March 2009 C1 [Pronk, Anjoeka; Coble, Joseph] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Stewart, Patricia A.] Stewart Exposure Assessments LLC, Arlington, VA USA. RP Pronk, A (reprint author), 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM pronka@mail.nih.gov FU National Cancer Institute FX We thank Dr. Mustafa Dosemeci for conducting the literature search and Mr. Dennis Zaebst for providing NIOSH Health Hazard Evaluation reports. This research was supported by the Intramural Research Program of the National Cancer Institute. NR 91 TC 56 Z9 57 U1 4 U2 52 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD JUL-AUG PY 2009 VL 19 IS 5 BP 443 EP 457 DI 10.1038/jes.2009.21 PG 15 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 468KX UT WOS:000267818200001 PM 19277070 ER PT J AU Abe, S Okuda, K Ura, T Kondo, A Yoshida, A Yoshizaki, S Mizuguchi, H Klinman, D Shimada, M AF Abe, Shinya Okuda, Kenji Ura, Takehiro Kondo, Asami Yoshida, Atsushi Yoshizaki, Shinji Mizuguchi, Hiroyuki Klinman, Dennis Shimada, Masaru TI Adenovirus type 5 with modified hexons induces robust transgene-specific immune responses in mice with pre-existing immunity against adenovirus type 5 SO JOURNAL OF GENE MEDICINE LA English DT Article DE HIV; neutralizing antibody; vaccine; virus vector ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODIES; RECOMBINANT ADENOVIRUS; RHESUS-MONKEYS; T-LYMPHOCYTES; GENE-THERAPY; IN-VITRO; VACCINE; VECTORS; PROTEIN AB Background Adenovirus type 5 (Ad5) is widely used as a vehicle for vaccine delivery in the treatment of infectious disease and cancer. However, the efficacy of Ad5 vectors has been limited in humans because exposure to Ad5 infections results in most adults having neutralizing antibodies against Ad5. To overcome this limitation, the hexon epitope present in the fifth hypervariable region of Ad5 was modified. Methods To evaluate the ability of Ad5 vectors encoding the HIV env protein to induce Ag-specific immune responses in the face of pre-existing anti-Ad5 immunity, mice were administrated intramuscularly with the Ad-Luc vector, and then vaccinated with parental or hexon-modified Ad5 vectors (Ad-HisHIV, Ad-END/AAAHIV or Ad-HIV) at week 8. HIV-specific cell-mediated immune responses were detected through a combination of tetramer assays and intracellular cytokine staining from weeks 8-23. Results The hexon-modified Ad vector was able to escape from anti-Ad5 neutralizing antibody, and mice with the modified vector generated significantly lower individual neutralizing antibody than those immunized with the parental vector. Furthermore, mice with pre-existing anti-Ad immunity immunized with the modified vector generated significantly stronger cell-mediated anti-env responses than those immunized with the parental vector. Conclusions These data demonstrate that Ad5 vector with hexon modification reduce their sensitivity to pre-existing anti-Ad immunity and improve their clinical utility. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Shimada, Masaru] Yokohama City Univ, Dept Mol Biodef Res, Grad Sch Med, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. [Mizuguchi, Hiroyuki] Natl Inst Biomed Innovat, Lab Gene Transfer & Regulat, Osaka, Japan. [Klinman, Dennis] NCI, NIH, Frederick, MD 21701 USA. RP Shimada, M (reprint author), Yokohama City Univ, Dept Mol Biodef Res, Grad Sch Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan. EM mshimada@med.yokohama-cu.ac.jp FU Ministry of Education, Science, Sports and Culture of Japan; Strategic Research Project of Yokohama City University, Japan; Research Foundation for the Advanced Medical Research Center; Japanese National Institute of Biomedical Innovation [05-1] FX We thank NIH Tetramer Core Facility (Atlanta, GA, USA) for the tetramer. This work was partially supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture of Japan; a Grant for the Strategic Research Project of Yokohama City University, Japan; a Research Foundation for the Advanced Medical Research Center and a Grant from the Japanese National Institute of Biomedical Innovation (No. 05-1). NR 49 TC 29 Z9 30 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1099-498X EI 1521-2254 J9 J GENE MED JI J. Gene. Med. PD JUL PY 2009 VL 11 IS 7 BP 570 EP 579 DI 10.1002/jgm.1332 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 472EU UT WOS:000268113100003 PM 19391169 ER PT J AU Racz, GZ Perez-Riveros, P Adriaansen, J Zheng, CY Baum, BJ AF Racz, Gabor Z. Perez-Riveros, Paola Adriaansen, Janik Zheng, Changyu Baum, Bruce J. TI In vivo secretion of the mouse immunoglobulin G Fc fragment from rat submandibular glands SO JOURNAL OF GENE MEDICINE LA English DT Article DE basolateral secretion; constitutive pathway; gene therapy; salivary glands; sorting ID MEDIATED GENE-TRANSFER; SALIVARY-GLANDS; GROWTH-HORMONE; ENDOCRINE SECRETION; EPITHELIAL-CELLS; PROTEIN; PATHWAYS; GRANULES; STORAGE; ERYTHROPOIETIN AB Background Salivary glands have been proposed as target organs for gene therapy. They secrete endogenous, as well as transgenic proteins, in a polarized manner. Transgene-encoded regulated pathway proteins primarily follow the regulated pathway in rat salivary glands and arc secreted into saliva in an exocrine manner. Conversely, constitutive pathway proteins generally are secreted more basolaterally and thus follow the endocrine route. in the present study, we studied in vivo the sorting of the mouse immunoglobulin G2b Fc fragment, which is physiologically secreted via the constitutive pathway. Methods Adenoviral vectors encoding the Fc fragment and human growth hormone were delivered into rat and mouse submandibular glands in vivo to compare their serum-to-saliva distribution. We also compared the intracellular localization of the Fc fragment and growth hormone by confocal microscopy. Results We found that the Fc fragment was secreted almost entirely into the bloodstream from rat and mouse submandibular glands via a constitutive or constitutive-like pathway. This sorting behaviour is clearly different from that of transgenic human growth hormone, which is secreted in a regulated pathway, both in neuroendocrine cells and as a transgenic protein from salivary gland cells. We also found that simultaneously expressed human growth hormone and the mouse Fc fragment do not appear to influence each other's sorting behaviour. The Fc fragment showed a primarily basal localization, whereas growth hormone showed an apical localization, in rat submandibular gland acinar cells. Conclusions The results obtained in the present study indicate that the Mouse Fc fragment is a useful model protein for examining the basolateral versus apical secretory pathways employed by transgenic secretory proteins in salivary glands. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Racz, Gabor Z.; Perez-Riveros, Paola; Adriaansen, Janik; Zheng, Changyu; Baum, Bruce J.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Racz, GZ (reprint author), Semmelweis Univ, Dept Oral Biol, Nagyvaradter 4, H-1089 Budapest, Hungary. EM gabor.z.racz@gmail.com FU Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, National Institutes of Health. The authors also Would like to especially thank Drs Anna and David Castle for providing the mouse Fc fragment construct. NR 26 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD JUL PY 2009 VL 11 IS 7 BP 580 EP 587 DI 10.1002/jgm.1340 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 472EU UT WOS:000268113100004 PM 19424985 ER PT J AU Adams, WC Bond, E Havenga, MJE Holterman, L Goudsmit, J Hedestam, GBK Koup, RA Lore, K AF Adams, William C. Bond, Emily Havenga, Menzo J. E. Holterman, Lennart Goudsmit, Jaap Hedestam, Gunilla B. Karlsson Koup, Richard A. Lore, Karin TI Adenovirus serotype 5 infects human dendritic cells via a coxsackievirus-adenovirus receptor-independent receptor pathway mediated by lactoferrin and DC-SIGN SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HEPARAN-SULFATE GLYCOSAMINOGLYCANS; HIGH-EFFICIENCY TRANSDUCTION; TIGHT JUNCTION PROTEINS; GENE-TRANSFER; BOVINE LACTOTRANSFERRIN; LANGERHANS CELLS; IN-VITRO; T-CELLS; VECTORS AB The coxsackievirus-adenovirus; receptor (CAR) is the described primary receptor for adenovirus serotype 5 (Ad5), a common human pathogen that has been exploited as a viral vector for gene therapy and vaccination. This study showed that monocytes and dendritic cells (DCs), such as freshly isolated human blood myeloid DCs, plasmacytoid DCs and monocyte-derived DCs, are susceptible to recombinant Ad5 (rAd5) infection despite their lack of CAR expression. Langerhans cells and dermal DCs from skin expressed CAR, but blocking CAR only partly decreased rAd5 infection, together suggesting that other receptor pathways mediate viral entry of these cells. Lactoferrin (Lf), an abundant protein in many bodily fluids known for its antiviral and antibacterial properties, promoted rAd5 infection in all cell populations except plasmacytoid DCs using a CAR-independent process. Lf caused phenotypic differentiation of the DCs, but cell activation played only a minor role in the increase in infection frequencies. The C-type lectin receptor DC-SIGN facilitated viral entry of rAd5-Lf complexes and this was dependent on high-mannose-type N-linked glycans on Lf. These results suggest that Lf present at high levels at mucosal sites can facilitate rAd5 attachment and enhance infection of DCs. A better understanding of the tropism and receptor mechanisms of Ad5 may help explain Ad5 pathogenesis and guide the engineering of improved rAd vectors. C1 [Adams, William C.; Bond, Emily; Lore, Karin] Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. [Adams, William C.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Adams, William C.; Bond, Emily; Hedestam, Gunilla B. Karlsson; Lore, Karin] Swedish Inst Infect Dis Control, Stockholm, Sweden. [Havenga, Menzo J. E.] TNO Biosci, Leiden, Netherlands. [Holterman, Lennart; Goudsmit, Jaap] Crucell Holland, Leiden, Netherlands. [Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. RP Lore, K (reprint author), Karolinska Inst, Dept Med, Ctr Infect Med, Stockholm, Sweden. EM Karin.lore@ki.se OI Bond, Emily/0000-0001-5374-7085 FU Swedish International Development Cooperation Agency (Sida) FX This study was supported by the Swedish International Development Cooperation Agency (Sida), the Swedish Council for Research (Vetenskapsradet), Ake Wiberg's Research Foundation, the Jeansson's Foundation, Clas Groschinsky's Foundation and the Swedish Society for Medicine (K.L. funding recipient). The authors would also like to thank Dr Leif Perbeck, Karolinska University Hospital, for providing skin specimens, as well as Kjefl-Olof Hedlund, Swedish Institute for Infectious Disease Control, and Pia Dosenovic and Christopher Sundling, Karolinska Institutet, for technical assistance and advice. NR 60 TC 33 Z9 33 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD JUL PY 2009 VL 90 BP 1600 EP 1610 DI 10.1099/vir.0.008342-0 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 470DX UT WOS:000267955900008 PM 19282435 ER PT J AU Gorodeski, EZ Cantillon, DJ Goel, SS Kaufman, ES Martin, DO Hsich, EM Blackstone, EH Lauer, MS AF Gorodeski, Eiran Z. Cantillon, Daniel J. Goel, Sachin S. Kaufman, Elizabeth S. Martin, David O. Hsich, Eileen M. Blackstone, Eugene H. Lauer, Michael S. TI Microvolt T-Wave Alternans, Peak Oxygen Consumption, and Outcome in Patients with Severely Impaired Left Ventricular Systolic Function SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID HEART-FAILURE; RISK STRATIFICATION; PROGNOSTIC VALUE; DEFIBRILLATOR IMPLANTATION; DILATED CARDIOMYOPATHY; TACHYARRHYTHMIC EVENTS; PROPENSITY SCORES; DEATH; EXERCISE; PREDICTOR AB Background: Abnormal microvolt T-wave alternans (MTWA) and low peak oxygen consumption (VO(2)) both predict poor outcome in heart failure. However, their independent predictive properties have not been assessed in large-scale cohorts. Methods: This was an observational prospective cohort study of 303 consecutive patients referred for metabolic stress testing. All had an ejection fraction < 40% and were considered candidates for transplantation. The exercise laboratory did not collect MTWA data from patients with implanted pacemakers or defibrillators. The primary end point was a composite of all-cause death or United Network for Organ Sharing status I transplantation. Results: During a 2.8-year period, there were 34 deaths and 17 transplantations. Patients with abnormal MTWA had a higher event rate of 23% (31 of 136) vs 12% (20 of 167), with an unadjusted hazard ratio (HR) of 1.90 (95% confidence interval [CI], 1.90-3-33; P = 0.03). The association remained significant after adjustment for 3 clinical variables (HR, 1.89; 95% CI, 1.05-3-39; P = 0.03). After adding peak VO(2) to the model, the association was no longer significant (adjusted HR, 1.18; 95% Cl, 0.64-2.17, P = 0.60). After accounting for peak VO(2), and 28 other confounders in a matched propensity analysis, MTWA was not predictive (propensity matched HR, 0.79; 95% Cl, 0.37-1-66; P = 0.53). Conclusions: These results confirm the association of abnormal MTWA with poor outcome amongst patients with impaired left ventricular systolic function. However, this association is markedly attenuated after accounting for peak VO(2). J Heart Lung Transplant 2009;28:689-96. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation. C1 [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci DPPS, NIH, Bethesda, MD 20892 USA. [Kaufman, Elizabeth S.] Case Western Reserve Univ, Heart & Vasc Res Ctr MetroHlth Campus, Cleveland, OH 44106 USA. [Gorodeski, Eiran Z.; Cantillon, Daniel J.; Goel, Sachin S.; Martin, David O.; Hsich, Eileen M.] Case Western Reserve Univ, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Blackstone, Eugene H.] Case Western Reserve Univ, Cleveland Clin, Dept Cardiothorac Surg, Cleveland, OH 44106 USA. RP Lauer, MS (reprint author), NHLBI, Div Prevent & Populat Sci DPPS, NIH, Rockledge Ctr 2,6701 Rockledge Dr,Rm 10122, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Gorodeski, Eiran/D-5384-2009; Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Gorodeski, Eiran/0000-0003-3756-8831 FU National Heart, Lung, and Blood Institute [8324207] FX This work was funded by National Heart, Lung, and Blood Institute grant CAN# 8324207. NR 38 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD JUL PY 2009 VL 28 IS 7 BP 689 EP 696 DI 10.1016/j.healun.2009.04.009 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 470QM UT WOS:000267993700007 PM 19560697 ER PT J AU Pogribny, IP Tryndyak, VP Bagnyukova, TV Melnyk, S Montgomery, B Ross, SA Latendresse, JR Rusyn, I Beland, FA AF Pogribny, Igor P. Tryndyak, Volodymyr P. Bagnyukova, Tetyana V. Melnyk, Stepan Montgomery, Beverly Ross, Sharon A. Latendresse, John R. Rusyn, Ivan Beland, Frederick A. TI Hepatic epigenetic phenotype predetermines individual susceptibility to hepatic steatosis in mice fed a lipogenic methyl-deficient diet SO JOURNAL OF HEPATOLOGY LA English DT Article DE Hepatic steatosis; Non-alcoholic steatohepatitis; DNA methylation; Histone modifications; Disease susceptibility ID HISTONE LYSINE METHYLATION; FATTY LIVER-DISEASE; NONALCOHOLIC STEATOHEPATITIS; DNA; HYPOMETHYLATION; MECHANISMS; PATTERNS; EXPOSURE; ELEMENTS; GENES AB Background/Aims: The importance of epigenetic changes in etiology and pathogenesis of disease has been increasingly recognized. However, the role of epigenetic alterations in the genesis of hepatic steatosis and cause of individual susceptibilities to this pathological state are largely unknown. Methods: Male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet (MDD) that causes liver injury similar to human non-alcoholic steatohepatitis (NASH) for 6, 12, or 18 weeks, and the status of global and repetitive elements cytosine methylation, histone modifications, and expression of proteins responsible for those epigenetic modifications in livers was determined. Results: The development of hepatic steatosis in inbred C57BL/6J and DBA/2J mice was accompanied by prominent epigenetic abnormalities. This was evidenced by pronounced loss of genomic and repetitive sequences cytosine methylation, especially at major and minor satellites, accompanied by increased levels of repeat-associated transcripts, aberrant histone modifications, and alterations in expression of the maintenance DNA methyltransferase 1 (DNMT1) and de novo DNMT3A proteins in the livers of both mouse strains. However, the DBA/2J mice, which were characterized by an initially lower degree of methylation of repetitive elements and lower extent of histone H3 lysine 9 (H3K9) and H3 lysine 27 (H3K27) trimethylation in the normal livers, as compared to those in the C57BL/6J mice, developed more prominent NASH-specific pathomorphological changes. Conclusions: These results mechanistically link epigenetic alterations to the pathogenesis of hepatic steatosis and strongly suggest that differences in the cellular epigenetic status may be a predetermining factor to individual susceptibilities to hepatic steatosis. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver. C1 [Pogribny, Igor P.; Tryndyak, Volodymyr P.; Bagnyukova, Tetyana V.; Montgomery, Beverly; Beland, Frederick A.] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Melnyk, Stepan] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Ross, Sharon A.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Rusyn, Ivan] Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC USA. RP Pogribny, IP (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM igor.pogribny@fda.hhs.gov RI Rusyn, Ivan/S-2426-2016 FU NIAAA NIH HHS [R01 AA016258, R01 AA016258-04]; NIEHS NIH HHS [P42 ES005948, P42 ES005948-170010, R01 ES015241, R01 ES015241-02] NR 31 TC 67 Z9 67 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2009 VL 51 IS 1 BP 176 EP 186 DI 10.1016/j.jhep.2009.03.021 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 467CF UT WOS:000267713400021 PM 19450891 ER PT J AU Abadie, J Hedan, B Cadieu, E De Brito, C Devauchelle, P Bourgain, C Parker, HG Vaysse, A Margaritte-Jeannin, P Galibert, F Ostrander, EA Andre, C AF Abadie, Jerome Hedan, Benoit Cadieu, Edouard De Brito, Clotilde Devauchelle, Patrick Bourgain, Catherine Parker, Heidi G. Vaysse, Amaury Margaritte-Jeannin, Patricia Galibert, Francis Ostrander, Elaine A. Andre, Catherine TI Epidemiology, Pathology, and Genetics of Histiocytic Sarcoma in the Bernese Mountain Dog Breed SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT 4th International Conference on Advances in Canine and Feline Genomics and Inherited Diseases CY MAY 21-24, 2008 CL St Malo, FR POLYNESIA SP CNRS, Univ Rennes 1 DE Bernese mountain dogs; cancer; dog; genetics; histiocytic sarcoma ID LANGERHANS CELL HISTIOCYTOSIS; MALIGNANT HISTIOCYTOSIS; SYSTEMIC HISTIOCYTOSIS; CANINE GENETICS; ASSOCIATION; GENOME; DYSREGULATION; CANCER AB Histiocytic sarcoma (HS) refers to a highly aggressive and frequently disseminated neoplastic disease belonging to the class of canine histiocytic proliferative disorders. Disseminated I-IS (previously called malignant histiocytosis) is highly breed specific, with Bernese mountain dogs (BMDs), rottweilers, and retrievers having a high prevalence with a frequency of approximately 25%, in the BMD, breed. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by I-IS. To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. The mean age of onset was 6.5 years, males and females being equally affected. The clinical features, biochemical parameters, and pathological features have been determined. The life span after diagnosis has been estimated to be 49 days. A large BM D pedigree of 327 dogs, 121 of which are affected, was assembled. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Whole-genome linkage scans as wed as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. Altogether, these complementary approaches are expected to localize the genes for HS in the BMD, leading to advances in our knowledge of histiocyte diseases in dogs and humans. C1 [Hedan, Benoit; De Brito, Clotilde; Vaysse, Amaury; Galibert, Francis; Andre, Catherine] Univ Rennes 1, Inst Genet & Dev, Une Unite Mixte Rech 6061, CNRS,Fac Med, Rennes, France. [Abadie, Jerome] Ecole Natl Vet Nantes, Unite Anat Pathol, F-44307 Nantes 3, France. [Cadieu, Edouard; Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Devauchelle, Patrick] Ecole Natl Vet, Ctr Anticanc, F-94700 Maisons Alfort, France. [Bourgain, Catherine; Margaritte-Jeannin, Patricia] Hop Paul Brousse, Inst Genet Epidemiol & Struct Populat Humaines, INSERM, U535, Villejuif, France. RP Andre, C (reprint author), Univ Rennes 1, Inst Genet & Dev, Une Unite Mixte Rech 6061, CNRS,Fac Med, Rennes, France. EM catherine.andre@univ-rennes1.fr OI Ostrander, Elaine/0000-0001-6075-9738 NR 30 TC 27 Z9 27 U1 1 U2 19 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 2009 VL 100 BP S19 EP S27 DI 10.1093/jhered/esp039 PG 9 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 478HM UT WOS:000268578400005 PM 19531730 ER PT J AU Chase, K Jones, P Martin, A Ostrander, EA Lark, KG AF Chase, Kevin Jones, Paul Martin, Alan Ostrander, Elaine A. Lark, Karl G. TI Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT 4th International Conference on Advances in Canine and Feline Genomics and Inherited Diseases CY MAY 21-24, 2008 CL St Malo, FR POLYNESIA SP CNRS, Univ Rennes 1 DE association; canine; disease; longevity; morphology; QTL ID MAJOR DETERMINANT; DOMESTIC DOG; SYSTEM; PANCREATITIS; GENOME AB Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis. C1 [Chase, Kevin; Lark, Karl G.] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. [Jones, Paul; Martin, Alan] WALTHAM Ctr Pet Nutr, Melton Mowbray, Leics, England. [Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Chase, K (reprint author), Univ Utah, Dept Biol, 257 South 1400 East, Salt Lake City, UT 84112 USA. EM kchase99@gmail.com OI Ostrander, Elaine/0000-0001-6075-9738 FU NIGMS NIH HHS [R01 GM063056, R01 GM063056-09] NR 17 TC 32 Z9 32 U1 11 U2 41 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 2009 VL 100 BP S37 EP S41 DI 10.1093/jhered/esp011 PG 5 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 478HM UT WOS:000268578400007 PM 19321632 ER PT J AU Li, X Glaser, D Li, WH Johnson, WE O'Brien, SJ Beauchamp, GK Brand, JG AF Li, Xia Glaser, Dieter Li, Weihua Johnson, Warren E. O'Brien, Stephen J. Beauchamp, Gary K. Brand, Joseph G. TI Analyses of Sweet Receptor Gene (Tas1r2) and Preference for Sweet Stimuli in Species of Carnivora SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT 4th International Conference on Advances in Canine and Feline Genomics and Inherited Diseases CY MAY 21-24, 2008 CL St Malo, FR POLYNESIA SP CNRS, Univ Rennes 1 DE carnivore; diet; sweeteners; sweet receptor; taste testing ID CANDIDATE TASTE RECEPTOR; UMAMI TASTE; SACCHARIN PREFERENCE; GUSTATORY RESPONSES; MAMMALIAN SWEET; T1R3; ASPARTAME; LOCUS; RATS; PHYLOGENY AB The extent to which taste receptor specificity correlates with, or even predicts, diet choice is not known. We recently reported that the insensitivity to sweeteners shown by species of Felidae can be explained by their lacking of a functional Tas1r2 gene. To broaden our understanding of the relationship between the structure of the sweet receptors and preference for Sugars and artificial sweeteners, we measured responses to 12 sweeteners in 6 species of Carnivora and sequenced the coding regions of Tas1r2 in these same or closely related species. The lion showed no preference for any of the 12 sweet compounds tested, and it possesses the pseudogenized Tas1r2. All other species preferred some of the natural sugars, and their Tas1r2 sequences, having complete open reading frames, predict functional sweet receptors. In addition to preferring natural sugars, the lesser panda also preferred 3 (neotame, sucralose, and aspartame) of the 6 artificial sweeteners. Heretofore, it had been reported that among vertebrates, only Old World simians could taste aspartame. The observation that the lesser panda highly preferred aspartame could be an example of evolutionary convergence in the identification of sweet stimuli. C1 [Li, Xia; Li, Weihua; Beauchamp, Gary K.; Brand, Joseph G.] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Glaser, Dieter] Univ Zurich, Anthropol Inst & Museum, Zurich, Switzerland. [Johnson, Warren E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Beauchamp, Gary K.] Univ Penn, Dept Psychol, Sch Arts & Sci, Philadelphia, PA 19104 USA. [Beauchamp, Gary K.] Univ Penn, Dept Anat, Sch Vet Med, Philadelphia, PA 19104 USA. [Brand, Joseph G.] Univ Penn, Sch Dent Med, Dept Biochem, Philadelphia, PA 19104 USA. RP Li, X (reprint author), Monell Chem Senses Ctr, 3500 Market St, Philadelphia, PA 19104 USA. EM xiali@monell.org; brand@monell.org RI Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X FU NIDCD NIH HHS [R01 DC000882, R01DC00882] NR 45 TC 12 Z9 12 U1 2 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 2009 VL 100 BP S90 EP S100 DI 10.1093/jhered/esp015 PG 11 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 478HM UT WOS:000268578400013 PM 19366814 ER PT J AU Menotti-Raymond, M David, VA Eizirik, E Roelke, ME Ghaffari, H O'Brien, SJ AF Menotti-Raymond, Marilyn David, Victor A. Eizirik, Eduardo Roelke, Melody E. Ghaffari, Helya O'Brien, Stephen J. TI Mapping of the Domestic Cat "SILVER" Coat Color Locus Identifies a Unique Genomic Location for Silver in Mammals SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT 4th International Conference on Advances in Canine and Feline Genomics and Inherited Diseases CY MAY 21-24, 2008 CL St Malo, FR POLYNESIA SP CNRS, Univ Rennes 1 DE coat color; domestic cat; genetic linkage mapping; pheomelanogenic; SILVER ID RADIATION HYBRID MAP; FELIS-CATUS; GENE; MUTATION; TYROSINASE; RESOURCE; ZEBRAFISH; PHENOTYPE; PROTEIN; SYSTEM AB The SILVER locus has been mapped in the domestic cat, identifying a unique genomic location distinct from that of any known reported gene associated with silver or hypopigmentation in mammals. A demonstrated lack of linkage to SILV the strong candidate gene for silver, led to the initiation of a genome scan utilizing 2 pedigrees segregating for silver coat color. Linkage mapping defined a genomic region for SILVER as a 3.3-Mb region, (95.87-99.21 Mb) on chromosome D2, (peak logarithm of the odds = 10.5, theta = 0), which displays conserved synteny to a genomic interval between 118.58 and 121.85 Mb on chromosome 10 in the human genome. In the domestic cat, mutations at the SILVER locus suppress the development of pigment in the hair, but in contrast to other mammalian silver variants, there is an apparently greater influence on the production of pheomelanin than eumelanin pigment. The mapping of a novel locus for SILVER offers much promise in identifying a gene that may help elucidate aspects of pheomelanogenesis, a pathway that has been very elusive, and illustrates the promise of the cat genome project in increasing our understanding of basic biological processes of general relevance for mammals. C1 [Menotti-Raymond, Marilyn; Roelke, Melody E.] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21702 USA. [Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande do Sul, Ctr Biol Genom & Mol, Fac Biociencias, BR-90619900 Porto Alegre, RS, Brazil. RP Menotti-Raymond, M (reprint author), NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21702 USA. EM raymond@ncifcrf.gov RI Eizirik, Eduardo/K-8034-2012 OI Eizirik, Eduardo/0000-0002-9658-0999 FU NCI NIH HHS [N01-CO-12400] NR 44 TC 7 Z9 7 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 2009 VL 100 BP S8 EP S13 DI 10.1093/jhered/esp018 PG 6 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 478HM UT WOS:000268578400003 PM 19398491 ER PT J AU Pontius, JU O'Brien, SJ AF Pontius, Joan U. O'Brien, Stephen J. TI Artifacts of the 1.9x Feline Genome Assembly Derived from the Feline-Specific Satellite Sequence SO JOURNAL OF HEREDITY LA English DT Article; Proceedings Paper CT 4th International Conference on Advances in Canine and Feline Genomics and Inherited Diseases CY MAY 21-24, 2008 CL St Malo, FR POLYNESIA SP CNRS, Univ Rennes 1 DE artifacts; FA-SAT; genome assembly; repetitive elements; satellite; whole-genome shotgun ID FAMILY FA-SAT; CHROMOSOMAL LOCALIZATION; DOMESTIC CAT; DNA; PHENOTYPE; DELETION; DATABASE; BROWSER; MODEL; DOG AB Two percentage of the cat genome is a repetitive, feline-specific satellite sequence (FA-SAT) of 483 bp and 65% guanine-cytosine content. Previous chromosomal localization of the satellite has demonstrated the satellite's presence on several discrete regions of the telomeres of chromosomes, predominately on the D, E, and F chromosome groups. The recent assembly of the 1.9x whole-genome shotgun (WGS) sequence of cat illustrates the challenge of the assembly of these large numbers of relatively short, similar sequences. Clones with paired end reads that include FA-SAT sequence have a high level of assembly discrepancies compared with clones with other types of repetitive elements, such as short interspersed nuclear elements (SINEs) and long interspersed nuclear elements (LINEs). The influence of the presence of FA-SAT but not SINEs and LINEs on genome assembly may likely reflect the evolutionary emergence of FA-SAT, which has lead to an excess of FA-SAT copies with identical sequence, which is less an issue with older, more diverse SINE and LINE sequences. The FA-SATs are restricted to a few hundred discrete regions of the cat genome, and associated errors in the assembly seem to be restricted to these loci. The findings regarding the feline-specific sequence should be considered in the pending 8x assembly of the cat genome. C1 [Pontius, Joan U.] NCI, Lab Genom Divers, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Pontius, JU (reprint author), NCI, Lab Genom Divers, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. EM pontiusj@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 21 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD JUL-AUG PY 2009 VL 100 BP S14 EP S18 DI 10.1093/jhered/esp035 PG 5 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 478HM UT WOS:000268578400004 PM 19531733 ER PT J AU Meerabux, JMA Ohba, H Iwayama, Y Maekawa, M Detera-Wadleigh, SD DeLisi, LE Yoshikawa, T AF Meerabux, Joanne M. A. Ohba, Hisako Iwayama, Yoshimi Maekawa, Motoko Detera-Wadleigh, Sevilla D. DeLisi, Lynn E. Yoshikawa, Takeo TI Analysis of a t(18;21)(p11.1;p11.1) translocation in a family with schizophrenia SO JOURNAL OF HUMAN GENETICS LA English DT Article DE bacterial artificial chromosome (BAC); breakpoint; C18orf1; chromosome 18; chromosome 21; fluorescence in situ hybridization (FISH); position effect; quantitative RT-PCR ID BIPOLAR-DISORDER; GENE; SUSCEPTIBILITY; 18P11.2; LINKAGE; ASSOCIATION; GENOME; REGION; LOCUS; C18ORF1 AB It is suggested that chromosome 18p11 is a susceptibility region for both bipolar disorder and schizophrenia. Aiming to identify susceptibility gene(s), we investigated a family whose members have either schizophrenia or schizophrenia-spectrum psychosis and carried a t(18;21)(p11.1;p11.1) translocation. Fluorescence in situ hybridization showed that the breakpoint on chromosome 21 was localized to a bacterial artificial chromosome (BAC) clone RP11-2503J9, which contained coding sequences for transmembrane phosphatase with tensin homology, although this gene was not disrupted. On chromosome 18p, the break point was narrowed to BAC clone RP11-527H14. In silico sequence analysis of this clone identified possible pseudo genes and gene fragments but no intact genes. RP11-527H14 also showed sites of cross hybridization, including 21p11.1. To test for a position effect on 18p11 sequences translocated to 21p11, we performed quantitative RT-PCR to measure the expression of the candidate gene C18orf1 in translocation carriers, but found no significant differences from controls in lymphoblastoid cells. Journal of Human Genetics (2009) 54, 386-391; doi: 10.1038/jhg.2009.47; published online 22 May 2009 C1 [Meerabux, Joanne M. A.; Ohba, Hisako; Iwayama, Yoshimi; Maekawa, Motoko; Yoshikawa, Takeo] RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. [Detera-Wadleigh, Sevilla D.] NIMH, Mood & Anxiety Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [DeLisi, Lynn E.] Harvard Univ, Sch Med, Brockton, MA 02401 USA. [DeLisi, Lynn E.] Boston VA Healthcare Syst, Brockton, MA USA. [Yoshikawa, Takeo] Japan Sci & Technol Agcy, CREST, Tokyo, Japan. RP Yoshikawa, T (reprint author), RIKEN, Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM takeo@brain.riken.jp FU RIKEN BSI Funds; MEXT of Japan; CREST funds; Japan Science and Technology Agency, Japan FX We acknowledge the assistance of Dr ML Yaspo in providing the BAC clone RP11-527H14. This work was supported by RIKEN BSI Funds, Grant-in-aid for scientific studies from the MEXT of Japan to TY and YI and CREST funds from the Japan Science and Technology Agency, Japan to TY. NR 23 TC 4 Z9 5 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 J9 J HUM GENET JI J. Hum. Genet. PD JUL PY 2009 VL 54 IS 7 BP 386 EP 391 DI 10.1038/jhg.2009.47 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 474WD UT WOS:000268314100003 PM 19461657 ER PT J AU Stewart, TJ Liewehr, DJ Steinberg, SM Greeneltch, KM Abrams, SI AF Stewart, Trina J. Liewehr, David J. Steinberg, Seth M. Greeneltch, Kristy M. Abrams, Scott I. TI Modulating the Expression of IFN Regulatory Factor 8 Alters the Protumorigenic Behavior of CD11b(+)Gr-1(+) Myeloid Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HOST-TUMOR INTERACTIONS; TRANSGENIC MOUSE MODEL; SUPPRESSOR-CELLS; T-CELLS; ANTITUMOR IMMUNITY; DENDRITIC CELLS; CANCER-PATIENTS; NITRIC-OXIDE; IMMUNOSUPPRESSIVE ACTIVITY; INDUCIBLE PROTEIN-10 AB CD11b(+)Gr-1(+)-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. However, the intrinsic molecular events that drive their protumorigenic behavior remain to be elucidated. Although CD11b(+)Gr-1(+) cells exist at low frequencies in normal mice, it also remains unresolved whether they are biologically distinct from those of tumor-bearing hosts. These objectives were investigated using CD11b(+)Gr-1(+) cells from both implantable (4T1) and autochthonous (mouse mammary tumor virus-polyomavirus middle T Ag (MMTV-PyMT)) mouse models of mammary carcinoma. Limited variation was observed in the expression of markers associated with immunoregulation between CD11b(+)Gr-1(+) cells of both tumor models, as well as with their respective controls (Cnt). Despite limited differences in phenotype, tumor-induced CD11b(+)Gr-1(+) cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b(+)Gr-1(+) cells. Furthermore, when admixed with tumor cells, CD11b(+)Gr-1(+) cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cut mice. However, the protumorigenic behavior of these tumor-induced CD11b(+)Gr-1(+) cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced. The loss of this protumorigenic effect occurred independently of the host immune system and correlated with a CD11b(+)Gr-1(+) cytokine/chemokine production pattern that resembled cells from nontumor-bearing Cnt mice. Overall, our data indicate that 1) tumor-induced CD11b(+)Gr-1(+) cells from both cancer models were phenotypically similar, but biologically distinct from their nontumor-bearing counterparts and 2) modulation of IFN regulatory factor 8 levels in tumor-induced CD11b(+)Gr-1(+) cells can significantly abrogate their protumorigenic behavior, which may have important implications for cancer therapy. The Journal of Immunology 2009, 183: 117-128. C1 [Abrams, Scott I.] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Stewart, Trina J.; Greeneltch, Kristy M.; Abrams, Scott I.] NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), Roswell Pk Canc Inst, Dept Immunol, Elm & Carlton St, Buffalo, NY 14263 USA. EM scott.abrams@roswellpark.org RI Stewart, Trina/F-5967-2012 OI Stewart, Trina/0000-0003-3220-9231 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; Roswell Park Cancer Institute FX This research was supported in part by the Intrmural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. S.I.A. was also supported in part by Roswell Park Cancer Institute Institutional Funding. NR 68 TC 19 Z9 20 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2009 VL 183 IS 1 BP 117 EP 128 DI 10.4049/jimmunol.0804132 PG 12 WC Immunology SC Immunology GA 563HS UT WOS:000275119400014 PM 19542426 ER PT J AU Percopo, CM Qiu, ZJ Phipps, S Foster, PS Domachowske, JB Rosenberg, HF AF Percopo, Caroline M. Qiu, Zhijun Phipps, Simon Foster, Paul S. Domachowske, Joseph B. Rosenberg, Helene F. TI Pulmonary Eosinophils and Their Role in Immunopathologic Responses to Formalin-Inactivated Pneumonia Virus of Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; VACCINE-ENHANCED DISEASE; MACROPHAGE-INFLAMMATORY PROTEIN-1-ALPHA; T-CELLS; G-GLYCOPROTEIN; RSV CHALLENGE; BALB/C MICE; HOST-DEFENSE; COTTON RATS; WILD-TYPE AB Enhanced disease is the term used to describe the aberrant Th2-skewed responses to naturally acquired human respiratory syncytial virus (hRSV) infection observed in individuals vaccinated with formalin-inactivated viral Ags. Here we explore this paradigm with pneumonia virus of mice (PVM), a pathogen that faithfully reproduces features of severe hRSV infection in a rodent host. We demonstrate that PVM infection in mice vaccinated with formalin-inactivated Ags from PVM-infected cells (PVM Ags) yields Th2-skewed hypersensitivity, analogous to that observed in response to hRSV. Specifically, we detect elevated levels of IL-4, IL-5, IL-13, and eosinophils in bronchoalveolar lavage fluid of PVM-infected mice that were vaccinated with PVM Ags, but not among mice vaccinated with formalin-inactivated Ags from uninfected cells (control Ags). Interestingly, infection in PVM Ag-vaccinated mice was associated with a similar to 10-fold reduction in lung virus titer and protection against weight loss when compared with infected mice vaccinated with control Ags, despite the absence of serum-neutralizing Abs. Given recent findings documenting a role for eosinophils in promoting clearance of hRSV in vivo, we explored the role of eosinophils in altering the pathogenesis of disease with eosinophil-deficient mice. We found that eosinophil deficiency had no impact on virus titer in PVM Ag-vaccinated mice, nor on weight loss or levels of CCL11 (eotaxin-1), IFN-gamma, IL-5, or IL-13 in bronchoalveolar lavage fluid. However, levels of both IL-4 and CCL3 (macrophage inflammatory protein-la) in bronchoalveolar lavage fluid were markedly diminished in PVM Ag-vaccinated, PVM-infected eosinophil-deficient mice when compared with wild-type controls. The Journal of Immunology, 2009, 183: 604-612. C1 [Percopo, Caroline M.; Qiu, Zhijun; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. [Phipps, Simon; Foster, Paul S.] Univ Newcastle, Prior Res Ctr Asthma & Resp Dis, Sch Biomed Sci, Newcastle, NSW 2308, Australia. [Phipps, Simon; Foster, Paul S.] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2308, Australia. [Domachowske, Joseph B.] Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, Natl Inst Hlth, Bldg 10,Room 11C215,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov RI Phipps, Simon/F-9170-2010; Foster, Paul/G-5057-2013 OI Phipps, Simon/0000-0002-7388-3612; FU National Institute of Allergy and Infectious Diseases Division of Intramural Research FX This work was supported by National Institute of Allergy and Infectious Diseases Division of Intramural Research funding to H.F.R. NR 65 TC 14 Z9 15 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2009 VL 183 IS 1 BP 604 EP 612 DI 10.4049/jimmunol.0802270 PG 9 WC Immunology SC Immunology GA 563HS UT WOS:000275119400066 PM 19542471 ER PT J AU Rodriguez-Galan, MC Reynolds, D Correa, SG Iribarren, P Watanabe, M Young, HA AF Cecilia Rodriguez-Galan, Maria Reynolds, Della Correa, Silvia G. Iribarren, Pablo Watanabe, Morihiro Young, Howard A. TI Coexpression of IL-18 Strongly Attenuates IL-12-Induced Systemic Toxicity through a Rapid Induction of IL-10 without Affecting its Antitumor Capacity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECOMBINANT HUMAN INTERLEUKIN-12; STEM-CELL TRANSPLANTATION; IFN-GAMMA; T-CELLS; INTERFERON-GAMMA; NK CELLS; PHASE-I; INFLAMMATORY RESPONSE; IMMUNE-RESPONSES; TH2 RESPONSES AB IL-12 is an excellent candidate for the treatment of cancer due to its ability to drive strong antitumor responses. Recombinant IL-12 protein is currently used in cancer patients; however, systemic expression of rIL-12 presents disadvantages including cost and dose limitation due to its toxicity. In this study, we used hydrodynamic shear of cDNA as a tool to achieve systemic expression of IL-12. We found that sustained but toxic levels of serum IL-12 could be generated in 6- to 7-wk-old B6 mice after a single injection of the cDNA. Unexpectedly, we observed that when IL-12 cDNA is coinjected with IL-18 cDNA, IL-12 antitumor activity was maintained, but there was a significant attenuation of IL-12 toxicity, as evidenced by a greater survival index and a diminution of liver enzymes (ALT and AST). Interestingly, after IL-12 plus IL-18 cDNA administration, more rapid and higher IL-10 levels were observed than after IL-12 cDNA treatment alone. To understand the mechanism of protection, we coinjected IL-12 plus IL-10 cDNAs and observed an increase in survival that correlated with diminished serum levels of the inflammatory cytokines TNF-alpha and IFN-gamma. Confirming the protective role of early IL-10 expression, we observed a significant decrease in survival in IL-10 knockout mice or IL-10R-blocked B6 mice after IL-12 plus IL-18 treatment. Thus, our data demonstrate that the high and early IL-10 expression induced after IL-12 plus IL-18 cDNA treatment is critical to rapidly attenuate IL-12 toxicity without affecting its antitumor capacity. These data could highly contribute to the design of more efficient/less toxic protocols for the treatment of cancer. The Journal of Immunology, 2009, 183: 740-748. C1 [Cecilia Rodriguez-Galan, Maria] Univ Nacl Cordoba, Fac Ciencias Quim, CONICET, CIBICI, RA-5000 Cordoba, Argentina. [Cecilia Rodriguez-Galan, Maria; Reynolds, Della; Watanabe, Morihiro; Young, Howard A.] NCI, Expt Immunol Lab, Frederick, MD 21702 USA. [Iribarren, Pablo] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. RP Rodriguez-Galan, MC (reprint author), Univ Nacl Cordoba, Fac Ciencias Quim, CONICET, CIBICI, RA-5000 Cordoba, Argentina. EM crodri@bioclin.fcq.unc.edu.ar FU National Cancer Institute, National Institute of Health [N01-CO-12400] FX This project has been funded with federal funds from the National Cancer Institute, National Institute of Health under Contract No. N01-CO-12400. NR 52 TC 17 Z9 17 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2009 VL 183 IS 1 BP 740 EP 748 DI 10.4049/jimmunol.0804166 PG 9 WC Immunology SC Immunology GA 563HS UT WOS:000275119400080 PM 19535628 ER PT J AU Kuniholm, MH Purcell, RH McQuillan, GM Engle, RE Wasley, A Nelson, KE AF Kuniholm, Mark H. Purcell, Robert H. McQuillan, Geraldine M. Engle, Ronald E. Wasley, Annemarie Nelson, Kenrad E. TI Epidemiology of Hepatitis E Virus in the United States: Results from the Third National Health and Nutrition Examination Survey, 1988-1994 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 13th International Symposium on Viral Hepatitis and Liver Disease CY MAR 21, 2009 CL Washington, DC ID BLOOD-DONORS; ENZYME-IMMUNOASSAY; HIGH PREVALENCE; E INFECTION; ANTIBODIES; HEV; GENOTYPE-3; SWINE; JAPAN; DISEASE AB Background. Hepatitis E virus (HEV) is prevalent and causes disease worldwide, but its epidemiological profile is only partially understood. Methods. We used an enzyme immunoassay to measure anti-HEV immunoglobulin G antibodies in 18,695 serum samples collected in the Third National Health and Nutrition Examination Survey. We calculated estimates of HEV seroprevalence and examined associations with putative risk factors. Results. The seroprevalence of HEV in the civilian noninstitutionalized United States (US) population during the period from 1988 through 1994 was 21.0% (95% confidence interval [CI], 19.0%-22.9%). Among US-born individuals, males, non-Hispanic whites, and individuals residing in the Midwest and/or in metropolitan areas had the highest seroprevalence estimates. Having a pet in the home (odds ratio [OR], 1.19 [95% CI, 1.01-1.40]) and consuming liver or other organ meats more than once per month (OR, 1.38 [95% CI, 1.01-1.88]) were significantly associated with increased odds of HEV seropositivity. Conclusions. Exposure to HEV is common in the US population, although hepatitis E is rarely reported. Having pets and consuming organ meats may play a role in HEV transmission in the United States, but other mechanisms of transmission may also exist. HEV may be considered a possible etiologic agent of acute and chronic hepatitis in US patients reporting no travel history. C1 [Kuniholm, Mark H.; Nelson, Kenrad E.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Purcell, Robert H.; Engle, Ronald E.] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [McQuillan, Geraldine M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Wasley, Annemarie] Ctr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA USA. RP Nelson, KE (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Ste E7132,615 N Wolfe St, Baltimore, MD 21205 USA. EM kenelson@jhsph.edu FU Intramural NIH HHS [Z01 AI000311-26]; NIAID NIH HHS [R21 AI067449] NR 51 TC 141 Z9 147 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2009 VL 200 IS 1 BP 48 EP 56 DI 10.1086/599319 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 452CG UT WOS:000266516700009 PM 19473098 ER PT J AU Geldmacher, C Heinrich, N Koup, RA Hoelscher, M AF Geldmacher, Christof Heinrich, Norbert Koup, Richard A. Hoelscher, Michael TI Significance of Early Secreted Antigenic Target 6-Specific T Cell Depletion after HIV-1 Infection Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID TUBERCULOSIS C1 [Geldmacher, Christof; Heinrich, Norbert; Hoelscher, Michael] Klinikum Ludwig Maximilians Univ Munich, Dept Trop Med & Infect Dis, D-80802 Munich, Germany. [Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Geldmacher, C (reprint author), Klinikum Ludwig Maximilians Univ Munich, Dept Trop Med & Infect Dis, Leopoldsstr 5, D-80802 Munich, Germany. EM geldmacher@lrz.uni-muenchen.de RI Heinrich, Norbert/B-3750-2014 NR 8 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 1 PY 2009 VL 200 IS 1 BP 158 EP 159 DI 10.1086/599361 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 452CG UT WOS:000266516700023 ER PT J AU Alevizaki, M Stratakis, CA AF Alevizaki, M. Stratakis, C. A. TI Multiple endocrine neoplasias: advances and challenges for the future SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE genetics; multiple neoplasia syndromes; oncogenes; tumour suppressor genes ID GERM-LINE MUTATIONS; GASTROINTESTINAL STROMAL TUMORS; ADRENAL-HYPERPLASIA; PHOSPHODIESTERASE; GENES; PATHWAYS; GENETICS; PDE11A AB Several important advances have been made over the last 2 years, since the last international workshop on multiple endocrine neoplasias (MENs) that was held in Marseilles, France (MEN2006). The series of articles that are included in this issue summarize the most important of these advances as they were presented in Delphi, Greece, during the 11th International Workshop on MENs, September 25-27, 2008 (MEN2008). This editorial summarizes some of these advances: the identification of the AIP, and the PDE11A and PDE8B genes by genome-wide association (GWA) studies as predisposing genes for pituitary and adrenal tumours, respectively, the discovery of p27 mutations in a new form of MEN similar to MEN type 1 (MEN 1) that is now known as MEN 4, the molecular investigations of Carney triad (CT), a disorder that associates paragangliomas (PGLs), gastrointestinal stromal tumour (GISTs), and pulmonary chondromas (PCH) with pheochromocytomas and adrenocortical adenomas and other lesions, and the molecular elucidation of the association of GISTs with paragangliomas (Carney-Stratakis syndrome) that is now known to be because of SDHB, SDHC, and SDHD mutations. Molecular investigations in Carney complex (another MEN also described by Dr. Carney, who during the meeting, along with Dr. Charles E. ('Gene') Jackson was honoured for his life-long and many contributions to the field) have also revealed the role of cyclic AMP signalling in tumorigenesis. As our knowledge of the molecular causes of MENs increases, the challenge is to translate these discoveries in better treatments for our patients. Indeed, new advances in the preventive diagnosis and molecular treatment of MEN 1 and MEN 2, respectively, continued unabated, and an update on this front was also presented at MEN2008 and is included in this issue. C1 [Alevizaki, M.] Univ Athens, Alexandra Hosp, Dept Med Therapeut, Sch Med, Athens 11528, Greece. [Alevizaki, M.] Evgenide Hosp, Endocrine Unit, Athens, Greece. [Stratakis, C. A.] NICHD, Sect Endocrinol & Genet, PDEGEN, NIH, Bethesda, MD USA. RP Alevizaki, M (reprint author), Univ Athens, Sch Med, 80 Vassilissis Sofias Ave, Athens 11528, Greece. EM mani@otenet.gr FU NIH [Z01-HD-000642-04]; Office of Rare Disorders (ORD), National Institute of Child Health & Human Development (NICHD), NIH FX This work was supported by NIH intramural project Z01-HD-000642-04 to Dr. C.A. Stratakis; and, in part, by an Award from the Office of Rare Disorders (ORD) and the National Institute of Child Health & Human Development (NICHD), NIH, towards the organization of the MEN2008 meeting. NR 26 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUL PY 2009 VL 266 IS 1 BP 1 EP 4 DI 10.1111/j.1365-2796.2009.02108.x PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 456JY UT WOS:000266842900001 PM 19522821 ER PT J AU Pasini, B Stratakis, CA AF Pasini, B. Stratakis, C. A. TI SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes SO JOURNAL OF INTERNAL MEDICINE LA English DT Review DE neuroendocrine tumours; succinate dehydrogenase; tumour suppressor genes ID RENAL-CELL CARCINOMA; GERM-LINE MUTATIONS; MITOCHONDRIAL RESPIRATORY-CHAIN; CAROTID-BODY PARAGANGLIOMA; DEHYDROGENASE-B GENE; FAMILIAL NONCHROMAFFIN PARAGANGLIOMAS; COMPARATIVE GENOMIC HYBRIDIZATION; AUTOSOMAL-DOMINANT PARAGANGLIOMA; MEDULLARY-THYROID CARCINOMA; COMPLEX-II GENE AB A genetic predisposition for paragangliomas and adrenal or extra-adrenal phaeochromocytomas was recognized years ago. Beside the well-known syndromes associated with an increased risk of adrenal phaeochromocytoma, Von Hippel Lindau disease, multiple endocrine neoplasia type 2 and neurofibromatosis type 1, the study of inherited predisposition to head and neck paragangliomas led to the discovery of the novel 'paraganglioma-phaeochromocytoma syndrome' caused by germline mutations in three genes encoding subunits of the succinate dehydrogenase (SDH) enzyme (SDHB, SDHC and SDHD) thus opening an unexpected connection between mitochondrial tumour suppressor genes and neural crest-derived cancers. Germline mutations in SDH genes are responsible for 6% and 9% of sporadic paragangliomas and phaeochromocytomas, respectively, 29% of paediatric cases, 38% of malignant tumours and more than 80% of familial aggregations of paraganglioma and phaeochromocytoma. The disease is characterized by autosomal dominant inheritance with a peculiar parent-of-origin effect for SDHD mutations. Life-time tumour risk seems higher than 70% with variable clinical manifestantions depending on the mutated gene. In this review we summarize the most recent knowledge about the role of SDH deficiency in tumorigenesis, the spectrum and prevalence of SDH mutations derived from several series of cases, the related clinical manifestantions including rare phenotypes, such as the association of paragangliomas with gastrointestinal stromal tumours and kidney cancers, and the biological hypotheses attempting to explain genotype to phenotype correlation. C1 [Pasini, B.] Univ Turin, Dept Genet Biol & Biochem, I-10126 Turin, Italy. [Stratakis, C. A.] NICHHD, Program Dev Endocrinol & Genet, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Pasini, B (reprint author), Univ Turin, Dept Genet Biol & Biochem, Via Santena 19, I-10126 Turin, Italy. EM barbara.pasini@unito.it FU NIH [Z01-HD-000642-04]; Office of Rare Disorders (ORD), National Institute of Child Health & Human Development (NICHD), NIH; Associazione Italiana per la Ricerca sul Cancro FX The work of Dr. B. Pasini has been supported by Compagnia di San Paolo (Progetto Oncologia), AIRC (Italian Association on Cancer Research), Ricerca finalizzata Regione Piemonte. Authors are grateful to Barbara Ferrando for helping in data management. This work was also supported, in part, by NIH intramural project Z01-HD-000642-04 to Dr. C.A. Stratakis; and, in part, by an Award from the Office of Rare Disorders (ORD) and the National Institute of Child Health & Human Development (NICHD), NIH, towards the organization of the MEN2008 meeting. NR 157 TC 97 Z9 100 U1 1 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUL PY 2009 VL 266 IS 1 BP 19 EP 42 DI 10.1111/j.1365-2796.2009.02111.x PG 24 WC Medicine, General & Internal SC General & Internal Medicine GA 456JY UT WOS:000266842900003 PM 19522823 ER PT J AU Stratakis, CA Carney, JA AF Stratakis, C. A. Carney, J. A. TI The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications SO JOURNAL OF INTERNAL MEDICINE LA English DT Article DE gastrointestinal stromal tumours; genetics; paraganglioma; succinate dehydrogenase subunits A; B; C and D; tumour suppressor genes ID EXTRA-ADRENAL PARAGANGLIOMA; GERMLINE MUTATIONS; LEIOMYOSARCOMA; DIAGNOSIS; GISTS AB Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs. C1 [Stratakis, C. A.] NICHD, SEGEN, PDEGEN, Pediat Endocrinol Training Program,NIH,CRC, Bethesda, MD 20892 USA. [Carney, J. A.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. RP Stratakis, CA (reprint author), NICHD, SEGEN, PDEGEN, Pediat Endocrinol Training Program,NIH,CRC, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NIH [Z01-HD-000642-04]; Office of Rare Disorders (ORD), National Institute of Child Health & Human Development (NICHD), NIH FX This work was supported by NIH intramural project Z01-HD-000642-04 to Dr C.A. Stratakis, and, in part, by a Bench-to-Bedside Award from the Office of Rare Disorders (ORD) and the National Institute of Child Health & Human Development (NICHD), NIH, for the study of the 'Genetics of inherited paragangliomas and gastric stromal tumors associated with adrenal and other tumors'. NR 32 TC 115 Z9 121 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0954-6820 J9 J INTERN MED JI J. Intern. Med. PD JUL PY 2009 VL 266 IS 1 BP 43 EP 52 DI 10.1111/j.1365-2796.2009.02110.x PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 456JY UT WOS:000266842900004 PM 19522824 ER PT J AU O'Connell, MP Fiori, JL Baugher, KM Indig, FE French, AD Camilli, TC Frank, BP Earley, R Hoek, KS Hasskamp, JH Elias, EG Taub, DD Bernier, M Weeraratna, AT AF O'Connell, Michael P. Fiori, Jennifer L. Baugher, Katherine M. Indig, Fred E. French, Amanda D. Camilli, Tura C. Frank, Brittany P. Earley, Rachel Hoek, Keith S. Hasskamp, Joanne H. Elias, E. George Taub, Dennis D. Bernier, Michel Weeraratna, Ashani T. TI Wnt5A Activates the Calpain-Mediated Cleavage of Filamin A SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE ` ID CELL-MIGRATION; MELANOMA-CELLS; CANCER CELLS; EXPRESSION; MOTILITY; METASTASIS; INVASION; RECEPTOR; SAGE; CYTOSKELETON AB We have previously shown that Wnt5A and ROR2, an orphan tyrosine kinase receptor, interact to mediate melanoma cell motility. In other cell types, this can occur through the interaction of ROR2 with the cytoskeletal protein filamin A. Here, we found that filamin A protein levels correlated with Wnt5A levels in melanoma cells. Small interfering RNA (siRNA) knockdown of WNT5A decreased filamin A expression. Knockdown of filamin A also corresponded to a decrease in melanoma cell motility. In metastatic cells, filamin A expression was predominant in the cytoplasm, which western analysis indicated was due to the cleavage of filamin A in these cells. Treatment of nonmetastatic melanoma cells with recombinant Wnt5A increased filamin A cleavage, and this could be prevented by the knockdown of ROR2 expression. Further, BAPTA-AM chelation of intracellular calcium also inhibited filamin A cleavage, leading to the hypothesis that Wnt5A/ROR2 signaling could cleave filamin A through activation of calcium-activated proteases, such as calpains. Indeed, WNT5A knockdown decreased calpain 1 expression, and by inhibiting calpain 1 either pharmacologically or using siRNA, it decreased cell motility. Our results indicate that Wnt5A activates calpain-1, leading to the cleavage of filamin A, which results in a remodeling of the cytoskeleton and an increase in melanoma cell motility. C1 [Weeraratna, Ashani T.] NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Fiori, Jennifer L.; Bernier, Michel] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Indig, Fred E.; Frank, Brittany P.; Earley, Rachel] NIA, Confocal Imaging Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Hoek, Keith S.] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. [Hasskamp, Joanne H.; Elias, E. George] Franklin Sq Hosp, Harry & Jeanette Weinberg Canc Inst, Div Surg Oncol, Baltimore, MD USA. RP Weeraratna, AT (reprint author), NIA, Immunol Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Bernierm@mail.nih.gov; weerarat@grc.nia.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU National Institute on Aging (NIA); National Institutes of Health (NIH); Swiss National Foundation [3100A0-103671]; Oncosuisse [OCS-01927-08-2006)] FX We thank Liqun Jiang for generously providing calpain inhibitor III. This research was supported by the Intramural Research Program (IRP) of the National Institute on Aging (NIA), National Institutes of Health (NIH). K. S. H. was supported by the Swiss National Foundation (3100A0-103671) and Oncosuisse (OCS-01927-08-2006). NR 29 TC 36 Z9 38 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2009 VL 129 IS 7 BP 1782 EP 1789 DI 10.1038/jid.2008.433 PG 8 WC Dermatology SC Dermatology GA 461ME UT WOS:000267270300026 PM 19177143 ER PT J AU Lang, L Ma, Y Kim, BM Jagoda, EM Rice, KC Szajek, LP Contoreggi, C Gold, PW Chrousos, GP Eckelman, WC Kiesewetter, DO AF Lang, L. Ma, Y. Kim, B. M. Jagoda, E. M. Rice, K. C. Szajek, L. P. Contoreggi, C. Gold, P. W. Chrousos, G. P. Eckelman, W. C. Kiesewetter, D. O. TI [Br-76]BMK-I-152, a non-peptide analogue for PET imaging of corticotropin-releasing hormone type 1 receptor (CRHR1) SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE corticotropin-releasing hormone; radiobromination; bromine-76; CRH; PET ID CRF1 RECEPTOR; STRESS; ANXIETY AB The study of corticotropin-releasing hormone is of significant interest in mental health. We have developed a radiobromination procedure for the preparation of [Br-76]BMK-I-152, a high-affinity corticotropin-releasing hormone type 1 receptor antagonist. The radiobromination procedure resulted in the formation of two radiobrominated products from the same trialkyltin precursor. Utilizing the results of several reaction conditions and the chromatographic and mass spectral data obtained from Waters Acquity and Q-TOF, we determined that both 3-bromo and 4-bromo isomers could be obtained. The authentic sample of the 3-bromo isomer was prepared to confirm the identity of a previously unknown radioactive side product; affinity assays revealed that the 4-bromo isomer had similar to 70 times higher affinity than that of the 3-bromo compound. By manipulation of reaction conditions, the individual products could be selected. Under no-carrier-added conditions at room temperature in aqueous acetonitrile, the major radioactive product (>80%) was identified as the 3-[Br-76]bromo-4-tributylstannyl analogue of BMK-I-152. The 4-[Br-76]bromo isomer accounted for less than 1% of the total activity. The 3-[Br-76]bromo BMK-I-152 could be obtained by treating this intermediate with trifluoroacetic acid to effect removal of the trialkyltin. if the radiobromination was conducted after first evaporating the water from the aqueous ammonium hydroxide solution of [Br-76]bromide, the desired 4-[Br-76]bromo isomer was obtained with a 58% radiochemical yield. C1 [Lang, L.; Ma, Y.; Jagoda, E. M.; Kiesewetter, D. O.] Natl Inst Biomed Imaging & Bioengn, PET Radiochem Grp, NIH, Bethesda, MD 20892 USA. [Kim, B. M.; Rice, K. C.; Contoreggi, C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Rockville, MD USA. [Kim, B. M.; Rice, K. C.; Contoreggi, C.] NIAAA, Rockville, MD 20852 USA. [Szajek, L. P.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Gold, P. W.] NIMH, Mood & Anxiety Res Program, Bethesda, MD 20892 USA. [Chrousos, G. P.] Univ Athens, Sch Med, Aghia Sophia Childrens Hosp, Dept Pediat 1, GR-11527 Athens, Greece. [Eckelman, W. C.] Mol Tracer LLC, Bethesda, MD USA. RP Lang, L (reprint author), Natl Inst Biomed Imaging & Bioengn, PET Radiochem Grp, NIH, Bldg 10,Room 1C401,10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. EM llang@mail.nih.gov FU intramural programs of the National Institute of Biomedical Imaging and Bioengineering; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism; National Institute on Diabetes and Digestive and Kidney Diseases FX This work was supported by the intramural programs of the National Institute of Biomedical Imaging and Bioengineering, the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Diabetes and Digestive and Kidney Diseases. NR 15 TC 8 Z9 8 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD JUL-AUG PY 2009 VL 52 IS 9-10 BP 394 EP 400 DI 10.1002/jlcr.1616 PG 7 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 506BY UT WOS:000270749400010 ER PT J AU Umhau, JC Zhou, WY Carson, RE Rapoport, SI Polozova, A Demar, J Hussein, N Bhattacharjee, AK Ma, KZ Esposito, G Majchrzak, S Herscovitch, P Eckelman, WC Kurdziel, KA Salem, N AF Umhau, John C. Zhou, Weiyin Carson, Richard E. Rapoport, Stanley I. Polozova, Alla Demar, James Hussein, Nahed Bhattacharjee, Abesh K. Ma, Kaizong Esposito, Giuseppe Majchrzak, Sharon Herscovitch, Peter Eckelman, William C. Kurdziel, Karen A. Salem, Norman, Jr. TI Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography SO JOURNAL OF LIPID RESEARCH LA English DT Article DE metabolism; blood flow; n-3 polyunsaturated fatty acid ID ALPHA-LINOLENIC ACID; POLYUNSATURATED FATTY-ACIDS; RAT-BRAIN; ARACHIDONIC-ACID; SIGNAL-TRANSDUCTION; NUTRITIONAL DEPRIVATION; LIQUID-CHROMATOGRAPHY; UNANESTHETIZED RATS; PHOSPHOLIPASE A(2); MAMMALIAN BRAIN AB Docosahexaenoic acid (DHA; 22: 6n-3) is a critical constituent of the brain, but its metabolism has not been measured in the human brain in vivo. In monkeys, using positron emission tomography (PET), we first showed that intravenously injected [1-(11)C] DHA mostly entered nonbrain organs, with similar to 0.5% entering the brain. Then, using PET and intravenous [1-(11)C] DHA in 14 healthy adult humans, we quantitatively imaged regional rates of incorporation (K*) of DHA. We also imaged regional cerebral blood flow (rCBF) using PET and intravenous [(15)O] water. Values of K* for DHA were higher in gray than white matter regions and correlated significantly with values of rCBF in 12 of 14 subjects despite evidence that rCBF does not directly influence K*. For the entire human brain, the net DHA incorporation rate J(in), the product of K*, and the unesterified plasma DHA concentration equaled 3.8 +/- 6 1.7 mg/day. This net rate is equivalent to the net rate of DHA consumption by brain and, considering the reported amount of DHA in brain, indicates that the half-life of DHA in the human brain approximates 2.5 years. Thus, PET with [1-11C] DHA can be used to quantify regional and global human brain DHA metabolism in relation to health and disease.-Umhau, J. C., W. Zhou, R. E. Carson, S. I. Rapoport, A. Polozova, J. Demar, N. Hussein, A. K. Bhattacharjee, K. Ma, G. Esposito, S. Majchrzak, P. Herscovitch, W. C. Eckelman, K. A. Kurdziel, and N. Salem, Jr. Imaging incorporation of circulating docosahexaenoic acid into the human brain using positron emission tomography. J. Lipid Res. 2009. 50: 1259-1268. C1 [Umhau, John C.; Zhou, Weiyin] NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. [Polozova, Alla; Demar, James; Hussein, Nahed; Majchrzak, Sharon; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Carson, Richard E.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Rapoport, Stanley I.; Demar, James; Bhattacharjee, Abesh K.; Ma, Kaizong; Esposito, Giuseppe] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Herscovitch, Peter; Eckelman, William C.] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. [Kurdziel, Karen A.] Virginia Commonwealth Univ, Richmond, VA 23298 USA. [Eckelman, William C.] Mol Tracer, Bethesda, MD 20814 USA. RP Umhau, JC (reprint author), NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. EM umhau@jhu.edu RI Carson, Richard/H-3250-2011; Majchrzak, Sharon/F-1830-2013 OI Carson, Richard/0000-0002-9338-7966; Majchrzak, Sharon/0000-0001-8934-7294 FU Intramural NIH HHS NR 74 TC 74 Z9 75 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2009 VL 50 IS 7 BP 1259 EP 1268 DI 10.1194/jlr.M800530-JLR200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457EV UT WOS:000266912200002 PM 19112173 ER PT J AU Cox, JT Moriarty, AT Castle, PE AF Cox, John Thomas Moriarty, Ann T. Castle, Philip E. TI Commentary on: Statement on HPV DNA Test Utilization SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Editorial Material DE human papillomavirus (HPV); HPV test; Pap test; cervical intraepithelial neoplasia (CIN); consensus guidelines ID HUMAN-PAPILLOMAVIRUS; CERVICAL-CANCER; SCREENING-TESTS; COHORT; WOMEN; NEOPLASIA; RISK; METAANALYSIS; MANAGEMENT; AMERICAN C1 [Cox, John Thomas] Univ Calif Santa Barbara, Student Hlth Serv, Gynecol & Colposcopy Clin, Santa Barbara, CA 93106 USA. [Moriarty, Ann T.] AmeriPath Indiana, Indianapolis, IN USA. [Castle, Philip E.] NCI, Div Canc Epidemiol, NIH, DHHS, Bethesda, MD 20892 USA. [Castle, Philip E.] NCI, Div Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Cox, JT (reprint author), Univ Calif Santa Barbara, Student Hlth Serv, Gynecol & Colposcopy Clin, Santa Barbara, CA 93106 USA. EM cox-t@sa.ucsb.edu NR 21 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JUL PY 2009 VL 13 IS 3 BP 131 EP 134 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 464IH UT WOS:000267498100002 PM 19550208 ER PT J AU Solomon, D Papillo, J Davey, DD AF Solomon, Diane Papillo, Jacalyn Davey, Diane Davis CA CETC TI Statement on HPV DNA Test Utilization SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Editorial Material DE HPV testing; cervical screening; cervical cancer prevention C1 [Solomon, Diane] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Papillo, Jacalyn] Fletcher Allen Hlth Care, Dept Anat Pathol, Burlington, VT USA. [Davey, Diane Davis] Univ Cent Florida, Coll Med, Orlando, FL 32816 USA. RP Solomon, D (reprint author), Execut Plaza N Room 2130,6130 Execut Blvd, Rockville, MD 20852 USA. EM ds87v@nih.gov NR 3 TC 11 Z9 11 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JUL PY 2009 VL 13 IS 3 BP 135 EP 136 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 464IH UT WOS:000267498100003 PM 19550209 ER PT J AU Massad, LS Jeronimo, J Katki, HA Schiffman, M AF Massad, L. Stewart Jeronimo, Jose Katki, Hormuzd A. Schiffman, Mark CA NIH ASCCP Res Grp TI The Accuracy of Colposcopic Grading for Detection of High-Grade Cervical Intraepithelial Neoplasia SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE colposcopy; acetowhite lesion; biopsy; Pap test; cervical intraepithelial neoplasia ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; DIRECTED BIOPSY; UNDETERMINED SIGNIFICANCE; INTEROBSERVER AGREEMENT; WOMEN; CANCER; SMEARS; INDEX AB Objective. To relate aspects of online colposcopic image assessment to the diagnosis of grades 2 and 3 cervical intraepithelial neoplasia (CIN 2+). Methods. To simulate colposcopic assessment, we obtained digitized cervical images at enrollment after acetic acid application from 919 women referred for equivocal or minor cytologic abnormalities into the ASCUS-LSIL Triage Study. For each, 2 randomly assigned evaluators from a pool of 20 colposcopists assessed images using a standardized tool online. We calculated the accuracy of these assessments for predicting histologic CIN 2+ over the 2 years of study. For validation, a subset of online results was compared with same-day enrollment colposcopic assessments. Results. Identifying any acetowhite lesion in images yielded high sensitivity: 93% of women with CIN 2+ had at least 1 acetowhite lesion. However, 74% of women without CIN 2+ also had acetowhitening, regardless of human papillomavirus status. The sensitivity for CIN 2+ of an online colpophotographic assessment of high-grade disease was 39%. The sensitivity for CIN 2+ of a high-grade diagnosis by Reid Index scoring was 30%, and individual Reid Index component scores had similar levels of sensitivity and specificity. The performance of online assessment was not meaningfully different from that of same-day enrollment colposcopy, suggesting that these approaches have similar utility. Conclusions. Finding acetowhite lesions identifies women with CIN 2+, but using subtler colposcopic characteristics to grade lesions is insensitive. All acetowhite lesions should be assessed with biopsy to maximize sensitivity of colposcopic diagnosis with good specificity. E C1 [Massad, L. Stewart] Washington Univ, Sch Med, Div Gynecol Oncol, St Louis, MO 63110 USA. [Jeronimo, Jose] Program Appropriate Technol Hlth, Seattle, WA USA. [Katki, Hormuzd A.; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Massad, LS (reprint author), Washington Univ, Sch Med, Div Gynecol Oncol, 4911 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM massadl@wudosis.wustl.edu RI Katki, Hormuzd/B-4003-2015; OI Antani, Sameer/0000-0002-0040-1387 FU NIH-ASCCP FX Affiliations of the NIH-ASCCP Research Group: NR 23 TC 60 Z9 61 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JUL PY 2009 VL 13 IS 3 BP 137 EP 144 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 464IH UT WOS:000267498100004 PM 19550210 ER PT J AU Gage, JC Rodriguez, AC Schiffman, M Garcia, FM Long, RL Budihas, SR Herrero, R Burk, RD Jeronimo, J AF Gage, Julia C. Cecilia Rodriguez, Ana Schiffman, Mark Garcia, Francisco M. Long, Rodney L. Budihas, Scott R. Herrero, Rolando Burk, Robert D. Jeronimo, Jose TI Treatability by Cryotherapy in a Screen-and-Treat Strategy SO JOURNAL OF LOWER GENITAL TRACT DISEASE LA English DT Article DE cervical intraepithelial neoplasia; cryotherapy; mass screening; human papillomavirus; low-resource settings ID HUMAN-PAPILLOMAVIRUS INFECTION; CERVICAL-CANCER PREVENTION; LOW-RESOURCE SETTINGS; COSTA-RICA; WOMEN; NEOPLASIA; GUANACASTE AB Objectives. We estimated the percentage of women infected with human papillomavirus (HPV+) who cannot be immediately treated with cryotherapy. Materials and Methods. In a 10,000-woman Costa Rican cohort, we analyzed the 559 HPV+ women aged 25 to 55 years and estimated the proportion for whom immediate cryotherapy was not indicated (i.e., invasive cancer, large precancerous lesions, or benign abnormalities that risk failure such as large ectopy, squamocolumnar junction not visualized, polyps, ulcers, or distorted or atrophied cervix). To determine whether cryotherapy at time of baseline HPV screening would effectively treat HPV+ women, 2 expert gynecologists independently judged entire clinical histories (5-7 years of cytology, histology, and HPV tests) and a full longitudinal series of digitized cervical images. Results. Reviewers judged 144 (25.8%) of 559 HPV+ women as not treatable by immediate cryotherapy. Among 72 women with cervical intraepithelial neoplasia grade 3 who would benefit most from a screening program, 35 (48.6%) were not treatable. In particular, 29 women (40.3%) were determined not treatable for reasons most likely associated with cryotherapy's inadequacy (lesion was large, suspected cancerous or in the endocervical canal or fornix). Conclusions. "Screen-and-treat" programs in low-resource settings will soon use a rapid HPV test to screen older women once or twice in their lifetime, identifying women at higher risk for precancer. Our findings suggest that cryotherapy might not effectively treat many precancers, and other safe, low-technology treatment options could be required, in a scenario where all HPV+ women in this targeted group would receive cryotherapy at the same visit. C1 [Gage, Julia C.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Cecilia Rodriguez, Ana; Herrero, Rolando] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Garcia, Francisco M.] Univ Arizona, Natl Ctr Excellence Womens Hlth, Tucson, AZ USA. [Long, Rodney L.; Budihas, Scott R.] Natl Lib Med, Commun Engn Branch, Bethesda, MD USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Obstet, Bronx, NY USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Gynecol, Bronx, NY USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Womens Hlth, Bronx, NY USA. [Burk, Robert D.] Albert Einstein Canc Ctr, Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY USA. [Jeronimo, Jose] Program Appropriate Technol Hlth, Seattle, WA USA. RP Gage, JC (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5102, Rockville, MD 20852 USA. EM gagej@mail.nih.gov FU Public Health Service [N01CP21081, N01CP31061]; National Institutes of Health, the Department of Health and Human Services; Costa Rican Foundation for Training in Health Sciences [FUCODOCSA]; NCI [N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, N01-CP-81023] FX Supported by Public Health Service (contracts N01CP21081 and N01CP31061 between the National Cancer Institute [NCI], the National Institutes of Health, the Department of Health and Human Services, and the Costa Rican Foundation for Training in Health Sciences [FUCODOCSA], Costa Rica); NCI (contracts N01-CP-21081, N01-CP-33061, N01-CP-40542, N01-CP-50535, and N01-CP-81023 with FUCODOCSA; grant CA78527 to R.D,B.). NR 21 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1089-2591 J9 J LOW GENIT TRACT DI JI J. Low. Genit. Tract. Dis. PD JUL PY 2009 VL 13 IS 3 BP 174 EP 181 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 464IH UT WOS:000267498100010 PM 19550216 ER PT J AU Ozarslan, E AF Ozarslan, Evren TI Compartment shape anisotropy (CSA) revealed by double pulsed field gradient MR SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Double; PGSE; PFG; Scattering; Multiple; Wavevector; Pore size; Shape; Eccentricity; Microscopic; Anisotropy; General gradient waveform ID SPIN-ECHO NMR; EXPERIMENTAL PARAMETERS; STRUCTURAL INFORMATION; RESTRICTED GEOMETRIES; DIFFUSION CORRELATION; WATER DIFFUSION; SIGNAL DECAY; TIME; TISSUE; RESOLUTION AB The multiple scattering extensions of the pulsed field gradient (PFG) experiments can be used to characterize restriction-induced anisotropy at different length scales. In double-PFG acquisitions that involve two pairs of diffusion gradient pulses, the dependence of the MR signal attenuation on the angle between the two gradients is a signature of restriction that can be observed even at low gradient strengths. In this article, a comprehensive theoretical treatment of the double-PFG observation of restricted diffusion is presented. In the first part of the article, the problem is treated for arbitrarily shaped pores under idealized experimental conditions, comprising infinitesimally narrow gradient pulses with long separation times and long or vanishing mixing times. New insights are obtained when the treatment is applied to simple pore shapes of spheres, ellipsoids, and capped cylinders. The capped cylinder geometry is considered in the second part of the article where the solution for a double-PFG experiment with arbitrary experimental parameters is introduced. Although compartment shape anisotropy (CSA) is emphasized here, the findings of this article can be used in gleaning the volume, eccentricity, and orientation distribution function associated with ensembles of anisotropic compartments using double-PFG acquisitions with arbitrary experimental parameters. Published by Elsevier Inc. C1 NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Ozarslan, E (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. EM evren@helix.nih.gov RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU National Institutes of Health (NIH) FX The author acknowledges Dr. Peter J. Basser for his encouragement and many stimulating discussions and Liz Salak for editing the manuscript. This research was supported by the Intramural Research Program of the NICHD at the National Institutes of Health (NIH). NR 40 TC 58 Z9 58 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2009 VL 199 IS 1 BP 56 EP 67 DI 10.1016/j.jmr.2009.04.002 PG 12 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 456YJ UT WOS:000266890300008 PM 19398210 ER PT J AU Koay, CG Ozarslan, E Pierpaoli, C AF Koay, Cheng Guan Ozarslan, Evren Pierpaoli, Carlo TI Probabilistic Identification and Estimation of Noise (PIESNO): A self-consistent approach and its applications in MRI SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Noise identification; Noise variance estimation; Rayleigh distribution; Gamma distribution; MR noise; Noise clustering; Graphical analysis of noise ID DIFFUSION TENSOR MRI; MAGNETIC-RESONANCE IMAGES; FIBER ORIENTATION; RESOLUTION; VARIANCE; UNCERTAINTY; FRAMEWORK; RECONSTRUCTION AB Data analysis in MRI usually entails a series of processing procedures. One of these procedures is noise assessment, which in the context of this work, includes both the identification of noise-only pixels and the estimation of noise variance (standard deviation). Although noise assessment is critical to many MRI processing techniques, the identification of noise-only pixels has received less attention than has the estimation of noise variance. The main objectives of this paper are, therefore, to demonstrate (a) that the identification of noise-only pixels has an important role to play in the analysis of MRI data, (b) that the identification of noise-only pixels and the estimation of noise variance can be combined into a coherent framework, and (c) that this framework can be made self-consistent. To this end, we propose a novel iterative approach to simultaneously identify noise-only pixels and estimate the noise standard deviation from these identified pixels in a commonly used data structure in MRI. Experimental and simulated data were used to investigate the feasibility, the accuracy and the stability of the proposed technique. Published by Elsevier Inc C1 [Koay, Cheng Guan; Ozarslan, Evren; Pierpaoli, Carlo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Koay, CG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, NIH, Bldg 13,Rm 3W16,13 South Dr,MSC 5772, Bethesda, MD 20892 USA. EM guankoac@mail.nih.gov RI Pierpaoli, Carlo/E-1672-2011; Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU Intramural NIH HHS [NIH0012236071, ]; PHS HHS [NIH0012236071] NR 44 TC 26 Z9 26 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUL PY 2009 VL 199 IS 1 BP 94 EP 103 DI 10.1016/j.jmr.2009.03.005 PG 10 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 456YJ UT WOS:000266890300012 PM 19346143 ER PT J AU Minter, L Kovacic, B Claborn, DM Lawyer, P Florin, D Brown, GC AF Minter, Logan Kovacic, Brian Claborn, David M. Lawyer, Phillip Florin, David Brown, G. C. TI New State Records for Lutzomyia shannoni and Lutzomyia vexator SO JOURNAL OF MEDICAL ENTOMOLOGY LA English DT Article DE leishmaniasis; vesicular stomatitis virus; phlebotomine ID VESICULAR STOMATITIS-VIRUS; PHLEBOTOMINE SAND FLIES; LEISHMANIA-MEXICANA; OSSABAW ISLAND; UNITED-STATES; PSYCHODIDAE; DIPTERA; TRANSMISSION; GEORGIA AB Two species of phlebotomine sand flies, Lutzomyia shannoni (Dyar) and Lutzomyia vexator (Coquillett), are reported for the first time from Kentucky and Ohio. L.vexator also is reported for the first time front Tennessee. These insects were found in a northeasterly band extending from southwestern Kentucky to Southwestern Ohio. Both species were consistently captured from mid-July through September in 2006 and 2007 by using CO(2)-baited Center for Disease Control light traps. Weekly sampling revealed that these flies are more abundant in the southern part of this band than in the northern part, but increasing densities throughout this new range indicate that the flies are currently expanding their range. Although both species have been reported further north along the Atlantic coast, and L. vexator along the Pacific coast, neither of them had been reported this far north along the Mississippi Valley. Previous reports established L. shannoni as far north as west central Tennessee and L. vexator in a similar spatial pattern in the ea-stern part of its range, extending as far north as northern Alabama. Whether the new records reported herein represent a northerly expansion of the geographic range of these species or are reflective of sampling changes is inconclusive. However, the former scenario could presage an increased prevalence of the diseases associated with this group of insects. C1 [Minter, Logan; Kovacic, Brian; Brown, G. C.] Univ Kentucky, Dept Entomol, Lexington, KY 40546 USA. [Claborn, David M.] Missouri State Univ, Dept Nursing, Publ Hlth Program, Springfield, MO 65897 USA. [Lawyer, Phillip] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Florin, David] WRAMC Forest Glen Annex, Armed Forces Pest Management Board, Washington, DC 20307 USA. RP Minter, L (reprint author), Univ Kentucky, Dept Entomol, S225 Agr Sci N, Lexington, KY 40546 USA. EM log_mint@yahoo.com NR 10 TC 11 Z9 11 U1 0 U2 0 PU ENTOMOLOGICAL SOC AMER PI LANHAM PA 10001 DEREKWOOD LANE, STE 100, LANHAM, MD 20706-4876 USA SN 0022-2585 J9 J MED ENTOMOL JI J. Med. Entomol. PD JUL PY 2009 VL 46 IS 4 BP 965 EP 968 DI 10.1603/033.046.0432 PG 4 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 465XQ UT WOS:000267623800033 PM 19645303 ER PT J AU Miller, FG Joffe, S AF Miller, F. G. Joffe, S. TI Limits to research risks SO JOURNAL OF MEDICAL ETHICS LA English DT Article ID CLINICAL-RESEARCH; ETHICS; EQUIPOISE; CRITIQUE AB Risk-benefit assessment is a routine requirement for research ethics committees that review and oversee biomedical research with human subjects. Nevertheless, it remains unclear how to weigh and balance risks to research participants against the social benefits that flow from generating biomedical knowledge. In this article, we address the question of whether there are any reasonable criteria for defining the limit of permissible risks to individuals who provide informed consent for research participation. We argue against any a priori limit to permissible research risks. However, attention to the uncertainty of potential social benefit that can be derived from any particular study warrants caution in exposing prospective research participants to a substantial likelihood of serious harm. C1 [Miller, F. G.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Joffe, S.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Dept Med, Boston, MA 02115 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov OI Joffe, Steven/0000-0002-0667-7384 NR 19 TC 24 Z9 26 U1 1 U2 6 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0306-6800 J9 J MED ETHICS JI J. Med. Ethics PD JUL PY 2009 VL 35 IS 7 BP 445 EP 449 DI 10.1136/jme.2008.026062 PG 5 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 465MO UT WOS:000267590300013 PM 19567696 ER PT J AU Li, X Monda, KL Goring, HHH Haack, K Cole, SA Diego, VP Almasy, L Laston, S Howard, BV Shara, NM Lee, ET Best, LG Fabsitz, RR MacCluer, JW North, KE AF Li, X. Monda, K. L. Goering, H. H. H. Haack, K. Cole, S. A. Diego, V. P. Almasy, L. Laston, S. Howard, B. V. Shara, N. M. Lee, E. T. Best, L. G. Fabsitz, R. R. MacCluer, J. W. North, Kari E. TI Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID CORONARY-ARTERY-DISEASE; QUANTITATIVE TRAIT LOCI; CARDIOVASCULAR-DISEASE; HDL-CHOLESTEROL; SUSCEPTIBILITY LOCUS; MEXICAN-AMERICANS; RISK; GENES; DYSLIPIDEMIA; PREVALENCE AB Background: Recent studies have identified chromosomal regions linked to variation in high density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apo A-1) and triglyceride (TG), although results have been inconsistent and previous studies of American Indian populations are limited. Objective: In an attempt to localise quantitative trait loci (QTLs) influencing HDL-C, apo A-1 and TG, we conducted genome-wide linkage scans of subjects of the Strong Heart Family Study. Methods: We implemented analyses in 3484 men and women aged 18 years or older, at three study centres. Results: With adjustment for age, sex and centre, we detected a QTL influencing both HDL-C (logarithm of odds (LOD) = 4.4, genome-wide p = 0.001) and apo A-1 (LOD = 3.2, genome-wide p = 0.020) nearest marker D6S289 at 6p23 in the Arizona sample. Another QTL influencing apo A-1 was found nearest marker D9S287 at 9q22.2 (LOD = 3.0, genome-wide p = 0.033) in the North and South Dakotas. We detected a QTL influencing TG nearest marker D15S153 at 15q22.31 (LOD = 4.5 in the overall sample and LOD = 3.8 in the Dakotas sample, genome-wide p = 0.0044) and when additionally adjusted for waist, current smoking, current alcohol, current oestrogen, lipid treatment, impaired fasting glucose, and diabetes, nearest marker D10S217 at 10q26.2 (LOD = 3.7, genome-wide p = 0.0058) in the Arizona population. Conclusions: The replication of QTLs in regions of the genome that harbour well known candidate genes suggest that chromosomes 6p, 9q and 15q warrant further investigation with fine mapping for causative polymorphisms in American Indians. C1 [Li, X.; Monda, K. L.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Goering, H. H. H.; Haack, K.; Cole, S. A.; Diego, V. P.; Almasy, L.; Laston, S.; MacCluer, J. W.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Howard, B. V.; Shara, N. M.] MedStar Res Inst, Washington, DC USA. [Lee, E. T.] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, Oklahoma City, OK USA. [Best, L. G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, R. R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. RP North, KE (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. EM kari_north@unc.edu OI Diego, Vincent/0000-0002-0007-2085 FU National Heart, Lung, and Blood Institute [U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521]; National Institutes of Health [MH059490]; National Center for Research Resources, National Institutes of Health [C06 RR13556, C06 RR017515] FX This research was funded by a cooperative agreement that includes grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, and U01 HL65521 from the National Heart, Lung, and Blood Institute. We would also like to acknowledge US Public Health Service grant MH059490 from the National Institutes of Health. This investigation was conducted in facilities constructed with support from Research Facilities Improvement Program Grants C06 RR13556 and C06 RR017515 from the National Center for Research Resources, National Institutes of Health. NR 47 TC 9 Z9 9 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD JUL PY 2009 VL 46 IS 7 BP 472 EP 479 DI 10.1136/jmg.2008.063891 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 465RD UT WOS:000267603600010 PM 19429595 ER PT J AU Waters, EA Sullivan, HW Nelson, W Hesse, BW AF Waters, Erika A. Sullivan, Helen W. Nelson, Wendy Hesse, Bradford W. TI What Is My Cancer Risk? How Internet-Based Cancer Risk Assessment Tools Communicate Individualized Risk Estimates to the Public: Content Analysis SO JOURNAL OF MEDICAL INTERNET RESEARCH LA English DT Article DE Risk; risk assessment; communication; risk communication; perception; risk perception; calculators, programmable; risk calculator; Internet; online; cancer ID SOCIAL-COMPARISON INFORMATION; TREATMENT DECISIONS; FREQUENCY FORMATS; PERCEIVED RISK; NUMERACY SCALE; HEALTH-RISK; COMPREHENSION; PROBABILITY; INSTRUCTION; RESPONSES AB Background: Internet-based cancer risk assessment tools have the potential to inform the public about cancer risk and promote risk-reducing behaviors. However, poorly communicated information oil these websites may result in unintended adverse health outcomes. Objective: This study examined whether: (1) Internet-based cancer risk assessment tools use risk communication formats that facilitate comprehension and reduce bias (as identified by the empirical literature); (2) the use of these formats varies by website affiliation; and (3) the websites provided information necessary to evaluate the quality of the risk estimate. Methods: A content analysis of Internet-based cancer risk assessment tools was conducted. The terms calculate cancer risk, cancer risk calculator, estimate cancer risk, assess cancer risk, and cancer risk assessment were searched using three search engines. We identified 47 risk assessment tools and coded each according to standardized criteria. We calculated simple frequencies on all coding categories and performed crosstabulations but did not conduct formal statistical analysis due to small cell sizes. Results: Use of risk communication formats that facilitate comprehension and reduce bias varied widely (eg, 30% of websites [14/47] provided absolute and comparative risk information but 83% [39/47] provided safety messages). Use of formats that facilitate comprehension varied by website affiliation and communication strategy (eg, only 8.3% [1/12] websites affiliated with the health care industry provided absolute and comparative risk information, but 83% [5/6] of websites affiliated with a governmental organization did so). Only 53% (25/47) of websites provided information about the statistical model or the peer-reviewed literature that was used to calculate the risk estimate. Conclusion: Internet-based cancer risk assessment tools varied in their use of risk communication formats that facilitate comprehension and reduce bias. Formats that are difficult to understand may cause people to misperceive their cancer risk and consequently take inappropriate action. C1 [Waters, Erika A.; Sullivan, Helen W.; Hesse, Bradford W.] NCI, Hlth Commun & Informat Res Branch, Bethesda, MD 20892 USA. [Nelson, Wendy] NCI, Basic & Biobehav Res Branch, Bethesda, MD 20892 USA. RP Waters, EA (reprint author), NCI, Hlth Commun & Informat Res Branch, Execut Plaza N Room 4051B,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM erika.a.waters@gmail.com OI Hesse, Bradford/0000-0003-1142-1161 NR 42 TC 12 Z9 12 U1 1 U2 12 PU JOURNAL MEDICAL INTERNET RESEARCH PI TORONTO PA TORONTO GENERAL HOSPITAL, R FRASER ELLIOTT BLDG, 4TH FL, R 4S435, 190 ELIZABETH ST, TORONTO, ON M5G 2C4, CANADA SN 1438-8871 J9 J MED INTERNET RES JI J. Med. Internet Res. PD JUL-SEP PY 2009 VL 11 IS 3 AR e33 DI 10.2196/jmir.1222 PG 14 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 556YV UT WOS:000274632900009 PM 19674958 ER PT J AU Harbecke, R Oxman, MN Arnold, BA Ip, C Johnson, GR Levin, MJ Gelb, LD Schmader, KE Straus, SE Wang, H Wright, PF Pachucki, CT Gershon, AA Arbeit, RD Davis, LE Simberkoff, MS Weinberg, A Williams, HM Cheney, C Petrukhin, L Abraham, KG Shaw, A Manoff, S Antonello, JM Green, T Wang, Y Tan, C Keller, PM AF Harbecke, Ruth Oxman, Michael N. Arnold, Beth A. Ip, Charlotte Johnson, Gary R. Levin, Myron J. Gelb, Lawrence D. Schmader, Kenneth E. Straus, Stephen E. Wang, Hui Wright, Peter F. Pachucki, Constance T. Gershon, Anne A. Arbeit, Robert D. Davis, Larry E. Simberkoff, Michael S. Weinberg, Adriana Williams, Heather M. Cheney, Carol Petrukhin, Luba Abraham, Katalin G. Shaw, Alan Manoff, Susan Antonello, Joseph M. Green, Tina Wang, Yue Tan, Charles Keller, Paul M. CA Shingles Prevention Study Grp TI A Real-Time PCR Assay to Identify and Discriminate Among Wild-Type and Vaccine Strains of Varicella-Zoster Virus and Herpes Simplex Virus in Clinical Specimens, and Comparison With the Clinical Diagnoses SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE zoster vaccine; Shingles Prevention Study; clinical trial; diagnosis of herpes zoster; VZV ORF 62 ID FRAGMENT-LENGTH-POLYMORPHISM; POLYMERASE-CHAIN-REACTION; LABORATORY DIAGNOSIS; SEQUENCE VARIABILITY; DNA-SEQUENCE; OKA VACCINE; DIFFERENTIATION; IDENTIFICATION AB A real-time PCR assay was developed to identify varicella-zoster virus (VZV) and herpes simplex virus (HSV) DNA in clinical specimens from subjects with suspected herpes zoster (HZ; shingles). Three sets of primers and probes were used in separate PCR reactions to detect and discriminate among wild-type VZV (VZV-WT), Oka vaccine strain VZV (VZV-Oka), and HSV DNA, and the reaction for each virus DNA was multiplexed with primers and probe specific for the human beta-globin gene to assess specimen adequacy. Discrimination of all VZV-WT strains, including Japanese isolates and the Oka parent strain, from VZV-Oka was based upon a single nucleotide polymorphism at position 106262 in ORF 62, resulting in preferential amplification by the homologous primer pair. The assay was highly sensitive and specific for the target virus DNA, and no cross-reactions were detected with any other infectious agent. With the PCR assay as the gold standard, the sensitivity of virus culture was 53% for VZV and 77% for HSV. There was 92% agreement between the clinical diagnosis of HZ by the Clinical Evaluation Committee and the PCR assay results. J. Med. Virol. 81: 1310-1322, 2009. Published 2009 Wiley-Liss, Inc. C1 [Harbecke, Ruth; Oxman, Michael N.; Williams, Heather M.] VA San Diego Healthcare Syst, Dept Vet Affairs, San Diego, CA USA. [Oxman, Michael N.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. [Oxman, Michael N.] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA. [Arnold, Beth A.; Ip, Charlotte; Wang, Hui; Cheney, Carol; Petrukhin, Luba; Abraham, Katalin G.; Shaw, Alan; Keller, Paul M.] Merck Res Labs, Dept Vaccine & Biol Res, West Point, PA USA. [Johnson, Gary R.] VA Connecticut Healthcare Syst, VA Cooperat Studies Program Coordinating Ctr, West Haven, CT USA. [Levin, Myron J.] Univ Colorado Denver, Sect Pediat Infect Dis, Aurora, CO USA. [Gelb, Lawrence D.] Washington Univ, Dept Med, St Louis VA Med Ctr, St Louis, MO USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Dept Med, GRECC,Durham VA Med Ctr, Durham, NC 27710 USA. [Straus, Stephen E.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Wright, Peter F.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Pachucki, Constance T.] Vet Affairs Edward Hines Jr Hosp, Chicago, IL USA. [Gershon, Anne A.] Columbia Univ, New York, NY USA. [Arbeit, Robert D.] Tufts Med Sch, Dept Med, Div Infect Dis, Boston, MA USA. [Davis, Larry E.] New Mexico VA Healthcare Syst, Albuquerque, NM USA. [Simberkoff, Michael S.] NYU, Sch Med, VA New York Harbor Healthcare Syst, New York, NY USA. [Weinberg, Adriana] Univ Colorado Denver, Dept Pediat, Aurora, CO USA. [Weinberg, Adriana] Univ Colorado Denver, Dept Med, Aurora, CO USA. [Weinberg, Adriana] Univ Colorado Denver, Dept Pathol, Aurora, CO USA. [Manoff, Susan] Merck Res Labs, Dept Infect Dis & Vaccines, West Point, PA USA. [Antonello, Joseph M.; Green, Tina; Wang, Yue; Tan, Charles] Merck Res Labs, Dept Vaccine Biometr Res, West Point, PA USA. RP Keller, PM (reprint author), Merck Res Labs, Dept Vaccine & Biol Res, 2057 Spring Valley Rd, Lansdale, PA 19446 USA. EM pkscience@gmail.com RI Irwin, Michael/H-4870-2013 OI Irwin, Michael/0000-0002-1502-8431 FU Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; Merck FX Grant sponsor: Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; Grant sponsor: Merck (to the Cooperative Studies Program); Grant sponsor: James R. and Jesse V. Scott Fund for Shingles Research (to Dr. Oxman). NR 25 TC 22 Z9 22 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD JUL PY 2009 VL 81 IS 7 BP 1310 EP 1322 DI 10.1002/jmv.21506 PG 13 WC Virology SC Virology GA 453ME UT WOS:000266613900024 PM 19475609 ER PT J AU Romero, EA Valdivieso, E Cohen, BE AF Romero, Eneida A. Valdivieso, Elizabeth Cohen, B. Eleazar TI Formation of Two Different Types of Ion Channels by Amphotericin B in Human Erythrocyte Membranes SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE Amphotericin B; Erythrocyte; Ion channel; Cholesterol; Lipid raft; Activation energy; Membrane potential ID ANTIBIOTIC-STEROL INTERACTIONS; ACHOLEPLASMA-LAIDLAWII CELLS; POLYENE ANTIBIOTICS; CONTAINING LIPOSOMES; LECITHIN LIPOSOMES; CIRCULAR-DICHROISM; LIPID-MEMBRANES; CHOLESTEROL; PERMEABILITY; TEMPERATURE AB The polyene antibiotic amphotericin B (AmB) is known to form aqueous pores in lipid membranes and biological membranes. Here, membrane potential and ion permeability measurements were used to demonstrate that AmB can form two types of selective ion channels in human erythrocytes, differing in their interaction with cholesterol. We show that AmB induced a cation efflux (negative membrane polarization) across cholesterol-containing liposomes and erythrocytes at low concentrations (a parts per thousand currency sign1.0 x 10(-6) M), but a sharp reversal of such polarization was observed at concentrations greater than 1.0 x 10(-6) M AmB, an indication that aqueous pores are formed. Cation-selective AmB channels are also formed across sterol-free liposomes, but aqueous pores are only formed at AmB concentrations 10 times greater. The effect of temperature on the AmB-mediated K+ efflux across erythrocytes revealed that the energies of activation for channel formation are negative and positive at AmB concentrations that lead predominantly to the formation of cation-selective channels and aqueous pores, respectively. These findings support the conclusion that the two types of AmB channels formed in human erythrocytes differ in their interactions with cholesterol and other membrane components. In effect, a membrane lipid reorganization, as induced by incubation of erythrocytes with tetrathionate, a cross-linking agent of the lipid raft-associated protein spectrin, led to differential changes in the activation parameters for the formation of both types of channels, reflecting the different lipid environments in which such structures are formed. C1 [Cohen, B. Eleazar] NIAID, Div External Act, Bethesda, MD 20982 USA. [Romero, Eneida A.; Valdivieso, Elizabeth] Cent Univ Venezuela, Fac Sci, Inst Expt Biol, Caracas, Venezuela. RP Cohen, BE (reprint author), NIAID, Div External Act, 6700B Rockledge Dr, Bethesda, MD 20982 USA. EM ec17w@nih.gov NR 54 TC 15 Z9 15 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-2631 EI 1432-1424 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD JUL PY 2009 VL 230 IS 2 BP 69 EP 81 DI 10.1007/s00232-009-9187-z PG 13 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 488VM UT WOS:000269378400002 PM 19629570 ER PT J AU Kim, JS Coon, SL Weller, JL Blackshaw, S Rath, MF Moller, M Klein, DC AF Kim, Jong-So Coon, Steven L. Weller, Joan L. Blackshaw, Seth Rath, Martin F. Moller, Morten Klein, David C. TI Muscleblind-like 2: circadian expression in the mammalian pineal gland is controlled by an adrenergic-cAMP mechanism SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cAMP; Mbnl2; muscleblind; pineal gland; retina; RNA splicing ID OTX2 HOMEOBOX GENE; PRE-MESSENGER-RNA; MYOTONIC-DYSTROPHY; SKELETAL-MUSCLE; EYE DEVELOPMENT; DAILY RHYTHM; CUG REPEATS; PROTEINS; RETINA; EVOLUTION AB Muscleblind-like 2 (Mbnl2) is a zinc finger protein first identified in Drosophila. It appears to be essential for photoreceptor development and to be involved in RNA splicing. Here we report that Mbnl2 is strongly expressed in the rat pineal gland. The abundance of pineal Mbnl2 transcripts follows a marked circadian rhythm with peak levels approximately sevenfold higher at night than day levels. Mbnl2 protein exhibits a similar rhythm. In vitro studies indicate that the abundance of Mbnl2 transcripts and protein are controlled by an adrenergic/cAMP mechanism. C1 [Kim, Jong-So; Coon, Steven L.; Weller, Joan L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Sect Neuroendocrinol, NIH, Bethesda, MD USA. [Blackshaw, Seth] Harvard Univ, Dept Genet, Cambridge, MA 02138 USA. [Rath, Martin F.; Moller, Morten] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. RP Klein, DC (reprint author), 49 Convent Dr,Bldg 49,Rm 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov OI Rath, Martin/0000-0002-4047-6324 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Danish Agency for Science Technology and Innovation; Lundbeck Foundation; Danish Medical Research Council [271-07-0412, 271-06-0754]; Novo Nordisk Foundation; Carlsberg Foundation; Simon Foughner Hartmann's foundation FX This research was supported in part by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (JK, SLC, JLW, and DCK) and grants from the Danish Agency for Science Technology and Innovation, the Lundbeck Foundation, the Danish Medical Research Council (grant numbers: 271-07-0412 and 271-06-0754), the Novo Nordisk Foundation, the Carlsberg Foundation, and Simon Foughner Hartmann's foundation (MM and MFR). SB was a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation. NR 37 TC 4 Z9 5 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUL PY 2009 VL 110 IS 2 BP 756 EP 764 DI 10.1111/j.1471-4159.2009.06184.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 463IX UT WOS:000267426700029 PM 19457059 ER PT J AU Bagnato, F AF Bagnato, Francesca TI Uncovering and Characterizing Multiple Sclerosis Lesions: The Aid of Fluid-Attenuated Inversion Recovery Images in the Presence of Gadolinium Contrast Agent SO JOURNAL OF NEUROIMAGING LA English DT Editorial Material ID BRAIN-BARRIER DISRUPTION; CEREBRAL GLIOMAS; MR-IMAGES; IN-VITRO; ENHANCEMENT; DEMYELINATION; CSF AB J Neuroimaging 2009;19:201-204. C1 NINDS, Neuroimmunol Branch NIB, NIH, Bethesda, MD 20892 USA. RP Bagnato, F (reprint author), NINDS, Neuroimmunol Branch NIB, NIH, Bldg 10,Room 5C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov NR 19 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1051-2284 J9 J NEUROIMAGING JI J. Neuroimaging PD JUL PY 2009 VL 19 IS 3 BP 201 EP 204 DI 10.1111/j.1552-6569.2008.00350.x PG 4 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 461QJ UT WOS:000267283300001 PM 19187471 ER PT J AU Nutt, D AF Nutt, D. TI WHAT WE KNOW AND WHAT WE DON'T KNOW ABOUT HOW NEUROLEPTICS WORK? SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT 22nd Annual Meeting of the British-Neuropsychiatry-Association CY FEB 04, 2008 CL London, ENGLAND SP British Neuropsychiat Assoc, Coll Psychiat C1 [Nutt, D.] Univ London Imperial Coll Sci Technol & Med, Dept Neuropsychopharmacol & Mol Imaging, London SW7 2AZ, England. [Nutt, D.] NIAAA, Clin Sci Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD JUL PY 2009 VL 80 IS 7 BP 817 EP 817 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 458TQ UT WOS:000267046800034 ER PT J AU Kim, YS Shin, JH Hall, FS Linden, DJ AF Kim, Yu Shin Shin, Jung Hoon Hall, F. Scott Linden, David J. TI Dopamine Signaling Is Required for Depolarization-Induced Slow Current in Cerebellar Purkinje Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSPORTER KNOCKOUT MICE; ENDOGENOUS CANNABINOIDS; TYROSINE-HYDROXYLASE; PRESYNAPTIC INHIBITION; RETROGRADE INHIBITION; DEVELOPMENTAL-CHANGES; SYNAPTIC INHIBITION; INDUCED SUPPRESSION; GABA RELEASE; HUMAN BRAIN AB Brief strong depolarization of cerebellar Purkinje cells produces a slow inward cation current. This current, called depolarization-induced slow current (DISC), is triggered by Ca influx in the Purkinje cell and is attenuated by a blocker of vesicular fusion. Previous work in other brain regions, such as the substantia nigra and ventral tegmental area, has shown that dopamine can be released from dendrites to produce paracrine and autocrine signaling. Here, we test the hypothesis that postsynaptic release of dopamine and autocrine activation of dopamine receptors is involved in DISC. Light immunohistochemistry showed that D3 dopamine receptors, vesicular monoamine transporter type 2 (VMAT2), and dopamine plasma membrane transporters (DATs) were all expressed in cerebellar Purkinje cells. However, their expression was strongest in the gyrus region of cerebellar lobules IX and X. Comparison of DISC across lobules revealed that it was weak in the anterior portions of the cerebellum (lobules II, V, and VI) and strong in lobules IX and X. DISC was blocked by dopamine receptor antagonists (haloperidol, clozapine, eticlopride, and SCH23390). Likewise, DISC was strongly attenuated by inhibitors of VMAT(reserpine and tetrabenazine) and DAT(GBR12909 and rimcazole). These drugs did not produce DISC attenuation through blockade of depolarization-evoked Purkinje cell Ca transients. Purkinje cells in cerebellar slices derived from DAT-null mice expressed DISC, but this DISC ran down at a significantly higher rate than littermate controls. Together, these results suggest that strong Purkinje cell depolarization produces Ca-dependent release of vesicular postsynaptic dopamine that then excites Purkinje cells in an autocrine manner. C1 [Kim, Yu Shin; Shin, Jung Hoon; Linden, David J.] Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. [Hall, F. Scott] NIH, Mol Neurobiol Branch, Intramural Res Program, Natl Inst Drug Abuse,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Linden, DJ (reprint author), Johns Hopkins Univ, Dept Neurosci, Sch Med, Baltimore, MD 21205 USA. EM dlinden@jhmi.edu RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU National Institutes of Health (NIH) [MH51106, MH084020] FX This work was supported by National Institutes of Health (NIH) Grants MH51106 and MH084020 and in part by intramural funding from the National Institute on Drug Abuse, NIH/Department of Health and Human Services (F. S. H.). We thank Dr. Masahiko Watanabe for the calbindin antibody. We also thank members of the laboratory of D. J. L. for creative and useful suggestions. Y. S. K. especially thanks Christopher Kim from his heart. DAT- null mice and DAT antibody were a generous gift from Dr. George Uhl. NR 33 TC 18 Z9 19 U1 1 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 1 PY 2009 VL 29 IS 26 BP 8530 EP 8538 DI 10.1523/JNEUROSCI.0468-09.2009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 465UM UT WOS:000267613400025 PM 19571144 ER PT J AU Tanaka, NK Ito, K Stopfer, M AF Tanaka, Nobuaki K. Ito, Kei Stopfer, Mark TI Odor-Evoked Neural Oscillations in Drosophila Are Mediated by Widely Branching Interneurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ANTENNAL LOBE; OLFACTORY SYSTEM; MUSHROOM BODY; NEURONS; REPRESENTATIONS; MELANOGASTER; ASSEMBLIES; SYNCHRONIZATION; DISCRIMINATION; TRANSMISSION AB Stimulus-evoked oscillatory synchronization of neurons has been observed in a wide range of species. Here, we combined genetic strategies with paired intracellular and local field potential (LFP) recordings from the intact brain of Drosophila to study mechanisms of odor-evoked neural oscillations. We found common food odors at natural concentrations elicited oscillations in LFP recordings made from the mushroom body (MB), a site of sensory integration and analogous to the vertebrate piriform cortex. The oscillations were reversibly abolished by application of the GABA(a) blocker picrotoxin. Intracellular recordings from local and projection neurons within the antennal lobe (AL) (analogous to the olfactory bulb) revealed odor-elicited spikes and subthreshold membrane potential oscillations that were tightly phase locked to LFP oscillations recorded downstream in the MBs. These results suggested that, as in locusts, odors may elicit the oscillatory synchronization of AL neurons by means of GABAergic inhibition from local neurons (LNs). An analysis of the morphologies of genetically distinguished LNs revealed two populations of GABAergic neurons in the AL. One population of LNs innervated parts of glomeruli lacking terminals of receptor neurons, whereas the other branched more widely, innervating throughout the glomeruli, suggesting that the two populations might participate in different neural circuits. To test the functional roles of these LNs, we used the temperature-sensitive dynamin mutant gene shibire to conditionally and reversibly block chemical transmission from each or both of these populations of LNs. We found only the more widely branching population of LNs is necessary for generating odor-elicited oscillations. C1 [Tanaka, Nobuaki K.; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. [Ito, Kei] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan. RP Stopfer, M (reprint author), NICHHD, NIH, 35 Lincoln Dr,MSC 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 FU Intramural NIH HHS [Z01 HD008760-05, Z99 HD999999] NR 35 TC 63 Z9 63 U1 0 U2 9 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 1 PY 2009 VL 29 IS 26 BP 8595 EP 8603 DI 10.1523/JNEUROSCI.1455-09.2009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 465UM UT WOS:000267613400031 PM 19571150 ER PT J AU Bjork, JM Grant, SJ AF Bjork, James M. Grant, Steven J. TI Does Traumatic Brain Injury Increase Risk for Substance Abuse? SO JOURNAL OF NEUROTRAUMA LA English DT Article DE addiction; closed-head injury; cognition; drug abuse; drug dependence; traumatic brain injury ID CONTROLLED CORTICAL IMPACT; SPINAL-CORD-INJURY; DECISION-MAKING; DRUG-USE; EMERGENCY-ROOM; IMPULSE CONTROL; COCAINE USERS; PRIMARY-CARE; ALCOHOL; DEFICITS AB Wars in Afghanistan and Iraq have resulted in thousands of military personnel suffering traumatic brain injury (TBI), including closed-head injuries. Of interest is whether these individuals and other TBI survivors are at increased risk for substance use disorder (SUD). While it has been well established that drug or alcohol intoxication itself increases probability of suffering a TBI in accidents or acts of violence, little is known about whether the brain insult itself increases the likelihood that a previously non-drug-abusing individual would develop SUD. Might TBI survivors be unusually vulnerable to addiction to opiate analgesics compared to other pain patients? Similarly, it is not known if TBI increases the likelihood of relapse among persons with SUD in remission. We highlight challenges in answering these questions, and review neurochemical and behavioral evidence that supports a causal relationship between TBI and SUD. In this review, we conclude that little is known regarding the directionality of TBI increasing drug abuse, and that collaborative research in this area is critically needed. C1 [Bjork, James M.; Grant, Steven J.] Natl Inst Drug Abuse, Div Clin Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), Natl Inst Drug Abuse, Div Clin Neurosci & Behav Res, NIH, 6001 Execut Blvd,Room 3151, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 NR 50 TC 34 Z9 34 U1 1 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD JUL PY 2009 VL 26 IS 7 BP 1077 EP 1082 DI 10.1089/neu.2008.0849 PG 6 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 470HJ UT WOS:000267965500013 PM 19203230 ER PT J AU Fujimura, Y Zoghbi, SS Simeon, FG Taku, A Pike, VW Innis, RB Fujita, M AF Fujimura, Yota Zoghbi, Sami S. Simeon, Fabrice G. Taku, Andrew Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Quantification of Translocator Protein (18 kDa) in the Human Brain with PET and a Novel Radioligand, (18)F-PBR06 SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE inflammation; microglia; distribution volume; aryloxyanilide; compartmental analysis; translocator protein (18 kDa) ID PERIPHERAL BENZODIAZEPINE-RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; NONHUMAN-PRIMATES; BINDING-SITES; LIGANDS; NEUROINFLAMMATION; DAA1106; MODEL AB Translocator protein (TSPO) (18 kDa), formerly called the peripheral benzodiazepine receptor, is upregulated on activated microglia and macrophages and is, thus, a biomarker of inflammation. We previously reported that an (11)C-labeled aryloxyanilide (half-life, 20 min) was able to quantify TSPOs in the healthy human brain. Because many PET centers would benefit from a longer-lived (18)F-labeled radioligand (half-life, 110 min), the objective of this study was to evaluate the ability of a closely related aryloxyanilide ((18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline [(18)F-PBR06]) to quantify TSPOs in the healthy human brain. Methods: A total of 9 human subjects were injected with (18)F-PBR06 (similar to 185 MBq) and scanned for 5 h, with rest periods outside the camera. The concentrations of (18)F-PBR06, separated from radiometabolites, were measured in arterial plasma. Results: Modeling of regional brain and plasma data showed that a 2-tissue-compartment model was superior to a 1-tissue-compartment model. Even if data for all time points were used for the fitting, concentrations of brain activity measured with PET were consistently greater than the modeled values at late (280-300 min) but not at early time points. The greater values may have been caused by the slow accumulation of radiometabolites in the brain. To determine an adequate time for more accurate measurement of distribution volume (V(T)), which is the summation of receptor binding and nondisplaceable activity, we investigated which scan duration would be associated with maximal or near-maximal identifiability. We found that a scan of 120 min provided the best identifiability of V(T) (similar to 2%). The images showed no significant defluorination. Conclusion: (18)F-PBR06 can quantify TSPOs in the healthy human brain using 120 min of image acquisition and concurrent measurements of radioligand in plasma. Although brain activity is likely contaminated with radiometabolites, the percentage contamination is thought to be small (<10%), because values of distribution volume are stable during 60-120 min and vary by less than 10%. (18)F-PBR06 is a longer-lived and promising alternative to (11)C-labeled radioligands to measure TSPOs as a biomarker of inflammation in the brain. C1 [Fujimura, Yota; Zoghbi, Sami S.; Simeon, Fabrice G.; Taku, Andrew; Pike, Victor W.; Innis, Robert B.; Fujita, Masahiro] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Fujimura, Yota] Teikyo Univ, Sch Med, Dept Psychiat, Tokyo 173, Japan. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 31,Room B2B37,31 Ctr Dr,MSC-2035, Bethesda, MD 20892 USA. EM fujitam@mail.nih.gov FU Intramural Program of NIMH [Z01-MH-002852-04] FX We thank the staff of the PET Department for successfully completing the PET scans, PMOD Technologies for providing its image-analysis and modeling software, Pavitra Kannan and Kimberly J. Jenko for providing support with the radiometabolite analysis, and Ioline Henter at NIMH for editing the manuscript. This research was supported by the Intramural Program of NIMH (project Z01-MH-002852-04). NR 29 TC 40 Z9 40 U1 0 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2009 VL 50 IS 7 BP 1047 EP 1053 DI 10.2967/jnumed.108.060186 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529VO UT WOS:000272547100014 PM 19525468 ER PT J AU Kramer-Marek, G Kiesewetter, DO Capala, J AF Kramer-Marek, Gabriela Kiesewetter, Dale O. Capala, Jacek TI Changes in HER2 Expression in Breast Cancer Xenografts After Therapy Can Be Quantified Using PET and (18)F-Labeled Affibody Molecules SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE Affibody molecule; molecular imaging; HER2; breast cancer; PET ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; MALIGNANT-TUMORS; HSP90; ANTIBODIES; INHIBITORS; IN-111; TRACER; CELLS AB In vivo imaging of human epidermal growth factor receptor type 2 (HER2) expression may allow direct assessment of HER2 status in tumor tissue and provide a means to quantify changes in receptor expression after HER2-targeted therapies. This work describes the in vivo characterization of the HER2-specific N-2-(4-(18)F-fluorobenzamido)ethyl]maleimide ((18)F-FBEM)-Z(HER2: 342) Affibody molecule and its application to study the effect of 17 (dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on HER2 expression by PET. Methods: To assess the correlation of signal observed by PET with receptor expression, we administered the tracer to athymic nude mice bearing subcutaneous human breast cancer xenografts with different levels of HER2 expression. To study the downregulation of HER2, we treated the mice with 4 doses (40 mg/kg) of 17-DMAG, an inhibitor of heat-shock protein 90, known to decrease HER2 expression. The animals were scanned before and after treatment. After the last scan, the mice were euthanized and tumors were frozen for receptor analysis. Results: The tracer was eliminated quickly from the blood and normal tissues, providing high tumor-to-blood and tumor-to-muscle ratios as early as 20 min after injection. The high-contrast images between normal and tumor tissue were recorded for BT474 and MCF7/clone18 tumors. Low but still detectable uptake was observed for MCF7 tumors, and none for MDA-MB-468. The signal correlated with the receptor expression as assessed by immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. The levels of HER2 expression estimated by post-treatment PET decreased 71% (P, 4 x 10(-6)) and 33% (P < 0.002), respectively, for mice bearing BT474 and MCF7/clone18 tumors. These changes were confirmed by the biodistribution studies, enzyme-linked immunosorbent assay, and Western blot. Conclusion: Our results suggest that the described (18)F-FBEM-Z(HER2:342) Affibody molecule can be used to assess HER2 expression in vivo by PET and monitor possible changes of receptor expression in response to therapeutic interventions. C1 [Kramer-Marek, Gabriela; Capala, Jacek] NCI, NIH, Bethesda, MD 20892 USA. [Kiesewetter, Dale O.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. RP Capala, J (reprint author), 10 Ctr Dr,Bldg 10,Room 1B-37A, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov FU Intramural NIH HHS [ZIA BC010727-04]; NCI NIH HHS [N01-CO-12400, N01-CO-12401, N01CO12400, N02CO12401] NR 33 TC 68 Z9 70 U1 2 U2 11 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUL PY 2009 VL 50 IS 7 BP 1131 EP 1139 DI 10.2967/jnumed.108.057695 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 529VO UT WOS:000272547100025 PM 19525458 ER PT J AU Kant, AK Leitzmann, ME Park, Y Hollenbeck, A Schatzkin, A AF Kant, Ashima K. Leitzmann, Michael E. Park, Yikyung Hollenbeck, Albert Schatzkin, Arthur TI Patterns of Recommended Dietary Behaviors Predict Subsequent Risk of Mortality in a Large Cohort of Men and Women in the United States SO JOURNAL OF NUTRITION LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; HEALTH-AMERICAN-ASSOCIATION; GUIDELINES-FOR-AMERICANS; MAJOR CHRONIC DISEASE; RETIRED-PERSONS DIET; NATIONAL-INSTITUTES; US POPULATION; NUTRITION; QUALITY; ABANDON AB Recommendations for intake of fruits and vegetables, whole grains, lean meats, and low-fat dairy form the underpinning of dietary guidance for health promotion. We examined the association of a summary index of food consumption behaviors compatible with the spirit of prevailing dietary guidance and mortality. We used data from the NIH-American Association of Retired Persons cohort In = 350,886), aged 50-71 y and disease free at baseline in 1995-1996, to examine the association of a dietary behavior score (DIBS) with mortality after 10.5 y of follow-up (deaths, n = 29,838). The DBS included 6 equally weighted components derived from responses to questions on usual dietary behaviors related to consumption of fruits, vegetables, low-fat dairy, whole grains, lean meat and poultry, and discretionary fat. The covariate-adjusted association of DBS and mortality from all causes, cancer, and coronary heart disease was examined using Cox proportional hazards regression methods. Compared with those in the lowest one-fifth of DBS, the multivariate-adjusted relative risk of mortality in the highest one-fifth of the DBS was 0.75 (95% Cl, 0.70-0.80) in women and 0.79 (95% Cl, 0.75-0.83) in men (P-trend < 0.0001). The inverse association of DBS and mortality was significant in both genders in nearly all categories of covariates. Similar trends were observed for DBS associations with mortality from cancer and heart disease. Nearly 12% of the covariate-adjusted population risk of mortality was attributable to nonconformity with dietary recommendations. Adoption of recommended dietary behaviors was associated with lower mortality in both men and women independent of other lifestyle risk factors. J. Nutr. 139: 1374-1380, 2009. C1 [Kant, Ashima K.] CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. [Leitzmann, Michael E.; Park, Yikyung; Schatzkin, Arthur] Natl Canc Inst, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Hollenbeck, Albert] Amer Assoc Retired Persons, Washington, DC 20049 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu OI Park, Yikyung/0000-0002-6281-489X FU NIH FX Supported by the intramural research program of the National Cancer Institute, NIH. NR 36 TC 30 Z9 30 U1 0 U2 10 PU AMER SOC NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUL PY 2009 VL 139 IS 7 BP 1374 EP 1380 DI 10.3945/jn.109.104505 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 462JC UT WOS:000267346900018 PM 19474153 ER PT J AU Bhattacharyya, T Koval, KJ AF Bhattacharyya, Timothy Koval, Kenneth J. TI Unipolar Versus Bipolar Hemiarthroplasty for Femoral Neck Fractures: Is There a Difference? SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE femoral neck fracture; arthroplasty; hip fracture ID HIP-FRACTURES; PROSTHESIS; ARTHROPLASTY; COMPONENTS; MOVEMENTS; FIXATION AB Arthroplasty has been shown to reduce the rate of reoperation after femoral neck fracture. A number of studies have compared the outcomes of unipolar and bipolar arthroplasty. At 1- to 3-year follow-up, the functional outcomes of unipolar and bipolar arthroplasty are equivalent. Bipolar arthroplasty has a higher initial cost. However, the long-term results of acetabular wear and need for revision are unknown. C1 [Bhattacharyya, Timothy] NIA, NIH, Bethesda, MD 20892 USA. [Koval, Kenneth J.] Dartmouth Hitchcock Med Ctr Orthopaed Surg, Lebanon, NH USA. RP Bhattacharyya, T (reprint author), NIA, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4-2339, Bethesda, MD 20892 USA. EM bhattacharyyat@mail.nih.gov NR 18 TC 11 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD JUL PY 2009 VL 23 IS 6 BP 426 EP 427 PG 2 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 464IV UT WOS:000267499500008 PM 19550229 ER PT J AU Kim, H Clark, D Dionne, RA AF Kim, Hyungsuk Clark, David Dionne, Raymond A. TI Genetic Contributions to Clinical Pain and Analgesia: Avoiding Pitfalls in Genetic Research SO JOURNAL OF PAIN LA English DT Review DE Genetic association study; single nucleotide polymorphism; haplotype; population stratification; multiple test correction ID CATECHOL-O-METHYLTRANSFERASE; GENOME-WIDE ASSOCIATION; OPIOID-INDUCED HYPERALGESIA; GTP CYCLOHYDROLASE; IMMPACT RECOMMENDATIONS; VAL158MET POLYMORPHISM; INDIVIDUAL-DIFFERENCES; INFLAMMATORY PAIN; HAPLOTYPE BLOCKS; NEUROPATHIC PAIN AB Understanding the genetic basis of human variations in pain is critical to elucidating the molecular basis of pain sensitivity, variable responses to analgesic drugs, and, ultimately, to individualized treatment of pain and improved public health. With the help of recently accumulated knowledge and advanced technologies, pain researchers hope to gain insight into genetic mechanisms of pain and eventually apply this knowledge to pain treatment. Perspective: We critically reviewed the published literature to examine the strength of evidence supporting genetic influences on clinical and human experimental pain. Based on this evidence and the experience of false associations that have occurred in other related disciplines, we provide recommendations for avoiding pitfalls in pain genetic research. (C) 2009 by the American Pain Society C1 [Kim, Hyungsuk; Dionne, Raymond A.] NINR, NIH, Bethesda, MD 20892 USA. [Clark, David] Vet Affairs Med Ctr, Palo Alto, CA 94304 USA. RP Dionne, RA (reprint author), Bldg 10 CRC 2-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov FU Division of Intramural Research; National Institute of Nursing Research; National Institutes of Health [20892] FX Supported by the Division of Intramural Research, National Institute of Nursing Research, National Institutes of Health, Bethesda, MID 20892, USA. NR 99 TC 43 Z9 43 U1 2 U2 7 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD JUL PY 2009 VL 10 IS 7 BP 663 EP 693 DI 10.1016/j.jpain.2009.04.001 PG 31 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 467BX UT WOS:000267712500002 PM 19559388 ER PT J AU Shavers, VL Harlan, LC Jackson, M Robinson, J AF Shavers, Vickie L. Harlan, Linda C. Jackson, Monica Robinson, JaMuir TI Racial/Ethnic Patterns of Care for Pancreatic Cancer SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID CELIAC PLEXUS BLOCK; RECEIPT; PAIN AB Introduction: The small proportion of cancers diagnosed at the local disease stage, resectable at the time diagnosis, and responsive to chemotherapy contribute to poor survival making pancreatic cancer the fourth leading cause of cancer death among Americans. This emphasizes the importance of receiving appropriate palliative care. Racial/ethnic cancer treatment disparities have been observed for many cancer sites. We examine patterns of care in a population-based sample of African American, Hispanic and non-Hispanic white patients diagnosed with pancreatic cancer. Methods: Eligible cases were age 20 or older and newly diagnosed in 1998 with primary adenocarcinoma of the pancreas reported to the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program and selected for the NCI Patterns of Care=Quality of Care (POC=QOC) project (n = 697). Results: Chemotherapy, the most frequently received treatment was less frequently received by African American patients (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.37-0.95) and radiation less frequently received by Hispanic compared to non-Hispanic white white patients (OR 0.50, 95% CI, 0.27-0.95) after adjustment for age, stage, size of tumor, and insurance status in a multivariate regression model. Cancer-directed surgery of the primary site was received by 14.1% of patients, which did not significantly differ by race/ethnicity. Uninsured patients less often were recommended for or received surgery (OR 0.09, 95% CI 0.01-0.62) and (OR 0.07, 95% CI, 0.01-0.49), respectively. Conclusion: Differences in primary tumor size, stage and insurance status contributed to racial/ethnic differences in the receipt of cancer-directed surgery but did not explain differences in the receipt of chemotherapy for African American or radiation for Hispanic patients. More population-based research is needed to examine race/ethnicity, insurance status and receipt of treatment and palliative care for pancreatic cancer. C1 [Shavers, Vickie L.; Harlan, Linda C.] NCI, Appl Res Program, Bethesda, MD 20892 USA. [Jackson, Monica] American Univ, Dept Math & Stat, Washington, DC 20016 USA. [Robinson, JaMuir] Walden Univ, Washington, DC USA. RP Shavers, VL (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov FU National Cancer Institute [N01-PC-35133, N01-PC-35135, N01-PC-35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35141, N01-PC-35142, N01-PC-35143, N01-PC-35145]; HHS Contract: Numbers [HHSN261200544 002C, HHSN261200544003C, HHSN261200544004C, HHSN 261200544005C]; Interagency agreement [Y1-PC-4033] FX The authors thank the participating SEER registries without whom this research would not have been possible. The authors also thank Dr. Rachel Ballard-Barbash, John Kerner, and Martin L. Brown of the National Cancer Institute for their review of the draft manuscript and Jennifer Stevens of Information Management Services for her assistance with the data analysis. Funding was provided by National Cancer Institute (NCI) Contract Numbers: N01-PC-35133, N01PC-35135,N01-PC- 35136, N01-PC-35137, N01-PC-35138, N01-PC-35139, N01-PC-35141, N01-PC- 35142, N01-PC-35143, N01-PC-35145; HHS Contract: Numbers: HHSN261200544 002C, HHSN261200544003C, HHSN261200544004C, HHSN 261200544005C; and Interagency agreement Y1-PC-4033. NR 28 TC 9 Z9 9 U1 5 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD JUL PY 2009 VL 12 IS 7 BP 623 EP 630 DI 10.1089/jpm.2009.0036 PG 8 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 469UR UT WOS:000267926700018 PM 19594347 ER PT J AU Carcillo, J Holubkov, R Dean, JM Berger, J Meert, KL Anand, KJS Zimmerman, J Newth, CJL Harrison, R Wilson, DF Nicholson, C AF Carcillo, Joseph Holubkov, Richard Dean, J. Michael Berger, John Meert, Kathleen L. Anand, K. J. S. Zimmerman, Jerry Newth, Christopher J. L. Harrison, Rick Wilson, Doughas F. Nicholson, Carol CA Child Hlth Human Dev Collaborative TI Rationale and Design of the Pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial SO JOURNAL OF PARENTERAL AND ENTERAL NUTRITION LA English DT Article DE critical care; nosocomial infection; prolactin; zinc; selenium; lymphocyte function ID RANDOMIZED CONTROLLED-TRIAL; ENRICHED ENTERAL NUTRITION; ORAL REHYDRATION THERAPY; BIRTH-WEIGHT INFANTS; NOSOCOMIAL INFECTION; ZINC SUPPLEMENTATION; ORGAN FAILURE; DOUBLE-BLIND; ILL PATIENTS; CHILDREN AB Despite implementation of CDC recommendations and bundled interventions for preventing catheter-associated blood stream infection, ventilator-associated pneumonia, or urinary catheter-associated infections, nosocomial infections and sepsis remain a significant cause of morbidity and mortality in critically ill children. Recent Studies suggest that acquired critical illness stress-induced immune Suppression (CRISIS) plays a role in the development of nosocomial infection and sepsis. This condition can be related to inadequate zinc, selenium, and glutamine levels, as well as hypoprolactinemia, leading to stress-induced lymphopenia, a predominant T(H)2 monocyte/macrophage state, and Subsequent immune suppression. Prolonged immune dysfunction increases the likelihood of nosocomial infections associated with invasive devices. Although strategies to prevent common complications of critical illness are routinely employed (eg, prophylaxis for gastrointestinal bleeding, thrombophlebitis), no prophylactic strategy is used to prevent stress-induced immune suppression. This is the authors' rationale for the pediatric CRISIS prevention trial (NCT00395161), designed as a randomized, double-blind, controlled clinical investigation to determine if daily enteral supplementation with zinc, selenium, and glutamine as well as parenteral metoclopramide (a dopamine 2 hypoprolactinemia) prolongs the time until onset of nosocomial infection or sepsis in critically ill children compared to enteral Supplementation with whey protein. If effective, this combined nutritional and pharmacologic approach may lessen the excess morbidity and mortality as well as resource utilization associated with nosocomial infections and sepsis in this Population. The authors present the design and analytic plan for the CRISIS prevention trial. (JPEN J Parenter Enteral Nutr. 2009;33:368-374) C1 [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15261 USA. [Holubkov, Richard; Dean, J. Michael] Univ Utah, Salt Lake City, UT 84112 USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Detroit, MI USA. [Anand, K. J. S.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Newth, Christopher J. L.] Childrens Hosp Los Angeles, Los Angeles, CA USA. [Harrison, Rick] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Wilson, Doughas F.] Univ Virginia, Childrens Hosp, Charlottesville, VA 22903 USA. [Nicholson, Carol] NICHHD, Bethesda, MD USA. RP Carcillo, J (reprint author), Childrens Hosp Pittsburgh, 3705 5th Ave,6th Floor, Pittsburgh, PA 15261 USA. EM carcilloja@ccm.upmc.edu OI Anand, Kanwaljeet/0000-0001-6498-1483 FU NICHD NIH HHS [U10HD049983, U01 HD049934, U01HD049934, U10 HD049945, U10 HD049981, U10 HD049983, U10 HD049983-01, U10 HD049983-05, U10HD049945, U10HD049981, UG1 HD050096, U10 HD050012, U10 HD050096, U10HD050012, U10HD050096, U10HD500009, UG1 HD049983] NR 32 TC 16 Z9 16 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0148-6071 J9 JPEN-PARENTER ENTER JI J. Parenter. Enter. Nutr. PD JUL-AUG PY 2009 VL 33 IS 4 BP 368 EP 374 DI 10.1177/0148607108327392 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 460JU UT WOS:000267184800003 PM 19380753 ER PT J AU McBride, CM Guttmacher, AE AF McBride, Colleen M. Guttmacher, Alan E. TI Commentary: Trailblazing a Research Agenda at the Interface of Pediatrics and Genomic Discoverya Commentary on the Psychological Aspects of Genomics and Child Health SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Editorial Material AB Unprecedented advances in human genome science are underway with potential to benefit public health. For example, it is estimated that within a decade, geneticists and epidemiologists will complete a catalog of the majority of genes associated with common chronic diseases. Such rapid advances create possibilities, if not the mandate, for translational research in how best to apply these and other anticipated discoveries for both individual and population health benefit. Driving these discoveries are rapid advances in infrastructure (e.g., the International HapMap Project to catalog human genetic variation; http://www.hapmap.org), analytical methods, and technology. This expansion in capabilities quickly has taken us from a genetics paradigmwhere the influence of individual genes on health outcomes is paramount, to a genomics paradigmwhere the complex influence of individual genes is considered in concert with each other and with environmental exposures on health outcomes. We discuss these and similar groundbreaking discoveries with an eye toward understanding their importance to child health and human development, and the role of behavioral science research conducted at the interface of pediatrics and genomic discovery. C1 [McBride, Colleen M.] NHGRI, Social & Behav Res Branch, NIH, Bethesda, MD 20892 USA. RP McBride, CM (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bldg 31,Room B1B54,31 Ctr Dr,MSC 2073, Bethesda, MD 20892 USA. EM cmcbride@mail.nih.gov NR 11 TC 9 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD JUL PY 2009 VL 34 IS 6 BP 662 EP 664 DI 10.1093/jpepsy/jsn125 PG 3 WC Psychology, Developmental SC Psychology GA 460XK UT WOS:000267225300008 PM 19129267 ER PT J AU Mazaki-Tovi, S Romero, R Vaisbuch, E Kusanovic, JP Erez, O Gotsch, F Chaiworapongsa, T Than, NG Kim, SK Nhan-Chang, CL Jodicke, C Pacora, P Yeo, L Dong, Z Yoon, BH Hassan, SS Mittal, P AF Mazaki-Tovi, Shali Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Erez, Offer Gotsch, Francesca Chaiworapongsa, Tinnakorn Than, Nandor Gabor Kim, Sun Kwon Nhan-Chang, Chia-Ling Jodicke, Cristiano Pacora, Percy Yeo, Lami Dong, Zhong Yoon, Bo Hyun Hassan, Sonia S. Mittal, Pooja TI Maternal serum adiponectin multimers in preeclampsia SO JOURNAL OF PERINATAL MEDICINE LA English DT Review DE Adipokines; BMI; high-molecular-weight (HMW) adiponectin; low-molecular-weight (LMW) adiponectin; medium-molecular-weight (MMW) adiponectin; obesity; overweight; pregnancy ID HIGH-MOLECULAR-WEIGHT; ENDOTHELIAL GROWTH-FACTOR; FOR-GESTATIONAL-AGE; HEALTHY NULLIPAROUS WOMEN; TUMOR-NECROSIS-FACTOR; COMPLEMENT-RELATED PROTEIN; ADIPOSE-SPECIFIC PROTEIN; TYPE-2 DIABETIC-PATIENTS; POPULATION-BASED COHORT; ISCHEMIC-HEART-DISEASE AB Objective: Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, "adipose tissue failure'', characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (S-A) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers. Study design: This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI ( normal weight <25 kg/m(2) vs. overweight/obese >= 25 kg/m(2)). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis. Results: 1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (P<0.001 and P=0.01, respectively); 2) patients with preeclampsia had a lower HMW/ total adiponectin ratio (P<0.001) and higher MMW/total adiponectin and LMW/total adiponectin ratios than those with a normal pregnancy (P<0.001 and P=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (P=0.001) and with a low HMW/ total adiponectin ratio (P<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) over-weight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia. Conclusion: 1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/ total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia. C1 [Mazaki-Tovi, Shali; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Gotsch, Francesca; Chaiworapongsa, Tinnakorn; Than, Nandor Gabor; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Jodicke, Cristiano; Pacora, Percy; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Mittal, Pooja] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Mazaki-Tovi, Shali; Romero, Roberto; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Gotsch, Francesca; Chaiworapongsa, Tinnakorn; Than, Nandor Gabor; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Jodicke, Cristiano; Pacora, Percy; Yeo, Lami; Dong, Zhong; Hassan, Sonia S.; Mittal, Pooja] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Erez, Offer; Chaiworapongsa, Tinnakorn; Nhan-Chang, Chia-Ling; Jodicke, Cristiano; Yeo, Lami; Hassan, Sonia S.; Mittal, Pooja] Wayne State Univ, Dept Obstet & Gynecol, Hutzel Womens Hosp, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Yoon, Bo Hyun] Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011; OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; DHHS FX Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 181 TC 39 Z9 40 U1 0 U2 4 PU WALTER DE GRUYTER GMBH PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0300-5577 EI 1619-3997 J9 J PERINAT MED JI J. Perinat. Med. PD JUL PY 2009 VL 37 IS 4 BP 349 EP 363 DI 10.1515/JPM.2009.085 PG 15 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 470MU UT WOS:000267979600007 PM 19348608 ER PT J AU Scimemi, A AF Scimemi, Annalisa TI The interrelated lives of NMDA receptors and glycine transporters SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID D-SERINE; RELEASE C1 Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Scimemi, A (reprint author), Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM scimemia@ninds.nih.gov RI Scimemi, Annalisa/O-5396-2014 OI Scimemi, Annalisa/0000-0003-4975-093X NR 11 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 1 PY 2009 VL 587 IS 13 BP 3061 EP 3062 DI 10.1113/jphysiol.2009.175976 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 464WO UT WOS:000267540500004 PM 19567742 ER PT J AU Oyelaran, O Li, Q Farnsworth, D Gildersleeve, JC AF Oyelaran, Oyindasola Li, Qian Farnsworth, David Gildersleeve, Jeffrey C. TI Microarrays with Varying Carbohydrate Density Reveal Distinct Subpopulations of Serum Antibodies SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Microarray; carbohydrate; antibodies; multivalency; antigen density; glycan array; lectin; Tn ID TN-ANTIGEN; BREAST-CANCER; VACCINE DEVELOPMENT; GLYCAN MICROARRAYS; SOYBEAN AGGLUTININ; CRYSTAL-STRUCTURE; IMMUNOREACTIVE T; LECTIN; BINDING; PROTEIN AB Antigen arrays have become important tools for profiling complex mixtures of proteins such as serum antibodies. These arrays can be used to better understand immune responses, discover new biomarkers, and guide the development of vaccines. Nevertheless, they are not perfect and improved array designs would enhance the information derived from this technology. In this study, we describe and evaluate a strategy for varying antigen density on an array and then use the array to study binding of lectins, monoclonal antibodies, and serum antibodies. To vary density, neoglycoproteins containing differing amounts of carbohydrate were synthesized and used to make a carbohydrate microarray with variations in both structure and density. We demonstrate that this method provides variations in density on the array surface within a range that is relevant for biological recognition events. The array was used to evaluate density dependent binding properties of three lectins (Vicia villosa lectin B(4), Helix pomatia agglutinin, and soybean agglutinin) and three monoclonal antibodies (HBTn-1, B1.1, and Bric111) that bind the tumor-associated Tn antigen. In addition, serum antibodies were profiled from 30 healthy donors. The results show that variations in antigen density are required to detect the full spectrum of antibodies that bind a particular antigen and can be used to reveal differences in antibody populations between individuals that are not detectable using a single antigen density. C1 [Gildersleeve, Jeffrey C.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Med Chem Lab, Ctr Canc Res, 376 Boyles St,Bldg 376,Rm 208, Frederick, MD 21702 USA. EM gildersleevej@ncifcrf.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU Intramural Research Program of the NIH, NCI FX we thank Jack Simpson (Protein Chemistry Laboratory, SAIC/NCI-Frederick) for MALDI-MS analysis of BSA conjugates. This research was supported by the Intramural Research Program of the NIH, NCI NR 65 TC 93 Z9 93 U1 2 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL PY 2009 VL 8 IS 7 BP 3529 EP 3538 DI 10.1021/pr9002245 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 466WL UT WOS:000267694600027 PM 19366269 ER PT J AU Rodriguez, H Snyder, M Uhlen, M Andrews, P Beavis, R Borchers, C Chalkley, RJ Cho, SY Cottingham, K Dunn, M Dylag, T Edgar, R Hare, P Heck, AJR Hirsch, RF Kennedy, K Kolar, P Kraus, HJ Mallick, P Nesvizhskii, A Ping, PP Ponten, F Yang, LM Yates, JR Stein, SE Hermjakob, H Kinsinger, CR Apweiler, R AF Rodriguez, Henry Snyder, Mike Uhlen, Mathias Andrews, Phil Beavis, Ronald Borchers, Christoph Chalkley, Robert J. Cho, Sang Yun Cottingham, Katie Dunn, Michael Dylag, Tomasz Edgar, Ron Hare, Peter Heck, Albert J. R. Hirsch, Roland F. Kennedy, Karen Kolar, Patrik Kraus, Hans-Joachim Mallick, Parag Nesvizhskii, Alexey Ping, Peipei Ponten, Fredrik Yang, Liming Yates, John R. Stein, Stephen E. Hermjakob, Henning Kinsinger, Christopher R. Apweiler, Rolf TI Recommendations from the 2008 International Summit on Proteomics Data Release and Sharing Policy: The Amsterdam Principles SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE proteomic; data; policy; release; resource; sharing; Bermuda principles; Amsterdam principles; open; standards AB Policies supporting the rapid and open sharing of genomic data have directly fueled the accelerated pace of discovery in large-scale genomics research. The proteomics community is starting to implement analogous policies and infrastructure for making large-scale proteomics data widely available on a precompetitive basis. On August 14, 2008, the National Cancer Institute (NCI) convened the "International Summit on Proteomics Data Release and Sharing Policy" in Amsterdam, The Netherlands, to identify and address potential roadblocks to rapid and open access to data. The six principles agreed upon by key stakeholders at the summit addressed issues surrounding (1) timing, (2) comprehensiveness, (3) format, (4) deposition to repositories, (5) quality metrics, and (6) responsibility for proteomics data release. This summit report explores various approaches to develop a framework of data release and sharing principles that will most effectively fulfill the needs of the funding agencies and the research community. C1 [Rodriguez, Henry; Kinsinger, Christopher R.] NCI, Ctr Strateg Sci Initiat, NIH, Bethesda, MD 20892 USA. [Snyder, Mike] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06620 USA. [Uhlen, Mathias] KTH AlabNova Univ Ctr, KTH Biotechnol, Stockholm, Sweden. [Andrews, Phil] Univ Michigan, Dept Biol Chem, Sch Med, Ann Arbor, MI 48109 USA. [Beavis, Ronald] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Borchers, Christoph] Univ Victoria, Prote Ctr, Vancouver, BC, Canada. [Chalkley, Robert J.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [Cho, Sang Yun] Yonsei Univ, Yonsei Proteome Res Ctr, Seoul 120749, South Korea. [Cottingham, Katie] Amer Chem Soc, Washington, DC 20036 USA. [Dunn, Michael] Wellcome Trust Res Labs, London, England. [Dylag, Tomasz; Kolar, Patrik; Kinsinger, Christopher R.] European Commiss, Directorate Gen Res, Brussels, Belgium. [Edgar, Ron] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Hare, Peter] Nat Biotechnol, New York, NY 10013 USA. [Heck, Albert J. R.; Nesvizhskii, Alexey] Univ Utrecht, NL-3508 TC Utrecht, Netherlands. [Hirsch, Roland F.] US DOE, OffBiol & Environm Res, Washington, DC 20585 USA. [Kennedy, Karen] Genome Canada, Int Genom Program, Ottawa, ON, Canada. [Kraus, Hans-Joachim] Wiley VCH Verlag, Weinheim, Germany. [Mallick, Parag] Univ Calif Los Angeles, Spielberg Family Ctr Appl Prote, Los Angeles, CA 90048 USA. [Nesvizhskii, Alexey] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Ping, Peipei] Univ Calif Los Angeles, Div Cardiol, Sch Med, Los Angeles, CA 90095 USA. [Ponten, Fredrik] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Yang, Liming] NCI, Ctr Biomed Informat & Informat Technol, Rockville, MD 20892 USA. [Yates, John R.] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 93037 USA. [Stein, Stephen E.] NIST, Mass Spectrometry Data Ctr, Gaithersburg, MD 20899 USA. [Hermjakob, Henning; Apweiler, Rolf] European Bioinformat Inst, Cambridge, England. RP Rodriguez, H (reprint author), NCI, Ctr Strateg Sci Initiat, NIH, 31 Ctr Dr,MS 2590, Bethesda, MD 20892 USA. EM rodriguezh@mail.nih.gov RI Heck, Albert/D-7098-2011; Nesvizhskii, Alexey/A-5410-2012; OI Heck, Albert/0000-0002-2405-4404; Nesvizhskii, Alexey/0000-0002-2806-7819; Apweiler, Rolf/0000-0001-7078-200X; Ping, Peipei/0000-0003-3583-3881; Andrews, Philip/0000-0001-6843-5420; Hermjakob, Henning/0000-0001-8479-0262 FU Intramural NIH HHS [Z99 CA999999] NR 8 TC 44 Z9 45 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD JUL PY 2009 VL 8 IS 7 BP 3689 EP 3692 DI 10.1021/pr900023z PG 4 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 466WL UT WOS:000267694600043 PM 19344107 ER PT J AU Issaq, HJ Van, QN Waybright, TJ Muschik, GM Veenstra, TD AF Issaq, Haleem J. Van, Que N. Waybright, Timothy J. Muschik, Gary M. Veenstra, Timothy D. TI Analytical and statistical approaches to metabolomics research SO JOURNAL OF SEPARATION SCIENCE LA English DT Review DE Biomarker detection; Chromatography; MS; Metabolomics; NMR; Statistical analysis ID ELECTROPHORESIS-MASS SPECTROMETRY; PRESSURE LIQUID-CHROMATOGRAPHY; STANDARD REPORTING REQUIREMENTS; MAGNETIC-RESONANCE-SPECTROSCOPY; GLOBAL BIOCHEMICAL APPROACH; COMPLEX MIXTURE ANALYSIS; SUPPORT VECTOR MACHINES; 2D NMR-SPECTROSCOPY; PATTERN-RECOGNITION; HUMAN URINE AB Metabolomics, the global profiling of metabolites in different living systems, has experienced a rekindling of interest partially due to the improved detection capabilities of the instrumental techniques currently being used in this area of biomedical research. The analytical methods of choice for the analysis of metabolites in search of disease biomarkers in biological specimens, and for the study of various low molecular weight metabolic pathways include NMR spectroscopy, GC/MS, CE/MS, and HPLC/MS. Global metabolite analysis and profiling of two different sets of data results in a plethora of data that is difficult to manage or interpret manually because of their subtle differences. Multivariate statistical methods and pattern-recognition programs were developed to handle the acquired data and to search for the discriminating features between data acquired from two sample sets, healthy and diseased. Metabolomics have been used in toxicology, plant physiology, and biomedical research. In this paper, we discuss various aspects of metabolomic research including sample collection, handling, storage, requirements for sample analysis, peak alignment, data interpretation using statistical approaches, metabolite identification, and finally recommendations for successful analysis. C1 [Issaq, Haleem J.; Van, Que N.; Waybright, Timothy J.; Muschik, Gary M.; Veenstra, Timothy D.] SAIC Frederick Inc, Lab Proteo & Analyt Technol, Adv Technol Program, NCI Frederick, Frederick, MD USA. RP Issaq, HJ (reprint author), SAIC Frederick Inc, Lab Proteo & Analyt Technol, Adv Technol Program, NCI Frederick, Frederick, MD USA. EM issaqh@mail.ncifcrf.gov FU National Institutes of Health [HHSN26120080001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations simply endorsement by the United States Government. NR 135 TC 104 Z9 111 U1 6 U2 103 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1615-9306 EI 1615-9314 J9 J SEP SCI JI J. Sep. Sci. PD JUL PY 2009 VL 32 IS 13 BP 2183 EP 2199 DI 10.1002/jssc.200900152 PG 17 WC Chemistry, Analytical SC Chemistry GA 473HY UT WOS:000268198100001 PM 19569098 ER PT J AU Li, QZ Yu, K AF Li, Qizhai Yu, Kai TI Inference of non-centrality parameter of a truncated non-central chi-squared distribution SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Truncated non-central chi-squared distribution; Moment estimate; Mean-squared error; Generalized Bayes rule; Inadmissibility ID GENERALIZED LINEAR-MODELS; COMPLETE CLASS THEOREM; LIKELIHOOD RATIO; POWER AB Non-central chi-squared distribution plays a vital role in statistical testing procedures. Estimation of the non-centrality parameter provides valuable information for the power calculation of the associated test. We are interested in the statistical inference property of the non-centrality parameter estimate based on one observation (usually a summary statistic) from a truncated chi-squared distribution. This work is motivated by the application of the flexible two-stage design in case-control studies, where the sample size needed for the second stage of a two-stage study can be determined adaptively by the results of the first stage. We first study the moment estimate for the truncated distribution and prove its existence, uniqueness, and inadmissibility and convergence properties. We then define a new class of estimates that includes the moment estimate as a special case. Among this class of estimates, we recommend to use one member that Outperforms the moment estimate in a wide range of scenarios. We also present two methods for constructing confidence intervals. Simulation studies are conducted to evaluate the performance of the proposed point and interval estimates. Published by Elsevier B.V C1 [Li, Qizhai; Yu, Kai] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. RP Yu, K (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM yuka@mail.nih.gov NR 23 TC 1 Z9 1 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 EI 1873-1171 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD JUL 1 PY 2009 VL 139 IS 7 BP 2431 EP 2444 DI 10.1016/j.jspi.2008.11.007 PG 14 WC Statistics & Probability SC Mathematics GA 432YP UT WOS:000265170600031 ER PT J AU DeJong, W Larimer, ME Wood, MD Hartman, R AF DeJong, William Larimer, Mary E. Wood, Mark D. Hartman, Roger TI NIAAA's Rapid Response to College Drinking Problems Initiative: Reinforcing the Use of Evidence-Based Approaches in College Alcohol Prevention SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID BRIEF INTERVENTION; CONTROL POLICIES; FOLLOW-UP; COMMUNITIES; STRATEGIES; DRINKERS; STUDENTS; PROGRAM AB Objective: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) created the Rapid Response to College Drinking Problems initiative so that senior college administrators facing an alcohol-related crisis could get assistance from well-established alcohol researchers and NIAAA staff. Method: Based on a competitive grant process, NIAAA selected live teams of research scientists with expertise in college drinking research. NIAAA then invited college administrators to propose interventions to address a recently experienced alcohol-related problem. Between September 2004 and September 2005, NIAAA selected 15 sites and paired each recipient college with a scientific team. Together, each program development/evaluation team, working closely with NIAAA scientific staff, jointly designed implemented, and evaluated a Rapid Response project. Results: This supplement reports the results of several Rapid Response projects, Plus other findings of interest that emerged from that research. Eight articles present evaluation findings for prevention and treatment interventions. which can be grouped by the individual, group/interpersonal, institutional, and community levels of the social ecological framework. Additional Studies provide further insights that can inform prevention and treatment programs designed to reduce alcohol-related problems among college Students. This article provides all overview of these findings, placing them in the context of the college drinking intervention literature. Conclusions: College drinking remains a daunting problem oil many campuses, but evidence-based strategies-such as those described in this supplement-provide hope that more effective solutions call be found. The Rapid Response initiative has helped solidify the necessary link between research and practice in college alcohol prevention and treatment. (J. Stud. Alcohol Drugs, Supplement No. 16: 5-11, 2009) C1 [DeJong, William] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA 02118 USA. [Larimer, Mary E.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Wood, Mark D.] Univ Rhode Isl, Dept Psychol, Kingston, RI 02881 USA. [Hartman, Roger] NIAAA, Bethesda, MD 20892 USA. RP DeJong, W (reprint author), Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, 801 Massachusetts Ave,3rd Floor, Boston, MA 02118 USA. EM wdejong@bu.edu RI Kim, Hyung Woo /G-7525-2011 FU National Institute on Alcohol Abuse and Alcoholism [U01 AA0 14749] FX Work on the supplement was supported by National Institute on Alcohol Abuse and Alcoholism grant U01 AA0 14749 to Mark D. Wood. NR 36 TC 13 Z9 13 U1 0 U2 3 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 EI 1938-4114 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2009 SU 16 BP 5 EP 11 PG 7 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 468SV UT WOS:000267842300001 PM 19538907 ER PT J AU Hingson, RW Zha, WX Weitzman, ER AF Hingson, Ralph W. Zha, Wenxing Weitzman, Elissa R. TI Magnitude of and Trends in Alcohol-Related Mortality and Morbidity Among US College Students Ages 18-24, 1998-2005 SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID DRINKING; PREVENTION AB Objective: The aim of this study was to estimate, among college students ages 18-24, the numbers of alcohol-related unintentional injury deaths and other problems over the period from 1998 through 2005. Method: The analysis integrated data on 18- to 24-year-olds and college students from each of the following data sources: the National Highway Traffic Safety Administration Fatality Analysis Reporting System, Centers for Disease Control and Prevention Injury Mortality Data, National Coroner Studies, census and college enrollment data, the National Household Survey on Drug Use and Health, and the College Alcohol Study. Results: Among college students ages 18-24, alcohol-related unintentional injury deaths increased 3% per 100,000 from 1,440 in 1998 to 1,825 in 2005. From 1999 to 2005, the proportions of college ages 18-24 who reported consuming five or more drinks on at least one occasion in the past month increased from 41.7% to 44.7% and the proportions who drove under the influence of alcohol in the past year increased from 26.5% to 28.9%-7% and 9% proportional increases, respectively. The increases occurred among college students ages 21-24, not 18-20. In 2001, 599,000 (10.5%) full-time 4-year college students were injured because of drinking, 696,000 (12%) were hit or assaulted by another drinking college student, and 97,000 (2%) were victims of alcohol-related sexual assault or date rape. A 2005 follow-up of students in schools with the highest proportions of heavy drinkers found no significant changes in the proportions experiencing these events. Conclusions: The persistence of college drinking problems underscores an urgent need to implement prevention and counseling approaches identified through research to reduce alcohol-related harms among college students and other young adults. (J. Stud. Alcohol Drugs, Supplement No. 16: 12-20, 2009) C1 [Hingson, Ralph W.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. [Weitzman, Elissa R.] Childrens Hosp Boston, Div Adolescent Med, Boston, MA USA. [Weitzman, Elissa R.] Harvard Univ, Sch Med, Dept Pediat, Cambridge, MA 02138 USA. [Weitzman, Elissa R.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Cambridge, MA 02138 USA. RP Hingson, RW (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2077, Bethesda, MD 20892 USA. EM rhingson@mail.nih.gov NR 28 TC 306 Z9 307 U1 1 U2 37 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2009 BP 12 EP 20 PG 9 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 468SV UT WOS:000267842300002 PM 19538908 ER PT J AU Faden, VB Corey, K Baskin, M AF Faden, Vivian B. Corey, Kristin Baskin, Marcy TI An Evaluation of College Online Alcohol-Policy Information: 2007 Compared With 2002 SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID BINGE DRINKING AB Objective: To receive federal funds, colleges and universities are required to provide information to students about their alcohol policies as part of their alcohol-abuse prevention efforts. This study investigated whether and how the availability and completeness of alcohol-policy information on college Web sites changed between 2002 and 2007. Method: The Web sites of the top 52 national universities listed in the 2002 rankings of U.S. News and World Report, which were reviewed for alcohol-policy information in 2002, were reviewed again in 2007 using the same Web search methodology. Results: Much more information regarding college alcohol policies was available on the Web sites of the 52 universities in 2007 than in 2002. Substantial increases were seen in the areas of (1) rules, restrictions, requirements; and (2) consequences for infractions, especially for student groups. In addition. information on university Web sites regarding their alcohol policies was easier to access in 2007 than in 2002. Conclusions: These findings indicate that colleges have made online alcohol-policy information more available and accessible to their students and other interested parties, including parents. This may reflect a greater engagement of colleges and universities in the issue of drinking on campus in general. (J. Stud. Alcohol Drugs, Supplement No. 16: 28-33, 2009) C1 [Faden, Vivian B.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. RP Faden, VB (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2087, Bethesda, MD 20892 USA. EM vfaden@mail.nih.gov NR 13 TC 3 Z9 3 U1 0 U2 1 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2009 BP 28 EP 33 PG 6 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 468SV UT WOS:000267842300004 PM 19538910 ER PT J AU Cranford, JA McCabe, SE Boyd, CJ Lange, JE Reed, MB Scott, MS AF Cranford, James A. McCabe, Sean Esteban Boyd, Carol J. Lange, James E. Reed, Mark B. Scott, Marcia S. TI Effects of Residential Learning Communities on Drinking Trajectories During the First Two Years of College SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID ANALYZING DEVELOPMENTAL TRAJECTORIES; VARIABLE-CENTERED ANALYSES; ALCOHOL-USE DISORDERS; BINGE DRINKING; HIGH-SCHOOL; EMERGING ADULTHOOD; LONGITUDINAL PHENOTYPES; SOCIAL INFLUENCES; YOUNG ADULTHOOD; ATTENDING PEERS AB Objective: Participation in residential learning communities (RLCs) is associated with lower rates of alcohol consumption among college students. This study used variable- and pattern-centered analytic approaches to examine the influence of RLCs on the drinking behavior of students during their first 2 years in college. Method: A Web-based survey was administered to a stratified random sample of 1,196 first-year students (51.8% women) attending a large university. The sample included 456 students (38.1%) who lived in and participated in RLCs and 740 students (61.9%) who did not participate in RLCs (non-RLCs). During their first semester, students reported on their precollege and current drinking. Students also completed measures of alcohol involvement 6 months later during their second semester and 18 months later during their fourth semester. Results: Mixed factorial analyses of variance showed that PLC students reported fewer drinks per occasion than non-RLC students before college. RLC and non-RLC students showed increases in maximum drinks per occasion from precollege to first and second semesters, but only non-RLC students continued to increase their drinking from second to fourth semester. Latent class growth analyses indicated four trajectory classes: (1) low stable (25.1%), (2) light increasing (19.2%), (3) moderate increasing (36.8%), and (4) heavy increasing (18.9%). Non-RLC students had higher odds of being in the heavy-increasing drinking trajectory class. Conclusions: Compared with their non-RLC peers, RLC students not only drink less before college and show smaller increases in drinking over time but also are less likely to be in a high-risk drinking trajectory group. Identification of selection, socialization, and reciprocal influence processes that underlie RLC effects can better inform prevention efforts for sustained lower risk drinking among college students. (J. Stud. Alcohol Drugs, Supplement No. 16: 86-95, 2009) C1 [McCabe, Sean Esteban] Univ Michigan, Substance Abuse Res Ctr, Ann Arbor, MI 48105 USA. [McCabe, Sean Esteban; Boyd, Carol J.] Univ Michigan, Inst Res Women & Gender, Ann Arbor, MI 48109 USA. [Cranford, James A.] Univ Michigan, Dept Psychiat, Addict Res Ctr, Ann Arbor, MI 48109 USA. [Lange, James E.] San Diego State Univ, Res Fdn, AOD Initiat Res, San Diego, CA 92182 USA. [Reed, Mark B.] San Diego State Univ, Sch Social Work, San Diego, CA 92182 USA. [Scott, Marcia S.] NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. RP McCabe, SE (reprint author), Univ Michigan, Substance Abuse Res Ctr, 2025 Traverwood Dr,Suite C, Ann Arbor, MI 48105 USA. EM plius@umich.edu OI McCabe, Sean/0000-0002-9622-4652 FU NIAAA NIH HHS [AA014738, AA015275, U01 AA014738, U18 AA015275] NR 55 TC 2 Z9 2 U1 2 U2 4 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD JUL PY 2009 BP 86 EP 95 PG 10 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 468SV UT WOS:000267842300010 PM 19538916 ER PT J AU Sul, B Iwasa, KH AF Sul, Bora Iwasa, Kuni H. TI Amplifying effect of a release mechanism for fast adaptation in the hair bundle SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article DE bioelectric phenomena; biomechanics; cellular biophysics; damping; ear; hearing ID CELLS; AMPLIFICATION; MECHANOTRANSDUCTION; MYOSIN-1C; MOVEMENTS; SACCULUS AB A "release" mechanism, which has been experimentally observed as the fast component in the hair bundle's response to mechanical stimulation, appears similar to common mechanical relaxation with a damping effect. This observation is puzzling because such a response is expected to have an amplifying role in the mechanoelectrical transduction process in hair cells. Here it is shown that a release mechanism can indeed have a role in amplification, if it is associated with negative stiffness due to the gating of the mechonoelectric transducer channel. C1 [Sul, Bora; Iwasa, Kuni H.] Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Natl Inst Hlth, Rockville, MD 20850 USA. RP Sul, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Natl Inst Hlth, 5 Res Court,Room 1B03, Rockville, MD 20850 USA. EM sulb@nidcd.nih.gov OI Iwasa, Kuni/0000-0002-9397-7704 FU NIDCD, NIH FX This research was supported by the Intramural Research Program of the NIDCD, NIH. NR 13 TC 4 Z9 4 U1 0 U2 3 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD JUL PY 2009 VL 126 IS 1 BP 4 EP 6 DI 10.1121/1.3143782 PG 3 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 471NL UT WOS:000268065100009 PM 19603855 ER PT J AU Domino, ME Foster, EM Vitiello, B Kratochvil, CJ Burns, BJ Silva, SG Reinecke, MA March, JS AF Domino, Marisa Elena Foster, E. Michael Vitiello, Benedetto Kratochvil, Christopher J. Burns, Barbara J. Silva, Susan G. Reinecke, Mark A. March, John S. TI Relative Cost-Effectiveness of Treatments for Adolescent Depression: 36-Week Results From the TADS Randomized Trial SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE depression; cost-effectiveness; cognitive-behavioral therapy; antidepressants ID NATION OUTCOME SCALES; QUALITY-OF-LIFE; MAJOR DEPRESSION; HEALTH-CARE; UTILITY; CHILDREN; HONOSCA; INTERVENTIONS; UNCERTAINTY; DISORDERS AB Objective: The cost-effectiveness of three active interventions for major depression in adolescents was compared after 36 weeks of treatment in the Treatment of Adolescents with Depression Study. Method: Outpatients aged 12 to 18 years with a primary diagnosis of major depression participated in a randomized controlled trial conducted at 13 U.S. academic and community clinics from 2000 to 2004. Three hundred twenty-seven participants randomized to 1 of 3 active treatment arms, fluoxetine alone (n = 109), cognitive-behavioral therapy (n = 111) alone, or their combination (n = 107), were evaluated for a 3-month acute treatment and a 6-month continuation/maintenance treatment period. Costs of services received for the 36 weeks were estimated and examined in relation to the number of depression-free days and quality-adjusted life-years. Cost-effectiveness acceptability curves were also generated. Sensitivity analyses were conducted to assess treatment differences on the quality-adjusted life-years and cost-effectiveness measures. Results: Cognitive-behavioral therapy was the most costly treatment component (mean $1,787 [in monotherapy] and $1,833 [in combination therapy], median $1,923 [for both]). Reflecting higher direct and indirect costs associated with psychiatric hospital use, the costs of services received outside Treatment of Adolescents with Depression Study in fluoxetine-treated patients (mean $5,382, median $2,341) were significantly higher than those in participants treated with cognitive-behavioral therapy (mean $3,102, median $1,373) or combination (mean $2,705, median $927). Accordingly, cost-effectiveness acceptability curves indicate that combination treatment is highly likely (> 90%) to be more cost-effective than fluoxetine alone at 36 weeks. Cognitive-behavioral therapy is not likely to be more cost-effective than fluoxetine. Conclusions: These findings support the use of combination treatment in adolescents with depression over monotherapy. J. Am. Acad. Child Adolesc. Psychiatry, 2009;48(7):711-720. C1 [Domino, Marisa Elena] Univ N Carolina, Dept Hlth Policy & Adm, Sch Publ Hlth, Chapel Hill, NC 27599 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. [Kratochvil, Christopher J.] Univ Nebraska Med Ctr, Omaha, NE USA. [Burns, Barbara J.] Duke Univ, Sch Med, Durham, NC 27706 USA. [Silva, Susan G.; March, John S.] Duke Univ, Med Ctr, Durham, NC 27706 USA. [Reinecke, Mark A.] Northwestern Univ, Evanston, IL 60208 USA. RP Domino, ME (reprint author), Univ N Carolina, Dept Hlth Policy & Adm, Sch Publ Hlth, 1104G McGavran Greenberg,CB 7411, Chapel Hill, NC 27599 USA. EM domino@unc.edu FU National Institute of Mental Health [N01 MH80008]; [K01-MH065639] FX This work was supported by contract N01 MH80008 from the National Institute of Mental Health to Duke University Medical Center (John S. March, Principal Investigator). Additional support was received by M.E.D. under K01-MH065639. NR 45 TC 27 Z9 27 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUL PY 2009 VL 48 IS 7 BP 711 EP 720 DI 10.1097/CHI.0b013e3181a2b319 PG 10 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 460ZA UT WOS:000267230700007 PM 19465880 ER PT J AU Wallerstedt, DB Sangare, J Bartlett, LD Mahoney, SF AF Wallerstedt, Dawn B. Sangare, Janet Bartlett, Linda D. Mahoney, Sheila F. TI The unique role of advanced practice nurses at the National Institutes of Health: Results of a 2006 survey SO JOURNAL OF THE AMERICAN ACADEMY OF NURSE PRACTITIONERS LA English DT Article DE Nurse practitioners; professional autonomy; nurse's role; research; questionnaire AB Purpose To characterize the role of advanced practice nurses (APNs), particularly nurse practitioners (NPs), in the practice setting of the National Institutes of Health (NIH), a Federal biomedical research facility. Data sources APNs with prescriptive authority employed at the NIH were surveyed using an adaptation of the American Academy of Nurse Practitioners (AANP) "2004 Nurse Practitioner Sample Survey." A total of 56 of 93 surveys were returned (63% response rate), and of these, 54 (96%) were completed by NPs. Conclusion In the 20 years they have been at NIH, the number of NPs has grown from less than 10 to more than 100. NIH NPs combine clinical research responsibilities with the provision of comprehensive medical management to patients enrolled on NIH protocols, blending clinical, research, educational, and administrative tasks into a unique and multifaceted role. There is a high level of satisfaction among NPs employed at the NIH, and they are considered an integral part of the research team. Implications for practice This survey shows the variability in practice opportunities available to NPs in a research environment and the impact they have on public health. C1 [Wallerstedt, Dawn B.] NIH, NCCAM, Off Sci Director, Bethesda, MD 20892 USA. [Sangare, Janet] Peace Corps Off, Med Serv, Washington, DC USA. [Bartlett, Linda D.] NIDDK, Nephrol Consult Serv, NIH, Bethesda, MD USA. [Mahoney, Sheila F.] NICHD, Gyn Consult Serv, RBMB, NIH, Bethesda, MD USA. RP Wallerstedt, DB (reprint author), NIH, NCCAM, Off Sci Director, 10 Ctr Dr,CRC Bldg 4NW 1740, Bethesda, MD 20892 USA. EM dbwallerstedt@gmail.com FU NIH; NCCAM; NIMH; NIDDK; NICHD FX This work was supported in part by the Intramural Research Program of the NIH, NCCAM, NIMH, NIDDK, and NICHD. NR 3 TC 3 Z9 3 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1041-2972 J9 J AM ACAD NURSE PRAC JI J. Am. Acad. Nurse Pract. PD JUL PY 2009 VL 21 IS 7 BP 351 EP 357 DI 10.1111/j.1745-7599.2009.00419.x PG 7 WC Health Care Sciences & Services; Nursing SC Health Care Sciences & Services; Nursing GA 462PZ UT WOS:000267369400001 PM 19594652 ER PT J AU Millen, AE Tooze, JA Subar, AF Kahle, LL Schatzkin, A Krebs-Smith, SM AF Millen, Amy E. Tooze, Janet A. Subar, Amy F. Kahle, Lisa L. Schatzkin, Arthur Krebs-Smith, Susan M. TI Differences between Food Group Reports of Low-Energy Reporters and Non-Low-Energy Reporters on a Food Frequency Questionnaire SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID DOUBLY LABELED WATER; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; DIETARY SURVEYS; OBSERVING PROTEIN; WEIGHT STATUS; LIFE-STYLE; ADULTS; VALIDATION; BIOMARKER AB Background Low-energy reporters (LERs) and non-LERs differ with respect to several characteristics, including self-reported intake of foods. Limited data exist regarding food intake difference between LERs and non-LERs identified using doubly labeled water (DLW). Objective In the Observing Protein and Energy Nutrition Study (September 1999-March 2000), differences were examined between food group reports of LERs and non-LERs on a food frequency questionnaire (FFQ) (n=440). Design LERs were identified using DLW. Responses of LERs (n=220) and non-LERs (n=220) for 43 food groups on the FFQ were examined in three ways: whether they reported consuming a food group (yes/no), how frequently they reported consuming it (times per day), and the reported portion size (small, medium, or large). Analyses were adjusted for total energy expenditure from DLW. Results LERs, compared to non-LERs, were less likely to report consumption for one food group among women (soft drinks/regular). Among men, there was no difference between LERs and non-LERs with respect to reporting consumption of food groups. Reported mean daily frequency of consumption was lower among LERs compared with non-LERs for 23 food groups among women and 24 food groups among men (18 food groups were similar in men and women). In addition, reported mean portion sizes were smaller for LERs compared with non-LERs for six food groups among women and five food groups among men (three food groups were similar in men and women). Results varied minimally by sex and body mass index. Conclusions LERs, compared with non-LERs, were more likely to differ regarding their reported frequency of consumption of food groups than their reported consumption (yes/no) or portion size of food groups. Results did not vary greatly by sex or body mass index. It still remains unclear whether improvement in questionnaire design or additional tools or methods would lead to a decrease in differential reporting due to LER status on an FFQ. J Am Diet Assoc. 2009;109:1194-1203. C1 [Millen, Amy E.] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Social & Prevent Med, Buffalo, NY 14214 USA. [Tooze, Janet A.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Subar, Amy F.; Krebs-Smith, Susan M.] NCI, Div Canc Control & Populat Sci, Risk Factor Monitoring & Methods Branch, Appl Res Program, Bethesda, MD 20892 USA. [Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. [Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kahle, Lisa L.] Informat Management Serv Inc, Silver Spring, MD USA. RP Millen, AE (reprint author), SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Social & Prevent Med, Farber Hall,Room 270, Buffalo, NY 14214 USA. EM aemillen@buffalo.edu FU Intramural NIH HHS [Z99 CA999999] NR 39 TC 12 Z9 12 U1 1 U2 5 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUL PY 2009 VL 109 IS 7 BP 1194 EP 1203 DI 10.1016/j.jada.2009.04.004 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 468UE UT WOS:000267847400016 PM 19559136 ER PT J AU Nahin, RL Pecha, M Welmerink, DB Sink, K DeKosky, ST Fitzpatrick, AL AF Nahin, Richard L. Pecha, Monica Welmerink, Diana B. Sink, Kaycee DeKosky, Steven T. Fitzpatrick, Annette L. CA Ginkgo Evaluation Memory Study Inv TI Concomitant Use of Prescription Drugs and Dietary Supplements in Ambulatory Elderly People SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cross-sectional study; prescription drugs; dietary supplements; herbal medicine; herb-drug interactions ID BASE-LINE DATA; ALTERNATIVE MEDICINE; GINKGO EVALUATION; VITAMIN-D; CONVENTIONAL MEDICINES; PATIENTS PERCEPTIONS; HERBAL PRODUCTS; UNITED-STATES; COMPLEMENTARY; HEALTH AB OBJECTIVES To analyze baseline data on concomitant use of prescription drugs and dietary supplements in elderly people from the Ginkgo Evaluation of Memory (GEM) Study, in which information was collected on all drugs and supplements used by participant. DESIGN Cross-sectional correlation analysis. SETTING GEM Study sites in California, Maryland, North Carolina, and Pennsylvania. PARTICIPANTS Three thousand seventy ambulatory individuals aged 75 and older enrolled between September 2000 and June 2002. MEASUREMENTS Use of prescription drugs and dietary supplements identified through bottles brought to the clinic. RESULTS Almost three-quarters (74.2%) of the cohort combined use of at least one prescription drug and one dietary supplement, with 32.5% using three or more prescription drugs and three or more supplements. The 15 most-prevalent prescription drugs exhibited substantial concomitant use with dietary supplements, ranging from 77.6% for diuretics to 93.6% for estrogen preparations. Although supplements were taken concomitantly with all classes of prescription drugs, the use of supplements was more likely in individuals using nonsteroidal anti-inflammatory drugs, thyroid drugs, and estrogens. The use of drugs for diabetes mellitus was negatively associated with the use of supplements, with most of this attributed to low use in those taking multivitamins, glucosamine and chondroitin, and echinacea. CONCLUSION There is substantial concomitant use of prescription drugs and dietary supplements in elderly people. Further investigations are needed to define the clinical importance of this concomitant use, especially in elderly patients who consume multiple prescription drugs or have experienced an adverse event secondary to their prescription medications. C1 [Nahin, Richard L.] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Pecha, Monica; Welmerink, Diana B.; Fitzpatrick, Annette L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Sink, Kaycee] Wake Forest Univ, Bowman Gray Sch Med, Ctr Aging, Winston Salem, NC USA. [DeKosky, Steven T.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 9000 Rockville Pike,Bldg 31,Rm 2B11, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 FU National Center for Complementary and Alternative Medicine (NCCAM) [5 U01 AT000162]; Office of Dietary Supplements, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke; Roena Kulynych Center for Memory and Cognition Research; Hartford Geriatrics Health Outcomes Program; WFU Claude D. Pepper Center [P30-AG21332] FX Sponsor's Role: The lead author is a U.S. government employee at NCCAM, the sponsoring federal agency. No other members of NCCAM or the National Institutes of Health were involved with any aspect of this study. The contents of this research are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM, or the National Institutes of Health. Schwabe Pharmaceuticals, Germany, donated investigational product (Ginkgo biloba) and matching placebo to the GEM Study. Schwabe Pharmaceuticals in no other way contributed to the design, conduct, analysis, or publication of this study. No authors have a financial or other conflict of interested with Schwabe Pharmaceuticals. NR 50 TC 31 Z9 33 U1 0 U2 10 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2009 VL 57 IS 7 BP 1197 EP 1205 DI 10.1111/j.1532-5415.2009.02329.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 464WI UT WOS:000267539800008 PM 19515113 ER PT J AU Hu, DL Pawlikowska, L Kanaya, A Hsueh, WC Colbert, L Newman, AB Satterfield, S Rosen, C Cummings, SR Harris, TB Ziv, E AF Hu, Donglei Pawlikowska, Ludmila Kanaya, Alka Hsueh, Wen-Chi Colbert, Lisa Newman, Anne B. Satterfield, Suzanne Rosen, Clifford Cummings, Steven R. Harris, Tamara B. Ziv, Elad CA Health Aging Body Composition Stud TI Serum Insulin-Like Growth Factor-1 Binding Proteins 1 and 2 and Mortality in Older Adults: The Health, Aging, and Body Composition Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; IGF-1; IGFBP; mortality ID GLUCOSE-INTOLERANCE; ELDERLY-MEN; LIFE-SPAN; AXIS; HOMEOSTASIS; RESISTANCE; DENSITY; STRESS; BRAIN; IGF-1 AB OBJECTIVE To evaluate the relationship between serum insulin-like growth factor 1 (IGF-1), IGF-1 binding protein 1 (IGFBP-1), and IGF-1 binding protein 2 (IGFBP-2) and fasting insulin, fasting glucose, adiposity, and mortality in older adults. DESIGN A prospective cohort study with mean follow-up of 6.2 years. SETTING Participants were recruited and followed at two centers affiliated with academic medical institutions. PARTICIPANTS Six hundred twenty-five men and women aged 70 and older and in good health at the time of enrollment. MEASUREMENTS Serum IGF-1, IGFBP-1, and IGFBP-2; fasting serum insulin; fasting serum glucose; visceral fat; and total percent fat. RESULTS Higher IGFBP-1 and higher IGFBP-2 were significantly associated with lower fasting insulin, lower fasting glucose, and lower adiposity, but higher IGFBP-1 and IGFBP-2 were associated with greater mortality. In multivariate adjusted models, the hazard ratio for all-cause mortality was 1.48 (95% confidence interval (CI)=1.14-1.92) per standard deviation (SD) increase in IGFBP-2 and 1.34 (95% CI=1.01-1.76) per SD increase in IGFBP-1. No association was found between IGF-1 and all-cause mortality. CONCLUSIONS Higher IGFBP-1 and IGFBP-2 are associated with lower adiposity and decreased glucose tolearance but also with greater all-cause mortality. Higher levels of serum IGF-1 binding protein (IGFBP) may indicate greater IGF-1 activity and thus represent an association between higher IGF-1 activity and mortality in humans. C1 [Hu, Donglei; Kanaya, Alka; Hsueh, Wen-Chi; Ziv, Elad] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Hu, Donglei; Pawlikowska, Ludmila; Hsueh, Wen-Chi; Ziv, Elad] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA. [Ziv, Elad] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Pawlikowska, Ludmila] Univ Calif San Francisco, Dept Anesthesia, San Francisco, CA 94143 USA. [Ziv, Elad] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Colbert, Lisa] Univ Wisconsin, Dept Kinesiol, Madison, WI USA. [Newman, Anne B.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Rosen, Clifford] Jackson Lab, Bangor, ME USA. [Rosen, Clifford] St Joseph Hosp, Bangor, ME USA. [Cummings, Steven R.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Ziv, E (reprint author), 1701 Divisadero St,Suite 554,UCSF Box 1732, San Francisco, CA 94115 USA. EM elad.ziv@ucsf.edu RI Newman, Anne/C-6408-2013; Ziv, Elad/L-5396-2014 OI Newman, Anne/0000-0002-0106-1150; FU National Institutes of Health, National Institute on Aging (NIH, NIA) [U19AG23122, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX Sponsor's Role: NA. NR 28 TC 29 Z9 29 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2009 VL 57 IS 7 BP 1213 EP 1218 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 464WI UT WOS:000267539800010 PM 19558480 ER PT J AU Shea, S Weinstock, RS Teresi, JA Palmas, W Starren, J Cimino, JJ Lai, AM Field, L Morin, PC Goland, R Izquierdo, RE Ebner, S Silver, S Petkova, E Kong, J Eimicke, JP AF Shea, Steven Weinstock, Ruth S. Teresi, Jeanne A. Palmas, Walter Starren, Justin Cimino, James J. Lai, Albert M. Field, Lesley Morin, Philip C. Goland, Robin Izquierdo, Roberto E. Ebner, Susana Silver, Stephanie Petkova, Eva Kong, Jian Eimicke, Joseph P. CA IDEATel Consortium TI A Randomized Trial Comparing Telemedicine Case Management with Usual Care in Older, Ethnically Diverse, Medically Underserved Patients with Diabetes Mellitus: 5 Year Results of the IDEATel Study SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID COLUMBIA-UNIVERSITY INFORMATICS; INTENSIVE GLYCEMIC CONTROL; BLOOD-PRESSURE CONTROL; TREATMENT PANEL-III; CARDIOVASCULAR-DISEASE; MICROVASCULAR COMPLICATIONS; COST-EFFECTIVENESS; GLUCOSE CONTROL; ELDERLY PEOPLE; HEALTH-CARE AB Context: Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care. Objectives: To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older, ethnically diverse, medically underserved patients with diabetes. Design, Setting, and Patients: A randomized controlled trial was conducted, comparing telemedicine case management to usual care, with blinded outcome evaluation, in 1,665 Medicare recipients with diabetes, aged 55 years, residing in federally designated medically underserved areas of New York State. Interventions: Home telemedicine unit with nurse case management versus usual care. Main Outcome Measures: The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c (HgbA1c), low density lipoprotein (LDL) cholesterol, and blood pressure levels. Results: Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints (HgbA1c, p = 0.001; LDL, p < 0.001; systolic and diastolic blood pressure, p = 0.024; p < 0.001). Estimated differences (95% CI) in year 5 were 0.29 (0.12, 0.46)% for HgbA1c, 3.84 (-0.08, 7.77) mg/dL for LDL cholesterol, and 4.32 (1.93, 6.72) mm Hg for systolic and 2.64 (1.53, 3,74) mm Hg for diastolic blood pressure. There were 176 deaths in the intervention group and 169 in the usual care group (hazard ratio 1.01 [0.82, 1.24]). Conclusions: Telemedicine case management resulted in net improvements in HgbA1c, LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries. Mortality was not different between the groups, although power was limited. C1 [Shea, Steven; Palmas, Walter; Field, Lesley; Goland, Robin; Ebner, Susana] Columbia Univ, Dept Med, New York, NY USA. [Shea, Steven] Columbia Univ, Joseph Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Shea, Steven; Cimino, James J.] Columbia Univ, Dept Biomed Informat, New York, NY USA. [Teresi, Jeanne A.] Columbia Univ, Stroud Ctr, New York, NY USA. [Goland, Robin; Ebner, Susana] Columbia Univ, Naomi Berrie Diabet Ctr, New York, NY USA. [Weinstock, Ruth S.; Morin, Philip C.; Izquierdo, Roberto E.] SUNY Upstate Med Univ, Joslin Diabet Ctr, Syracuse, NY USA. [Weinstock, Ruth S.; Morin, Philip C.; Izquierdo, Roberto E.] SUNY Upstate Med Univ, Div Endocrinol Diabet & Metab, Syracuse, NY USA. [Weinstock, Ruth S.] VA Med Ctr, Dept Vet Affairs, Syracuse, NY USA. [Teresi, Jeanne A.; Silver, Stephanie; Kong, Jian; Eimicke, Joseph P.] Res Div Hebrew Home Riverdale, Bronx, NY USA. [Teresi, Jeanne A.] Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. [Starren, Justin] Marshfield Clin Fdn Med Res & Educ, Marshfield, MN USA. [Cimino, James J.] Natl Inst Hlth Clin Ctr, Lab Informat Dept, Bethesda, MD USA. [Lai, Albert M.] Ohio State Univ, Columbus, OH 43210 USA. [Petkova, Eva] NYU, Sch Med, Div Biostat, Dept Child & Adolescent Psychiat, New York, NY USA. RP Shea, S (reprint author), Div Gen Med, 630 W 168th St, New York, NY 10032 USA. EM ss35@columbia.edu RI Lai, Albert/E-3453-2011; OI Lai, Albert/0000-0002-9241-2656; Petkova, Eva/0000-0001-5129-9442; Cimino, James/0000-0003-4101-1622 NR 47 TC 131 Z9 134 U1 4 U2 28 PU HANLEY & BELFUS-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD JUL-AUG PY 2009 VL 16 IS 4 BP 446 EP 456 DI 10.1197/jamia.M3157 PG 11 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 470QZ UT WOS:000267995500003 PM 19390093 ER PT J AU Douglas, PS Taylor, A Bild, D Bonow, R Greenland, P Lauer, M Peacock, F Udelson, J AF Douglas, Pamela S. Taylor, Allen Bild, Diane Bonow, Robert Greenland, Philip Lauer, Michael Peacock, Frank Udelson, James TI Outcomes Research in Cardiovascular Imaging: Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Cardiovascular imaging; Chest pain diagnosis; Clinical trials ID CORONARY-ARTERY-DISEASE; ABDOMINAL AORTIC-ANEURYSM; COMPUTED-TOMOGRAPHY ANGIOGRAPHY; ISCHEMIC MITRAL REGURGITATION; INCREMENTAL PROGNOSTIC VALUE; RANDOMIZED CONTROLLED TRIAL; ACUTE MYOCARDIAL-INFARCTION; ASSOCIATION TASK-FORCE; INTIMA-MEDIA THICKNESS; ACUTE CARDIAC ISCHEMIA AB In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation. (J Am Soc Echocardiogr 2009; 22: 766-773.) C1 [Douglas, Pamela S.] Duke Univ, Med Ctr, Div Cardiovasc Med, Durham, NC USA. [Taylor, Allen] Washington Hosp Ctr, Dept Med, Cardiovasc Res Inst, Washington, DC 20010 USA. [Bild, Diane] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Lauer, Michael] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Bonow, Robert; Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Peacock, Frank] Cleveland Clin, Cleveland, OH 44106 USA. [Udelson, James] Tufts Med Ctr, Div Cardiol, Boston, MA USA. RP Douglas, PS (reprint author), 7022 N Pavil DUMC,POB 17969, Durham, NC 27715 USA. EM pamela.douglas@duke.edu FU Intramural NIH HHS [Z99 HL999999] NR 71 TC 5 Z9 5 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD JUL PY 2009 VL 22 IS 7 BP 766 EP 773 DI 10.1016/j.echo.2009.05.026 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465KG UT WOS:000267582100004 PM 19560655 ER PT J AU Mottl, AK Vupputuri, S Cole, SA Almasy, L Goring, HHH Diego, VP Laston, S Shara, N Lee, ET Best, LG Fabsitz, RR MacCluer, JW Umans, JG North, KE AF Mottl, Amy K. Vupputuri, Suma Cole, Shelley A. Almasy, Laura Goering, Harald H. H. Diego, Vincent P. Laston, Sandra Shara, Nawar Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. MacCluer, Jean W. Umans, Jason G. North, Kari E. TI Linkage Analysis of Albuminuria SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; FACTOR-7-LIKE-2 TCF7L2 GENE; GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; STRONG HEART FAMILY; GENOME-WIDE SCANS; FAWN-HOODED RAT; DIABETIC-NEPHROPATHY; AMERICAN-INDIANS; CARDIOVASCULAR-DISEASE AB American Indians have a higher prevalence of albuminuria than the general population, likely resulting from a combination of environmental and genetic risk factors. To localize gene regions influencing variation in urinary albumin-to-creatinine ratio, we performed a linkage analysis and explored gene-by-diabetes, -hypertension, and -obesity interactions in a large cohort of American Indian families. We recruited >3600 individuals from 13 American Indian tribes from three centers (Arizona, North and South Dakota, and Oklahoma). We performed multipoint variance component linkage analysis in each center as well as in the entire cohort after controlling for center effects. We used two modeling strategies: Model 1 incorporated age, gender, and interaction terms; model 2 also controlled for diabetes, BP, body mass index, HDL, LDL, triglycerides, and smoking status. We evaluated interactions with diabetes, hypertension, and obesity using additive, interaction-specific linkage and stratified analyses. Loci suggestive for linkage to urinary albumin-to-creatinine ratio included 1q, 6p, 9q, 18q, and 20p. Gene-by-diabetes interaction was present with a quantitative trait locus specific to the diabetic stratum in the Dakotas isolated on 18q21.2 to 21.3 using model 1 (logarithm of odds = 3.3). Gene-by-hypertension interaction was present with quantitative trait loci specific to the hypertensive stratum in the Dakotas on 7q21.11 using model 1 (logarithm of odds = 3.4) and 10q25.1 using model 2 (logarithm of odds = 3.3). These loci replicate findings from multiple other genome scans of kidney disease phenotypes with distinct populations and are worthy of further study. C1 [Mottl, Amy K.; Vupputuri, Suma] Univ N Carolina, Kidney Ctr, Sch Med, Chapel Hill, NC 27599 USA. [Vupputuri, Suma; North, Kari E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. [North, Kari E.] Univ N Carolina, Carolinas Ctr Genome Sci, Chapel Hill, NC 27599 USA. [Cole, Shelley A.; Almasy, Laura; Goering, Harald H. H.; Diego, Vincent P.; Laston, Sandra; MacCluer, Jean W.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Shara, Nawar; Umans, Jason G.] MedStar Res Inst, Bethesda, MD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res, Timber Lake, SD USA. [Umans, Jason G.] Georgetown Univ, Med Ctr, Gen Clin Res Ctr, Dept Med Obstet & Gynecol, Washington, DC 20007 USA. RP Mottl, AK (reprint author), Univ N Carolina, Kidney Ctr, Sch Med, CB 7155,6008 Burnett Womack Bldg, Chapel Hill, NC 27599 USA. EM amy_mottl@med.unc.edu OI Mottl, Amy/0000-0002-4258-1726; Diego, Vincent/0000-0002-0007-2085 FU NHLBI NIH HHS [U01 HL65521, U01 HL041642, U01 HL041652, U01 HL041654, U01 HL065520, U01 HL065521, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65520]; NIMH NIH HHS [MH059490, R01 MH059490, R37 MH059490] NR 66 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUL PY 2009 VL 20 IS 7 BP 1597 EP 1606 DI 10.1681/ASN.2008080895 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 467XC UT WOS:000267775400024 PM 19369405 ER PT J AU Dotson, VM Kitner-Triolo, MH Evans, MK Zonderman, AB AF Dotson, Vonetta M. Kitner-Triolo, Melissa H. Evans, Michele K. Zonderman, Alan B. TI Effects of race and socioeconomic status on the relative influence of education and literacy on cognitive functioning SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Reading; Income; Demographics; Ethnicity; Neuropsychological testing; Cognition ID ETHNICALLY DIVERSE ELDERS; NEUROPSYCHOLOGICAL ASSESSMENT; AFRICAN-AMERICANS; READING-ABILITY; LEVEL; TASKS; PERFORMANCE; DECLINE; ADULT AB Previous research has shown that reading ability is a stronger predictor of cognitive functioning than years of education, particularly for African Americans. The current Study was designed to determine whether the relative influence of literacy and education on cognitive abilities varies as a function of race or socioeconomic status (SES). We examined the unique influence of education and reading scores on a range of cognitive tests in low- and higher-SES African Americans and Whites. Literacy significantly predicted scores on all but one cognitive measure in both African American groups and low-SES Whites, while education was not significantly associated with any cognitive measure. In Contrast, both education and reading scores predicted performance on many cognitive measures in higher-SES Whites. These findings provide further evidence that reading ability better predicts cognitive functioning than years of education and suggest that disadvantages associated with racial minority status and low SES affect the relative influence of literacy and years of education on cognition. (JINS, 2009, 15, 580-589.) C1 [Dotson, Vonetta M.] NIA, Biomed Res Ctr, Intramural Res Program, NIH,Lab Personal & Cognit, Baltimore, MD 21224 USA. [Evans, Michele K.; Zonderman, Alan B.] NIA, Clin Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Dotson, VM (reprint author), NIA, Biomed Res Ctr, Intramural Res Program, NIH,Lab Personal & Cognit, 251 Bayview Blvd,Suite 100,Room 04B316, Baltimore, MD 21224 USA. EM dotsonv@mail.nih.gov RI Dotson, Vonetta/K-6090-2015; OI Dotson, Vonetta/0000-0002-3043-3320; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z01 AG000194-01] NR 45 TC 25 Z9 26 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD JUL PY 2009 VL 15 IS 4 BP 580 EP 589 DI 10.1017/S1355617709090821 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 470EU UT WOS:000267958600010 PM 19573276 ER PT J AU Longo, DL AF Longo, Dan L. TI Late Effects From Radiation Therapy: The Hits Just Keep on Coming SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HODGKINS-DISEASE; LYMPHOMA; CANCER; RISK; CHEMOTHERAPY; SURVIVORS; STROKE C1 NIA, Baltimore, MD 21224 USA. RP Longo, DL (reprint author), NIA, 251 Bayview Blvd,Ste 100,Rm 04C224, Baltimore, MD 21224 USA. EM longod@grc.nia.nih.gov NR 12 TC 4 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 1 PY 2009 VL 101 IS 13 BP 904 EP 905 DI 10.1093/jnci/djp164 PG 2 WC Oncology SC Oncology GA 466MS UT WOS:000267666900002 PM 19535779 ER PT J AU Gail, MH AF Gail, Mitchell H. TI Value of Adding Single-Nucleotide Polymorphism Genotypes to a Breast Cancer Risk Model SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SUSCEPTIBILITY; PREVENTION; PREDICTION; VALIDATION; TAMOXIFEN AB Adding genotypes from seven single-nucleotide polymorphisms (SNPs), which had previously been associated with breast cancer, to the National Cancer Institute's Breast Cancer Risk Assessment Tool (BCRAT) increases the area under the receiver operating characteristic curve from 0.607 to 0.632. Criteria that are based on four clinical or public health applications were used to compare BCRAT with BCRATplus7, which includes the seven genotypes. Criteria included number of expected life-threatening events for the decision to take tamoxifen, expected decision losses (in units of the loss from giving a mammogram to a woman without detectable breast cancer) for the decision to have a mammogram, rates of risk reclassification, and number of lives saved by risk-based allocation of screening mammography. For all calculations, the following assumptions were made: Hardy-Weinberg equilibrium, linkage equilibrium across SNPs, additive effects of alleles at each locus, no interactions on the logistic scale among SNPs or with factors in BCRAT, and independence of SNPs from factors in BCRAT. Improvements in expected numbers of life-threatening events were only 0.07% and 0.81% for deciding whether to take tamoxifen to prevent breast cancer for women aged 50-59 and 40-49 years, respectively. For deciding whether to recommend screening mammograms to women aged 50-54 years, the reduction in expected losses was 0.86% if the ideal breast cancer prevalence threshold for recommending mammography was that of women aged 50-54 years. Cross-classification of risks indicated that some women classified by BCRAT would have different classifications with BCRATplus7, which might be useful if BCRATplus7 was well calibrated. Improvements from BCRATplus7 were small for risk-based allocation of mammograms under costs constraints. The gains from BCRATplus7 are small in the applications examined. Models with SNPs, such as BCRATplus7, have not been validated for calibration in independent cohort data. Additional studies are needed to validate a model with SNPs and justify its use. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, MH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 8032, Bethesda, MD 20892 USA. EM gailm@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology; Genetics, National Cancer Institute; National Institutes on Health FX The Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute and National Institutes on Health, supported this work. NR 17 TC 84 Z9 86 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 1 PY 2009 VL 101 IS 13 BP 959 EP 963 DI 10.1093/jnci/djp130 PG 5 WC Oncology SC Oncology GA 466MS UT WOS:000267666900013 PM 19535781 ER PT J AU Shavers, VL Underwood, W Moser, RP AF Shavers, Vickie L. Underwood, Willie, III Moser, Richard P. TI Race/Ethnicity, Risk Perception, and Receipt of Prostate-Specific Antigen Testing SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE race/ethnicity; screening; prostate cancer ID AFRICAN-AMERICAN; CANCER; STAGE; MEN AB Background: Men who do not perceive themselves to be at risk of developing and dying from prostate cancer may be less likely to utilize prostate cancer screening. This, coupled with variation among organizations in recommendations about screening with prostate-specific antigen (PSA), may contribute to confusion for providers and/or patients making prostate cancer screening decisions. Methods: Data on 1075 African American, Hispanic, and non-Hispanic white male respondents to the 2003 Health Information National Trends Study (HINTS) were analyzed to examine the association among demographic characteristics, perception of the risk of developing prostate cancer, and PSA test utilization among men aged 45 or older. Results: African American men less frequently, while Hispanic men more frequently, perceived their risk of developing prostate cancer to be higher than the average same-age man compared to non-Hispanic white men. Overall, men who perceived their likelihood of getting prostate cancer as very low to moderate (OR, 0.42; 95% Cl, 0.24-0.73) or perceived the likelihood compared to the average same age man as less or about as likely (OR, 0.47; 95% Cl, 0.27-0.81) were significantly less likely to have received a PSA test in a model adjusted for age, marital status, education, and health insurance coverage. Conclusions: These findings suggest that all men, but particularly African American and Hispanic men, could benefit from information regarding their specific risk of developing prostate cancer before making a decision about prostate cancer screening. C1 [Shavers, Vickie L.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. [Moser, Richard P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Underwood, Willie, III] Roswell Pk Canc Inst, Dept Urol Oncol, Buffalo, NY 14263 USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, 6130 Execut Blvd,MSC 7344,EPN Rm 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 22 TC 7 Z9 7 U1 1 U2 3 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD JUL PY 2009 VL 101 IS 7 BP 698 EP 704 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 476UB UT WOS:000268470300008 PM 19634591 ER PT J AU Antonellis, A Ionasescu, V Lupski, JR Nicholson, GA Talbot, K Vance, J Zuchner, S Green, E AF Antonellis, A. Ionasescu, V Lupski, J. R. Nicholson, G. A. Talbot, K. Vance, J. Zuchner, S. Green, E. CA NISC Comparative Sequencing Progra TI HIGH-THROUGHPUT MUTATION ANALYSIS OF THE HUMAN AMINOACYL-tRNA SYNTHETASE GENES: IN SEARCH OF ADDITIONAL LOCI RESPONSIBLE FOR INHERITED PERIPHERAL NEUROPATHIES SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Annual Meeting of the Peripheral-Nerve-Society CY JUL 04-08, 2009 CL Wurzburg, GERMANY SP Peripheral Nerve Soc C1 [Antonellis, A.] Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI USA. [Antonellis, A.] Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI USA. [Green, E.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, E.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. [Ionasescu, V] Univ Iowa, Dept Pediat, Div Med Genet, Iowa City, IA 52242 USA. [Lupski, J. R.] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Lupski, J. R.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Lupski, J. R.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [Lupski, J. R.] Texas Childrens Hosp, Houston, TX 77030 USA. [Nicholson, G. A.] Concord Hosp, ANZAC Res Inst, Northcott Neurosci Lab, Concord, NSW, Australia. [Nicholson, G. A.] Concord Hosp, Mol Med Lab, Concord, NSW, Australia. [Nicholson, G. A.] Univ Sydney, Fac Med, Camperdown, NSW, Australia. [Talbot, K.] Univ Oxford, Dept Clin Neurol, Oxford, England. [Vance, J.; Zuchner, S.] Univ Miami, Miller Sch Med, Miami Inst Human Genom, Miami, FL 33136 USA. RI Talbot, Kevin /F-7361-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUL PY 2009 VL 14 BP 7 EP 8 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 490TE UT WOS:000269527000018 ER PT J AU Dalakas, MC Rakocevic, G Salajegheh, M Dambrosia, JM Hahn, AF Raju, R McElroy, B AF Dalakas, M. C. Rakocevic, G. Salajegheh, M. Dambrosia, J. M. Hahn, A. F. Raju, R. McElroy, B. TI A PLACEBO-CONTROLLED TRIAL OF RITUXIMAB IN IgM ANTI-MAG ANTIBODY DEMYELINATING NEUROPATHY SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Meeting Abstract CT Annual Meeting of the Peripheral-Nerve-Society CY JUL 04-08, 2009 CL Wurzburg, GERMANY SP Peripheral Nerve Soc C1 [Dalakas, M. C.] Univ London Imperial Coll Sci Technol & Med, Dept Clin Neurosci, London, England. [Rakocevic, G.] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA. [Salajegheh, M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Dambrosia, J. M.] NIH, Biostat Branch, Bethesda, MD 20892 USA. [Hahn, A. F.] Univ Western Ontario, Dept Neurol, London, ON, Canada. [Raju, R.] Univ Alabama, Dept Immunol, Birmingham, AL USA. [McElroy, B.] NIH, Off Clin Director, Bethesda, MD 20892 USA. RI Raju, Raghavan/E-9219-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUL PY 2009 VL 14 BP 38 EP 39 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 490TE UT WOS:000269527000089 ER PT J AU Compton, W Normand, J Lambert, E AF Compton, Wilson Normand, Jacques Lambert, Elizabeth TI Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP), July 2009 Introduction SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Editorial Material ID INJECTION-DRUG-USERS C1 [Compton, Wilson; Lambert, Elizabeth] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Normand, Jacques] Natl Inst Drug Abuse, AIDS Res Program, Bethesda, MD 20892 USA. RP Lambert, E (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM elambert@nida.nih.gov NR 5 TC 3 Z9 3 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD JUL PY 2009 VL 86 BP S1 EP S4 DI 10.1007/s11524-009-9373-4 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 478HN UT WOS:000268578500001 PM 19543977 ER PT J AU Rothenberg, R Jenkins, R Lambert, E AF Rothenberg, Richard Jenkins, Richard Lambert, Elizabeth TI Special Issue: Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP), July 2009 SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Editorial Material ID US METROPOLITAN-AREAS; GENERAL-POPULATION; MEN; WORKERS; CHINA; PREVALENCE; BEHAVIORS; CLIENTS; SPREAD; RISK C1 [Jenkins, Richard; Lambert, Elizabeth] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Rothenberg, Richard] Georgia State Univ, Inst Publ Hlth, Atlanta, GA 30303 USA. RP Lambert, E (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM elambert@nida.nih.gov NR 24 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD JUL PY 2009 VL 86 BP S144 EP S148 DI 10.1007/s11524-009-9374-3 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 478HN UT WOS:000268578500011 PM 19513852 ER PT J AU Loeb, S Carter, HB Walsh, PC Isaacs, WB Kettermann, A Tanaka, T Ferrucci, L Metter, EJ AF Loeb, Stacy Carter, H. Ballentine Walsh, Patrick C. Isaacs, William B. Kettermann, Anna Tanaka, Toshiko Ferrucci, Luigi Metter, E. Jeffrey TI Single Nucleotide Polymorphisms and the Likelihood of Prostate Cancer at a Given Prostate Specific Antigen Level SO JOURNAL OF UROLOGY LA English DT Article DE prostate-specific antigen; prostatic neoplasms; polymorphism, single nucleotide; mass screening; genetics ID ASSOCIATION; VARIANTS; RISK; MEN AB Purpose: Prostate specific antigen is used for prostate cancer screening but its specificity is limited. Specificity might be increased by considering genotype associated prostate specific antigen levels. Materials and Methods: We examined associations between single nucleotide polymorphisms on chromosomes 10 and 19 (previously shown to be associated with prostate specific antigen) with prostate specific antigen and prostate cancer in 505 men from the Baltimore Longitudinal Study of Aging. Results: In a model with age and date the risk ratio for prostate cancer was 1.18 (95% CI 1.13-1.23) per unit increase in prostate specific antigen. Including the interaction between alleles and prostate specific antigen significantly altered the risk ratio for prostate cancer (Cox proportional hazards p <0.001). Specifically prostate cancer risk per unit increase in prostate specific antigen was significantly different in carriers than in nonearriers of a minor allele (1.28 vs 1.10, respectively, Cox proportional hazards p <0.001), whereas men with a minor allele had a significantly higher risk of prostate cancer at prostate specific antigen levels greater than 6 ng/ml. Conclusions: Our data suggest that genotype influences the risk of prostate cancer per unit increase in prostate specific antigen. Prostate cancer risk stratification using prostate specific antigen and genotype could improve prostate specific antigen test performance. C1 [Loeb, Stacy; Carter, H. Ballentine; Walsh, Patrick C.; Isaacs, William B.; Kettermann, Anna] Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. [Tanaka, Toshiko; Ferrucci, Luigi; Metter, E. Jeffrey] NIA, NIH, Clin Res Branch, Baltimore, MD 21224 USA. RP Loeb, S (reprint author), 600 N Wolfe St,Marburg 100, Baltimore, MD 21287 USA. EM stacyloeb@gmail.com OI Loeb, Stacy/0000-0003-3933-9207 FU Intramural Research Program of the National Institutes of Health, National Institute on Aging FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 10 TC 21 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2009 VL 182 IS 1 BP 101 EP 104 DI 10.1016/j.juro.2009.02.126 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 457RI UT WOS:000266949800035 PM 19450841 ER PT J AU Kramer, BS Hagerty, KL Justman, S Somerfield, MR Albertsen, PC Blot, WJ Carter, HB Epstein, JI Godley, PA Harris, RP Wilt, TJ Wittes, J Zon, R Schellhammer, P AF Kramer, B. S. Hagerty, K. L. Justman, S. Somerfield, M. R. Albertsen, P. C. Blot, W. J. Carter, H. B. Epstein, J. I. Godley, P. A. Harris, R. P. Wilt, T. J. Wittes, J. Zon, R. Schellhammer, P. TI Use of 5-alpha-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline Editorial Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 [Kramer, B. S.] NIH, Bethesda, MD 20892 USA. Int Epidemiol Inst, Rockville, MD USA. Johns Hopkins Univ, Baltimore, MD USA. Alexandria & Eastern Virginia Med Sch, Amer Soc Clin Oncol, Norfolk, VA USA. Univ Montana Liberal Studies, Missoula, MT USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ N Carolina, Chapel Hill, NC USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Stat Collaborat, Washington, DC USA. Michiana Hematol Oncol, Granger, IN USA. RP Kramer, BS (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUL PY 2009 VL 182 IS 1 BP 147 EP 148 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 457RI UT WOS:000266949800051 ER PT J AU Vogt, MR Moesker, B Goudsmit, J Jongeneelen, M Austin, SK Oliphant, T Nelson, S Pierson, TC Wilschut, J Throsby, M Diamond, MS AF Vogt, Matthew R. Moesker, Bastiaan Goudsmit, Jaap Jongeneelen, Mandy Austin, S. Kyle Oliphant, Theodore Nelson, Steevenson Pierson, Theodore C. Wilschut, Jan Throsby, Mark Diamond, Michael S. TI Human Monoclonal Antibodies against West Nile Virus Induced by Natural Infection Neutralize at a Postattachment Step SO JOURNAL OF VIROLOGY LA English DT Article ID JAPANESE ENCEPHALITIS-VIRUS; TICK-BORNE ENCEPHALITIS; PROTEIN DOMAIN-III; FLAVIVIRUS ENVELOPE GLYCOPROTEIN; MEMBRANE-FUSION PROTEINS; CROSS-REACTIVE EPITOPES; DENGUE-VIRUS; MEDIATED NEUTRALIZATION; ANTIGENIC STRUCTURE; CRYSTAL-STRUCTURE AB West Nile virus (WNV) is a neurotropic flavivirus that is now a primary cause of epidemic encephalitis in North America. Studies of mice have demonstrated that the humoral immune response against WNV limits primary infection and protects against a secondary challenge. The most-potent neutralizing mouse monoclonal antibodies (MAbs) recognize an epitope on the lateral ridge of domain III (DIII-lr) of the envelope (E) protein. However, studies with serum from human patients show that antibodies against the DIII-lr epitope comprise, at best, a minor component of the human anti-WNV antibody response. Herein, we characterize in detail two WNV-specific human MAbs, CR4348 and CR4354, that were isolated from B-cell populations of convalescent patients. These MAbs strongly neutralize WNV infection of cultured cells, protect mice against lethal infection in vivo, and yet poorly recognize recombinant forms of the E protein. Instead, CR4348 and CR4354 bind determinants on intact WNV virions and subviral particles in a pH-sensitive manner, and neutralization is altered by mutations at the dimer interface in domain II and the hinge between domains I and II, respectively. CR4348 and CR4354 human MAbs neutralize infection at a postattachment step in the viral life cycle, likely by inhibiting acid-induced fusion within the endosome. C1 [Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Vogt, Matthew R.; Austin, S. Kyle; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Oliphant, Theodore; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Moesker, Bastiaan; Wilschut, Jan] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, NL-9700 RB Groningen, Netherlands. [Goudsmit, Jaap; Jongeneelen, Mandy; Throsby, Mark] Crucell Holland BV, NL-2301 CA Leiden, Netherlands. [Nelson, Steevenson; Pierson, Theodore C.] NIH, Viral Dis Lab, Viral Pathogenesis Sect, Bethesda, MD 20892 USA. RP Diamond, MS (reprint author), Washington Univ, Sch Med, Dept Med, 660 S Euclid Ave,Box 8051, St Louis, MO 63110 USA. EM diamond@borcim.wustl.edu FU NIH [U01 AI061373]; Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research [U54 AI057160] FX This work was supported by grants from the NIH (grant U01 AI061373 [M.S.D.]) and the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research (grant U54 AI057160). NR 88 TC 64 Z9 65 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6494 EP 6507 DI 10.1128/JVI.00286-09 PG 14 WC Virology SC Virology GA 462LM UT WOS:000267354100018 PM 19386704 ER PT J AU Wilson, NA Keele, BF Reed, JS Piaskowski, SM MacNair, CE Bett, AJ Liang, XP Wang, FB Thoryk, E Heidecker, GJ Citron, MP Huang, LY Lin, J Vitelli, S Ahn, CD Kaizu, M Maness, NJ Reynolds, MR Friedrich, TC Loffredo, JT Rakasz, EG Erickson, S Allison, DB Piatak, M Lifson, JD Shiver, JW Casimiro, DR Shaw, GM Hahn, BH Watkins, DI AF Wilson, Nancy A. Keele, Brandon F. Reed, Jason S. Piaskowski, Shari M. MacNair, Caitlin E. Bett, Andrew J. Liang, Xiaoping Wang, Fubao Thoryk, Elizabeth Heidecker, Gwendolyn J. Citron, Michael P. Huang, Lingyi Lin, Jing Vitelli, Salvatore Ahn, Chanook D. Kaizu, Masahiko Maness, Nicholas J. Reynolds, Matthew R. Friedrich, Thomas C. Loffredo, John T. Rakasz, Eva G. Erickson, Stephen Allison, David B. Piatak, Michael, Jr. Lifson, Jeffrey D. Shiver, John W. Casimiro, Danilo R. Shaw, George M. Hahn, Beatrice H. Watkins, David I. TI Vaccine-Induced Cellular Responses Control Simian Immunodeficiency Virus Replication after Heterologous Challenge SO JOURNAL OF VIROLOGY LA English DT Article ID RHESUS-MONKEYS; HIV-1 VACCINE; VIRAL REPLICATION; SIVMAC239 REPLICATION; MUCOSAL CHALLENGE; IMMUNE-RESPONSES; PATHOGENIC SIV; DOSE CHALLENGE; AIDS VACCINE; STEP BACK AB All human immunodeficiency virus (HIV) vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T-cell responses against 11 to 34 epitopes. We challenged the vaccinees and eight naive animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both the peak (1.9-log reduction; P < 0.03) and at the set point (2.6-log reduction; P < 0.006) than those in control naive animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 viral RNA (vRNA) copy eq/ml and to less than 100 vRNA copy eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T-cell-based vaccines may have greater potential than previously appreciated. C1 [Wilson, Nancy A.] Univ Wisconsin, AIDS Vaccine Dev Lab, Dept Pathol & Lab Med, Madison, WI 53711 USA. [Friedrich, Thomas C.] Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53711 USA. [Keele, Brandon F.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Keele, Brandon F.; Shaw, George M.; Hahn, Beatrice H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Erickson, Stephen; Allison, David B.] Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Bett, Andrew J.; Liang, Xiaoping; Wang, Fubao; Thoryk, Elizabeth; Heidecker, Gwendolyn J.; Citron, Michael P.; Huang, Lingyi; Lin, Jing; Vitelli, Salvatore; Shiver, John W.; Casimiro, Danilo R.] Merck Res Labs, West Point, PA USA. [Piatak, Michael, Jr.; Lifson, Jeffrey D.] NCI Frederick, SAIC Frederick Inc, Frederick, MD USA. RP Wilson, NA (reprint author), Univ Wisconsin, AIDS Vaccine Dev Lab, Dept Pathol & Lab Med, 555 Sci Dr, Madison, WI 53711 USA. EM nwilson@primate.wisc.edu OI Allison, David/0000-0003-3566-9399; Friedrich, Thomas/0000-0001-9831-6895 FU U. S. National Institutes of Health [R01 AI049120, R37 AI052056, R01 AI076114, R24 RR015371, R24 RR016038, R21 AI077472, HHSN266200400088C]; Wisconsin National Primate Research Center [P51 RR000167]; International AIDS Vaccine Initiative [RR15459-01, RR020141-01]; CHAVI FX D. I. W. and his laboratory are supported by the U. S. National Institutes of Health (grants R01 AI049120, R37 AI052056, R01 AI076114, R24 RR015371, R24 RR016038, and R21 AI077472; contract HHSN266200400088C). This publication was made possible in part by P51 RR000167 from the Wisconsin National Primate Research Center. This research was conducted at a facility constructed with support from the Research Facilities Improvement Program grants RR15459-01 and RR020141-01 and was also supported by grants from the International AIDS Vaccine Initiative. This work was supported in part by the CHAVI. NR 62 TC 94 Z9 95 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6508 EP 6521 DI 10.1128/JVI.00272-09 PG 14 WC Virology SC Virology GA 462LM UT WOS:000267354100019 PM 19403685 ER PT J AU daSilva, LLP Sougrat, R Burgos, PV Janvier, K Mattera, R Bonifacino, JS AF daSilva, Luis L. P. Sougrat, Rachid Burgos, Patricia V. Janvier, Katy Mattera, Rafael Bonifacino, Juan S. TI Human Immunodeficiency Virus Type 1 Nef Protein Targets CD4 to the Multivesicular Body Pathway SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-SURFACE CD4; DOWN-REGULATION; HIV-1 NEF; MHC-I; RAPID INTERNALIZATION; CYTOPLASMIC DOMAIN; UBIQUITIN LIGASE; DILEUCINE MOTIF; DIRECT BINDING; BETA-COP AB The Nef protein of human immunodeficiency virus type 1 downregulates the CD4 coreceptor from the surface of host cells by accelerating the rate of CD4 endocytosis through a clathrin/AP-2 pathway. Herein, we report that Nef has the additional function of targeting CD4 to the multivesicular body (MVB) pathway for eventual delivery to lysosomes. This targeting involves the endosomal sorting complex required for transport (ESCRT) machinery. Perturbation of this machinery does not prevent removal of CD4 from the cell surface but precludes its lysosomal degradation, indicating that accelerated endocytosis and targeting to the MVB pathway are separate functions of Nef. We also show that both CD4 and Nef are ubiquitinated on lysine residues, but this modification is dispensable for Nef-induced targeting of CD4 to the MVB pathway. C1 [daSilva, Luis L. P.; Sougrat, Rachid; Burgos, Patricia V.; Janvier, Katy; Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov RI LP daSilva, Luis/A-9949-2010; OI LP daSilva, Luis/0000-0003-3558-0087; Sougrat, Rachid/0000-0001-6476-1886; Bonifacino, Juan S./0000-0002-5673-6370 FU NIH; National Institute of Child Health and Human Development FX This work was supported by the NIH Intramural AIDS Targeted Antiviral Program and the Intramural Program of the National Institute of Child Health and Human Development. NR 79 TC 31 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6578 EP 6590 DI 10.1128/JVI.00548-09 PG 13 WC Virology SC Virology GA 462LM UT WOS:000267354100025 PM 19403684 ER PT J AU Freundt, EC Yu, L Park, E Lenardo, MJ Xu, XN AF Freundt, Eric C. Yu, Li Park, Elizabeth Lenardo, Michael J. Xu, Xiao-Ning TI Molecular Determinants for Subcellular Localization of the Severe Acute Respiratory Syndrome Coronavirus Open Reading Frame 3b Protein SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOPLASMIC RNA VIRUSES; NUCLEAR-EXPORT SIGNALS; I HTLV-I; INNATE IMMUNITY; CELL-DEATH; P13(II) PROTEIN; RIG-I; MITOCHONDRIA; APOPTOSIS; SARS AB Viruses such as hepatitis C and the severe acute respiratory syndrome coronavirus (SARS-CoV) encode proteins that are distributed between mitochondria and the nucleus, but little is known about the factors that control partitioning between these sites. SARS-CoV encodes a unique accessory gene called open reading frame (ORF) 3b that, like other unique accessory genes in SARS-CoV, likely contributes to viral pathogenicity. The ORF 3b protein is 154 amino acids and is predicted to express from the second ORF in subgenomic RNA3. In this report, we have characterized the molecular components that regulate intracellular localization of the ORF 3b protein. We demonstrate unique shuttling behavior of ORF 3b, whereby the protein initially accumulates in the nucleus and subsequently translocates to mitochondria. Following nuclear localization, ORF 3b traffics to the outer membrane of mitochondria via a predicted amphipathic alpha-helix. Additionally, ORF 3b contains a consensus nuclear export sequence, and we demonstrate that nuclear export and thus mitochondrial translocation are dependent on a leptomycin B-sensitive nuclear export mechanism. We further show that ORF 3b inhibits induction of type I interferon induced by retinoic acid-induced gene 1 and the mitochondrial antiviral signaling protein. Our observations provide insights into the cellular localization of ORF 3b that may enhance our understanding of the mechanisms by which ORF 3b contributes to SARS-CoV pathogenesis. The findings reported here reveal that for multilocalized proteins, consideration of the spatiotemporal distribution may be crucial for understanding viral protein behavior and function. C1 [Freundt, Eric C.; Xu, Xiao-Ning] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC,Human Immunol Unit, Oxford OX3 9DS, England. [Freundt, Eric C.; Yu, Li; Park, Elizabeth; Lenardo, Michael J.] NIH, Immunol Lab, Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. RP Xu, XN (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC,Human Immunol Unit, Oxford OX3 9DS, England. EM xiaoning.xu@imm.ox.ac.uk FU NIAID, National Institutes of Health; National Institutes of Health-University of Oxford Biomedical Research Scholarship FX The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the funding agency. NR 44 TC 22 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6631 EP 6640 DI 10.1128/JVI.00367-09 PG 10 WC Virology SC Virology GA 462LM UT WOS:000267354100030 PM 19403678 ER PT J AU Kubota, T Matsuoka, M Chang, TH Bray, M Jones, S Tashiro, M Kato, A Ozato, K AF Kubota, Toru Matsuoka, Mayumi Chang, Tsung-Hsien Bray, Mike Jones, Steven Tashiro, Masato Kato, Atsushi Ozato, Keiko TI Ebolavirus VP35 Interacts with the Cytoplasmic Dynein Light Chain 8 SO JOURNAL OF VIROLOGY LA English DT Article ID RABIES VIRUS PHOSPHOPROTEIN; INTERFERON REGULATORY FACTOR-3; HEMORRHAGIC-FEVER; DENDRITIC CELLS; MARBURG-VIRUS; NITRIC-OXIDE; BINDING-SITE; P-PROTEIN; INFECTION; PATHOGENESIS AB The viral protein VP35 of ebolavirus (EBOV) is implicated to have diverse roles in the viral life cycle. We employed a yeast two-hybrid screen to search for VP35 binding partners and identified the cytoplasmic dynein light chain (DLC8) as a protein that interacts with VP35. Mapping analysis unraveled a consensus motif, SQTQT, within VP35 through which VP35 binds to DLC8. The disruption of DLC8 binding does not affect the ability of VP35 to inhibit type I IFN production. Given that VP35 from various EBOV species interacts with DLC8, this interaction may have a role in regulating the EBOV life cycle. C1 [Kubota, Toru; Tashiro, Masato; Kato, Atsushi] Natl Inst Infect Dis, Dept Virol 3, Tokyo 2080011, Japan. [Matsuoka, Mayumi] Natl Inst Infect Dis, Dept Bacterial Pathogenesis & Infect Control, Tokyo 2080011, Japan. [Kubota, Toru; Matsuoka, Mayumi; Chang, Tsung-Hsien; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Genom Differentiat Program, NIH, Bethesda, MD 20892 USA. [Bray, Mike] NIAID, Integrated Res Facil, NIH, Bethesda, MD 20892 USA. [Jones, Steven] Canadian Sci Ctr Human & Anim Hlth, Natl Microbiol Lab, Populat & Publ Hlth Branch, Winnipeg, MB R3E 3R2, Canada. RP Kubota, T (reprint author), Natl Inst Infect Dis, Dept Virol 3, Gakuen 4-7-1, Tokyo 2080011, Japan. EM kubota@nih.go.jp FU NIH; National Institute of Child Health and Human Development; Trans NIH Biodefense Program FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development, and the Trans NIH Biodefense Program. NR 35 TC 20 Z9 20 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUL PY 2009 VL 83 IS 13 BP 6952 EP 6956 DI 10.1128/JVI.00480-09 PG 5 WC Virology SC Virology GA 462LM UT WOS:000267354100063 PM 19403681 ER PT J AU Eggermont, LHP Bean, JF Guralnik, JM Leveille, SG AF Eggermont, Laura H. P. Bean, Jonathan F. Guralnik, Jack M. Leveille, Suzanne G. TI Comparing Pain Severity Versus Pain Location in the MOBILIZE Boston Study: Chronic Pain and Lower Extremity Function* SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Pain; Mobility; Aging; Lower extremity function; Epidemiology ID LOW-BACK-PAIN; OLDER DISABLED WOMEN; PHYSICAL PERFORMANCE-MEASURES; KNEE PAIN; MUSCULOSKELETAL PAIN; SUBSEQUENT DISABILITY; ADULTS; COMMUNITY; ASSOCIATION; HEALTH AB This study compared measures of chronic pain, for example, number of pain sites and overall pain severity, in relation to lower extremity function in the older population. Six hundred older adults (mean age 77.9 years, 64% female) were queried about presence of chronic pain. Number of pain sites was categorized as none, single site, multisite, or widespread. Pain severity was measured in quartiles of the Brief Pain Inventory pain severity subscale. Lower extremity function was assessed by the Short Physical Performance Battery (SPPB), a composite measure of gait speed, balance, and chair stands. Many older persons reported multisite or widespread pain (40%). Increased pain sites and pain severity were associated with poorer SPPB performance after adjusting for age, sex, height, and weight. With further adjustment for education, comorbid conditions, and depressive symptoms, multisite pain (p < .001) and most severe pain (p < .05) were associated with poorer SPPB performance, but assessed together in the same model, only the association with multisite/widespread pain remained significant (p < .01). When specific joint pain sites were evaluated together, only knee pain was associated with lower SPPB score. Pain severity was independently associated with slower gait, pain location was associated with poorer balance, and chair stands performance was associated with both pain measures. Although multisite pain rather than pain severity was more strongly associated with overall lower extremity function, differences emerged with specific SPPB subtests. Longitudinal studies are needed to understand risk for lower extremity function decline related to chronic pain characteristics in older adults. C1 [Eggermont, Laura H. P.] Vrije Univ Amsterdam, Dept Clin Neuropsychol, NL-1081 BT Amsterdam, Netherlands. [Eggermont, Laura H. P.] Boston Univ, Rush Alzheimers Dis Ctr, Boston, MA 02215 USA. [Bean, Jonathan F.] Harvard Univ, Sch Med, Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Leveille, Suzanne G.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA USA. RP Eggermont, LHP (reprint author), Vrije Univ Amsterdam, Dept Clin Neuropsychol, Boechorststr 1, NL-1081 BT Amsterdam, Netherlands. EM lhp.eggermont@psy.vu.nl RI Bean, Jonathan/F-5798-2017 OI Bean, Jonathan/0000-0001-8385-8210 FU National Institute on Aging [P01AG004390, 446-07-002] FX This research was supported by the National Institute on Aging: Research Nursing Home Program Project grant P01AG004390 and Rubicon 446-07-002 ( Netherlands Organization for Scientific Research, NWO). NR 42 TC 37 Z9 40 U1 5 U2 8 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2009 VL 64 IS 7 BP 763 EP 770 DI 10.1093/gerona/glp016 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 457UQ UT WOS:000266959800007 PM 19228782 ER PT J AU Muntner, P Vupputuri, S Coresh, J Uribarri, J Fox, CS AF Muntner, Paul Vupputuri, Suma Coresh, Josef Uribarri, Jaime Fox, Caroline S. TI Metabolic abnormalities are present in adults with elevated serum cystatin C SO KIDNEY INTERNATIONAL LA English DT Article DE anemia; C-reactive protein; cystatin C; hyperuricemia; kidney disease; metabolic abnormalities ID GLOMERULAR-FILTRATION-RATE; CHRONIC KIDNEY-DISEASE; NONTRADITIONAL RISK-FACTORS; CORONARY-HEART-DISEASE; 3RD NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; DIALYSIS PATIENTS; BODY-COMPOSITION; ELDERLY PERSONS; MORTALITY RISK AB Although metabolic anomalies are often seen in advanced chronic kidney disease (CKD), their presence in more mild states is unknown. We studied 6722 participants in the Third National Health and Nutrition Examination Survey, dividing them into three mutually exclusive groups consisting of those having a normal or mildly reduced estimated glomerular filtration rate (eGFR) (Modification of Diet in Renal Disease (MDRD) formula), those with normal or elevated serum cystatin C, and those with clinically relevant moderate or severely reduced eGFR (stage 3 or 4 of CKD). The prevalence of several metabolic abnormalities associated with moderate to advanced CKD was determined after standardization for age, race-ethnicity, and gender. In the absence of stage 3 or 4 CKD, patients with elevated serum cystatin C had a higher prevalence of low hemoglobin and elevated uric acid, homocysteine, phosphorus, fibrinogen, and C-reactive protein than patients with a normal serum cystatin C. Our results show that in adults with normal or mildly reduced eGFR, elevated serum cystatin C is associated with an increased prevalence of metabolic abnormalities traditionally found in moderate or severe CKD. Elevated serum cystatin C may identify patients with 'preclinical' kidney disease not detected by traditional serum creatinine measurements. Kidney International (2009) 76, 81-88; doi: 10.1038/ki.2009.76; published online 18 March 2009 C1 [Muntner, Paul] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY 10029 USA. [Muntner, Paul; Uribarri, Jaime] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY 10029 USA. [Vupputuri, Suma] Kaiser Permanente Georgia, Ctr Hlth Res, Atlanta, GA USA. [Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Coresh, Josef] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Muntner, P (reprint author), Mt Sinai Sch Med, Dept Community & Prevent Med, 1 Gustave L Levy Pl,Box 1057, New York, NY 10029 USA. EM paul.muntner@mssm.edu FU CKD-EPI; [U01 DK 053869]; [U01 DK 067651]; [U01 DK 35073] FX The measurement of cystatin C in the Third National Health and Nutrition Examination Survey and Dr Coresh were supported by the CKD-EPI Collaboration funded by Grants U01 DK 053869, U01 DK 067651, and U01 DK 35073. NR 33 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2009 VL 76 IS 1 BP 81 EP 88 DI 10.1038/ki.2009.76 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 461KR UT WOS:000267266200013 PM 19295502 ER PT J AU Brown, P Gipson, C AF Brown, Patricia Gipson, Chester TI A word from OLAW and USDA SO LAB ANIMAL LA English DT Editorial Material C1 [Brown, Patricia] NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. [Gipson, Chester] USDA, APHIS, AC, Washington, DC USA. RP Brown, P (reprint author), NIH, OLAW, OER, OD,HHS, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD JUL PY 2009 VL 38 IS 7 BP 227 EP 227 DI 10.1038/laban0709-227 PG 1 WC Veterinary Sciences SC Veterinary Sciences GA 517KD UT WOS:000271611400010 PM 19543257 ER PT J AU Bellgowan, PSF Buffalo, EA Bodurka, J Martin, A AF Bellgowan, Patrick S. F. Buffalo, Elizabeth A. Bodurka, Jerzy Martin, Alex TI Lateralized spatial and object memory encoding in entorhinal and perirhinal cortices SO LEARNING & MEMORY LA English DT Article ID MEDIAL TEMPORAL-LOBE; PARAHIPPOCAMPAL REGION; HEMISPHERIC-SPECIALIZATION; FUNCTIONAL NEUROANATOMY; RECOGNITION MEMORY; MACAQUE MONKEY; CORTEX; ACTIVATION; SYSTEM; TEMPOROPOLAR AB The perirhinal and entorhinal cortices are critical components of the medial temporal lobe (MTL) declarative memory system. Study of their specific functions using blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI), however, has suffered from severe magnetic susceptibility signal dropout resulting in poor temporal signal-to-noise (tSNR) and thus weak BOLD signal detectability. We have demonstrated that higher spatial resolution in the z-plane leads to improved BOLD fMRI signal quality in the anterior medial temporal lobes when using a 16-element surface coil array at 3 T (Tesla). Using this technique, the present study investigated the roles of the anterior medial temporal lobe, particularly the entorhinal and perirhinal cortices, in both object and spatial memory. Participants viewed a series of fractal images and were instructed to encode either the object's identity or location. Object and spatial recognition memory were tested after 18-sec delays. Both the perirhinal and entorhinal cortices were active during the object and spatial encoding tasks. In both regions, object encoding was biased to the left hemisphere, whereas spatial encoding was biased to the right. A similar hemispheric bias was evident for recognition memory. Recent animal studies suggest functional dissociations among regions of the entorhinal cortex for spatial vs. object processing. Our findings suggest that this process-specific distinction may be expressed in the human brain as a hemispheric division of labor. C1 [Bellgowan, Patrick S. F.; Martin, Alex] NIMH, Sect Cognit Neuropsychol, Bethesda, MD 20892 USA. [Buffalo, Elizabeth A.] Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. [Buffalo, Elizabeth A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30329 USA. [Bodurka, Jerzy] NIMH, Funct MRI Facil, Bethesda, MD 20892 USA. RP Bellgowan, PSF (reprint author), Laureate Inst Brain Res, Tulsa, OK 74133 USA. EM pfbellgowan@saintfrancis.com RI martin, alex/B-6176-2009 FU NIMH; NIH FX We thank Paula Rowser and Alda Ottley for their assistance in data collection and W. Kyle Simmons for insightful comments. This research was supported by the Intramural Research Program of the NIMH, NIH. NR 42 TC 25 Z9 25 U1 0 U2 8 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1072-0502 J9 LEARN MEMORY JI Learn. Mem. PD JUL PY 2009 VL 16 IS 7 BP 433 EP 438 DI 10.1101/lm.1357309 PG 6 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 462HD UT WOS:000267340800006 PM 19553381 ER PT J AU Zou, JX Rollison, DE Boulware, D Chen, DT Sloand, EM Pfannes, LV Goronzy, JJ Bai, F Painter, JS Wei, S Cosgrove, D List, AF Epling-Burnette, PK AF Zou, J. X. Rollison, D. E. Boulware, D. Chen, D-T Sloand, E. M. Pfannes, L. V. Goronzy, J. J. Bai, F. Painter, J. S. Wei, S. Cosgrove, D. List, A. F. Epling-Burnette, P. K. TI Altered naive and memory CD4+T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome SO LEUKEMIA LA English DT Article DE immunosuppressive therapy; myelodysplastic syndrome; aging; bone marrow; homeostasis; T lymphocytes ID REGULATORY T-CELLS; LARGE GRANULAR LYMPHOCYTES; NECROSIS-FACTOR-ALPHA; RHEUMATOID-ARTHRITIS; ANTITHYMOCYTE GLOBULIN; IMMUNOSUPPRESSIVE THERAPY; APLASTIC-ANEMIA; EXPRESSION; AUTOIMMUNITY; CD4(+) AB Response to immunosuppressive therapy (IST) in younger patients with myelodysplastic syndrome (MDS) has been linked to a T-cell-dominant autoimmune process that impairs hematopoiesis. Analysis of the age-adjusted CD4:CD8 ratio in 76 MDS patients compared with 54 healthy controls showed that inadequate CD4+, rather than expansion of CD8+ T cells, was associated with a lower ratio in a group that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System. In younger MDS patients, naive and memory phenotypes defined by CD45RA and CD62L display showed depletion of naive CD4+ and CD8+ T cells, suggesting a possible relationship to IST responsiveness. To determine the correlation between T-cell subset distribution, T-cell turnover and autoimmunity, a cohort of 20 patients were studied before and after IST. The CD4: CD8 ratio correlated inversely with the proliferative T-cell index before treatment in IST-responsive patients, suggesting that proliferation may be linked to accelerated CD4+ T-cell turnover and hematopoietic failure. Our data show seminal findings that both CD4+ and CD8+ T-cell subsets are dysregulated in MDS. Association between these T-cell defects and response to IST suggests that aberrant T-cell homeostasis and chronic activation are critical determinants influencing autoimmune hematopoietic suppression in younger patients. Leukemia (2009) 23, 1288-1296; doi: 10.1038/leu.2009.14; published online 12 March 2009 C1 [Epling-Burnette, P. K.] H Lee Moffitt Canc Ctr & Res Inst, Program Immunol, Malignant Hematol Div, Tampa, FL 33612 USA. [Rollison, D. E.] H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, Tampa, FL 33612 USA. [Boulware, D.; Chen, D-T] H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, Tampa, FL 33612 USA. [Sloand, E. M.; Pfannes, L. V.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Goronzy, J. J.; Epling-Burnette, P. K.] Emory Univ, Sch Med, Lowance Ctr Human Immunol, Atlanta, GA USA. [Cosgrove, D.; List, A. F.] H Lee Moffitt Canc Ctr & Res Inst, Div Hematol Malignancies, Tampa, FL 33612 USA. [Epling-Burnette, P. K.] James A Haley VA Hosp, Tampa, FL USA. RP Epling-Burnette, PK (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Program Immunol, Malignant Hematol Div, MRC 4 E,12902 Magnolia Dr,SRB 22001, Tampa, FL 33612 USA. EM Pearlie.Burnette@moffitt.org FU Veterans' Administration Hospital; NCI [CA112112-01]; NIH [U54RR019397-05] FX This work was conducted by Moffitt Cancer Center Malignant Hematology Program and partially supported by grants from the Veterans' Administration Hospital and NCI (CA112112-01). The project described was supported by U54RR019397-05 from the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We would like to thank the Flow Cytometry Core Facility for assistance with this project. NR 62 TC 33 Z9 34 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUL PY 2009 VL 23 IS 7 BP 1288 EP 1296 DI 10.1038/leu.2009.14 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 470KB UT WOS:000267972500013 PM 19282834 ER PT J AU Ozarslan, E Koay, CG Basser, PJ AF Oezarslan, Evren Koay, Cheng Guan Basser, Peter J. TI Remarks on q-space MR propagator in partially restricted, axially-symmetric, and isotropic environments SO MAGNETIC RESONANCE IMAGING LA English DT Article DE MR; MRI; Diffusion; PGSE; PFG; q-space; Propagator; Surface-normal; Curving fibers; Tractography; Axial symmetry; Isotropy; Restricted; Porous media ID THE-ORIGIN PROBABILITY; FIELD-GRADIENT; SELF-DIFFUSION; NMR MICROSCOPY; POROUS-MEDIA; SPIN ECHOES; TISSUE; RETURN; BOUNDARIES; RESOLUTION AB The problem of reconstruction of an apparent propagator from a series of diffusion-attenuated magnetic resonance (MR) signals is revisited. In nonimaging acquisitions, the inverse Fourier transform of the MR signal attenuation is consistent with the notion of an ensemble average propagator. However, in image acquisitions where one is interested in quantifying a displacement distribution in every voxel of the image, the propagator derived in the traditional way may lead to a counter-intuitive profile when it is nonsymmetric, which could be a problem in partially restricted environments. By exploiting the reciprocity of the diffusion propagator, an alternative is introduced, which implies a forward Fourier transform of the MR signal attenuations yielding a propagator reflected around the origin. Two simple problems were considered as examples. In the case of diffusion in the proximity of a restricting barrier, the reflected propagator yields a more meaningful result, whereas in the case of curving fibers, the original propagator is more intuitive. In the final section of the article, two more one-dimensional transformations are introduced, which enable the reconstruction of two-and three-dimensional propagators in, respectively, axially symmetric and isotropic environments-in both cases, from one-dimensional q-space MR data. Published by Elsevier Inc. C1 [Oezarslan, Evren; Koay, Cheng Guan; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, LIMB, NIH, Bethesda, MD 20892 USA. RP Ozarslan, E (reprint author), NICHD, Sect Tissue Biophys & Biomimet, LIMB, NIH, Bethesda, MD 20892 USA. EM evren@helix.nih.gov RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011 OI Ozarslan, Evren/0000-0003-0859-1311; FU Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) FX We would like to thank Drs. Maher Moakher and Denis Grebenkov for helpful discussions and Liz Salak for editing the manuscript. This research was supported by the Intramural Research Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH). NR 27 TC 12 Z9 12 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD JUL PY 2009 VL 27 IS 6 BP 834 EP 844 DI 10.1016/j.mri.2009.01.005 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 533GK UT WOS:000272811500013 PM 19269765 ER PT J AU Novotny, E Compton, S Liu, PP Collins, FS Chandrasekharappa, SC AF Novotny, Elizabeth Compton, Sheila Liu, P. Paul Collins, Francis S. Chandrasekharappa, Settara C. TI In vitro hematopoietic differentiation of mouse embryonic stem cells requires the tumor suppressor menin and is mediated by Hoxa9 SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Embryonic stem cells; ES; Hematopoiesis; Mixed-lineage leukemia; Multiple endocrine neoplasia type 1; Menin; Hoxa9 ID HISTONE METHYLTRANSFERASE COMPLEX; MULTIPLE-ENDOCRINE-NEOPLASIA; GENE-EXPRESSION; LEUKEMIA GENE; TRANSFORMATION; PROGENITORS; PROTEIN; TYPE-1; LOCUS AB Inactivating mutations in the tumor suppressor gene MEN1 cause the inherited cancer syndrome multiple endocrine neoplasia type 1 (MEN1). The ubiquitously expressed MEN1 encoded protein, menin, interacts with MLL (mixed-lineage leukemia protein), and together they are essential components of a multiprotein complex with histone methyl transferase activity. MLL is also essential for hematopoiesis, and plays a critical role in leukemogenesis via epigenetic regulation of Hoxa9 expression that also requires menin. Therefore we chose to explore the role of menin in hematopoiesis. We generated Men1(-/-) embryonic stem (ES) cell lines, and induced them to differentiate in vitro. While these cells were able to form embryoid bodies (EBs) expressing the early markers Flk-1 and c-Kit, their ability to further differentiate into hematopoietic colonies was compromised. The Men1(-/-) ES cells show reduced expression of Hoxa9 that can be recovered by reexpression of Menin. We demonstrate that the block in differentiation of Men1(-/-) ES cell lines can be rescued not only by the expression of menin but also that of Hoxa9. These results suggest that, similar to MLL, menin is required for hematopoiesis, and this requirement may be mediated through regulation of Hoxa9 expression. Published by Elsevier Ireland Ltd. C1 [Novotny, Elizabeth; Collins, Francis S.; Chandrasekharappa, Settara C.] NHGRI, GTB, NIH, Bethesda, MD 20892 USA. [Compton, Sheila; Liu, P. Paul] NHGRI, Genet & Mol Biol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Chandrasekharappa, SC (reprint author), NHGRI, GTB, NIH, Bldg 50,Rm 5232,50 S Dr, Bethesda, MD 20892 USA. EM chandra@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, National Institutes of Health FX We thank Patricia Ernst for the HOXA9 and Jyotshna Kanungo for the MEN1 expression constructs, David Bodine for helpful suggestions, Stacie Anderson for flow cytometry. This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 19 TC 8 Z9 8 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUL PY 2009 VL 126 IS 7 BP 517 EP 522 DI 10.1016/j.mod.2009.04.001 PG 6 WC Developmental Biology SC Developmental Biology GA 465SX UT WOS:000267608800003 PM 19393316 ER PT J AU Wang, CY Baldwin, LM Saver, BG Dobie, SA Green, PK Cai, Y Klabunde, CN AF Wang, C. Y. Baldwin, Laura-Mae Saver, Barry G. Dobie, Sharon A. Green, Pamela K. Cai, Yong Klabunde, Carrie N. TI The Contribution of Longitudinal Comorbidity Measurements to Survival Analysis SO MEDICAL CARE LA English DT Article DE claims data; comorbidity; missing data; Medicare ID FAILURE TIME REGRESSION; SOCIOECONOMIC-STATUS; ADMINISTRATIVE DATA; CANCER-PATIENTS; CLAIMS DATA; INDEX; IMPACT; CALIBRATION; ESTIMATOR; MORTALITY AB Background: Many clinical and health services research studies are longitudinal, raising questions about how best to use an individual's comorbidity measurements over time to predict survival. Objectives: To evaluate the performance of different approaches to longitudinal comorbidity measurement in predicting survival, and to examine strategies for addressing the inevitable issue of missing data. Research Design: Retrospective cohort study using Cox regression analysis to examine the association between various Romano-Charlson comorbidity measures and survival. Subjects: Fifty thousand cancer-free individuals aged 66 or older enrolled in Medicare between 1991 and 1999 for at least I year. Results: The best fitting model combined both time independent baseline comorbidity and the time dependent prior year comorbidity measure. The worst fitting model included baseline comorbidity only. Overall, the models fit best when using the "rolling" comorbidity measures that assumed chronic conditions persisted rather than measures using only prior year's recorded diagnoses. Conclusions: Longitudinal comorbidity is an important predictor of survival, and investigators should make use of individuals' longitudinal comorbidity data in their regression modeling. C1 [Wang, C. Y.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Baldwin, Laura-Mae; Dobie, Sharon A.; Green, Pamela K.] Univ Washington, Sch Med, Dept Family Med, Seattle, WA 98195 USA. [Saver, Barry G.] Univ Massachusetts, Sch Med, Dept Family Med & Community Hlth, Worcester, MA USA. [Cai, Yong] Univ Utah, Dept Sociol, Salt Lake City, UT USA. [Klabunde, Carrie N.] NCI, Hlth Serv & Econ Branch, Rockville, MD USA. RP Wang, CY (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,POB 19024,M2-B500, Seattle, WA 98109 USA. EM cywang@fhcrc.org FU National Cancer Institute [1 R01 CA 104935, 1 R01 CA53996] FX Supported from the National Cancer Institute by grants 1 R01 CA 104935 and CA53996. NR 28 TC 10 Z9 10 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP 813 EP 820 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463VZ UT WOS:000267462400014 PM 19536031 ER PT J AU Lipscomb, J Barnett, PG Brown, ML Lawrence, W Yabroff, KR AF Lipscomb, Joseph Barnett, Paul G. Brown, Martin L. Lawrence, William Yabroff, K. Robin TI Advancing the Science of Health Care Costing SO MEDICAL CARE LA English DT Article ID UNITED-STATES; CANCER CARE; PROJECTIONS; ILLNESS; TIME C1 [Lipscomb, Joseph] Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth Emory, Atlanta, GA 30322 USA. [Barnett, Paul G.] Hlth Econ Resource Ctr, Dept Vet Affairs, Palo Alto, CA USA. [Brown, Martin L.; Yabroff, K. Robin] Appl Res Progam, Hlth Serv & Econ Branch, Rockville, MD USA. [Brown, Martin L.; Yabroff, K. Robin] Natl Canc Inst, Div Canc Control & Populat Sci, Rockville, MD USA. [Lawrence, William] Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Gaithersburg, MD USA. RP Lipscomb, J (reprint author), Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth Emory, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM jlipsco@sph.emory.edu NR 32 TC 10 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S120 EP S126 PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500020 PM 19536003 ER PT J AU Lipscomb, J Yabroff, KR Brown, ML Lawrence, W Barnett, PG AF Lipscomb, Joseph Yabroff, K. Robin Brown, Martin L. Lawrence, William Barnett, Paul G. TI Health Care Costing: Data, Methods, Current Applications INTRODUCTION SO MEDICAL CARE LA English DT Editorial Material C1 [Lipscomb, Joseph] Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Yabroff, K. Robin; Brown, Martin L.] Natl Canc Inst, Div Canc Control & Populat Sci, Appl Res Program, Rockville, MD USA. [Lawrence, William] Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Gaithersburg, MD USA. [Barnett, Paul G.] Hlth Econ Res Ctr, Dept Vet Affairs, Palo Alto, CA USA. RP Lipscomb, J (reprint author), Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth, 1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM jlipsco@sph.emory.edu NR 24 TC 31 Z9 31 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S1 EP S6 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500001 PM 19536004 ER PT J AU Lund, JL Yabroff, KR Ibuka, Y Russell, LB Barnett, PG Lipscomb, J Lawrence, WF Brown, ML AF Lund, Jennifer L. Yabroff, K. Robin Ibuka, Yoko Russell, Louise B. Barnett, Paul G. Lipscomb, Joseph Lawrence, William F. Brown, Martin L. TI Inventory of Data Sources for Estimating Health Care Costs in the United States SO MEDICAL CARE LA English DT Article DE health care costs; data sources; administrative data; linked data; survey; health economics ID OF-ILLNESS; MEDICARE AB Objective: To develop an inventory of data sources for estimating health care costs in the United States and provide information to aid researchers in identifying appropriate data sources for their specific research questions. Methods: We identified data sources for estimating health care costs using 3 approaches: (1) a review of the 18 articles included in this Supplement, (2) an evaluation of websites of federal government agencies, non profit foundations, and related societies that support health care research or provide health care services, and (3) a systematic review of the recently published literature. Descriptive information was abstracted from each data source, including sponsor, website, lowest level of data aggregation, type of data source, population included, cross-sectional or longitudinal data capture, Source of diagnosis information, and cost of obtaining the data source. Details about the cost elements available in each data Source were also abstracted. Results: We identified 88 data sources that can be used to estimate health care costs in the United States. Most data Sources were sponsored by government agencies, national or nationally representative, and cross-sectional. About 40% were surveys, followed by administrative or linked administrative data, fee or cost schedules, discharges, and other types of data. Diagnosis information was available in most data sources through procedure or diagnosis codes, self-report, registry, or chart review. Cost elements included inpatient hospitalizations (42.0%), physician and other outpatient services (45.5%), Outpatient pharmacy or laboratory (28.4%), out-of-pocket (22.7%), patient time and other direct nonmedical costs (35.2%), and wages (13.6%). About half were freely available for downloading or available for a nominal fee, and the cost of obtaining the remaining data sources varied by the scope of the project. Conclusions: Available data sources vary in population included, type of data source, scope, and accessibility, and have different strengths and weaknesses for specific research questions. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Lund, Jennifer L.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Ibuka, Yoko; Russell, Louise B.] Rutgers State Univ, Inst Hlth, New Brunswick, NJ USA. [Ibuka, Yoko] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Barnett, Paul G.] Hlth Econ Resource Ctr, Dept Vet Affairs, Palo Alto, CA USA. [Lipscomb, Joseph] Emory Univ, Dept Hlth Policy & Management, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Lawrence, William F.] Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Gaithersburg, MD USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov RI Lund, Jennifer/G-9420-2012 FU NIDDK NIH HHS [T32 DK007634, T32 DK007634-09] NR 27 TC 10 Z9 10 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S127 EP S142 PG 16 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500021 PM 19536009 ER PT J AU Yabroff, KR Warren, JL Schrag, D Mariotto, A Meekins, A Topor, M Brown, ML AF Yabroff, K. Robin Warren, Joan L. Schrag, Deborah Mariotto, Angela Meekins, Angela Topor, Marie Brown, Martin L. TI Comparison of Approaches for Estimating Incidence Costs of Care for Colorectal Cancer Patients SO MEDICAL CARE LA English DT Article DE health care costs; health services research; cost and cost analysis; neoplasms; medicare; SEER program ID STAGE BREAST-CANCER; SEER-MEDICARE DATA; UNITED-STATES; ENROLLEES; DIAGNOSIS; WOMEN AB Background: Estimates of the costs of medical care vary across patient populations, data sources, and methods. The objective of this study was to compare 3 approaches for estimating the incidence costs of colorectal cancer (CRC) care using similar patient populations, but different data sources and methods. Methods: We used 2 data sources, linked SEER-Medicare and Medicare claims alone, to identify newly diagnosed CRC patients aged 65 and older and estimated their healthcare costs during the observation period, 1998 to 2002. Controls were matched by sex, age-group, and geographic location. We compared mean net costs, measured as the difference in total cost between cases and controls, for: (1) a SEER-Medicare cohort, (2) a Medicare claims alone cohort, and (3) a modeled phase of care approach using linked SEER-Medicare data. The SEER-Medicare cohort approach was considered the reference. Results: We found considerable variability across approaches for estimating net costs of care in CRC patients. In the first year after diagnosis, mean net costs were $32,648 (95% CI: $31,826 and $33,470) in the SEER-Medicare cohort. The other approaches understated mean net costs in year 1 by about 16%. Mean net 5-year costs of care were $37,227 (95% CI: $35,711 and $38,744) in the SEER-Medicare cohort, and $30,310 (95% CI: $25,894 and $34,726) in the claims only approach, with the largest difference in the 65 to 69 age group. Mean net 5-year costs of care were more similar to the reference in the modeled phase of care approach ($37,701 [range: $36,972 and $38,4461]). Differences from the SEER-Medicare cohort estimates reflect misclassification of prevalent cancer patients as newly diagnosed patients in the Medicare claims only approach, and differences in years of data and assumptions about comparison groups in the modeled phase of care approach. Conclusions: CRC incidence cost estimates vary substantially depending on the strategy and data source for identifying newly diagnosed cancer patients and methods for estimating longitudinal costs. Our findings may inform estimation of costs for other cancers as well as other diseases. C1 [Yabroff, K. Robin] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Schrag, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA USA. [Meekins, Angela; Topor, Marie] Informat Management Serv Inc, Rockville, MD USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov NR 27 TC 31 Z9 32 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S56 EP S63 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500010 PM 19536010 ER PT J AU Yabroff, KR Warren, JL Banthin, J Schrag, D Mariotto, A Lawrence, W Meekins, A Topor, M Brown, ML AF Yabroff, K. Robin Warren, Joan L. Banthin, Jessica Schrag, Deborah Mariotto, Angela Lawrence, William Meekins, Angela Topor, Marie Brown, Martin L. TI Comparison of Approaches for Estimating Prevalence Costs of Care for Cancer Patients What Is the Impact of Data Source? SO MEDICAL CARE LA English DT Article DE health care costs; health services research; cost and cost analysis; colorectal neoplasms; Medicare; SEER program; MEPS ID SEER-MEDICARE DATA; UNITED-STATES; LIFE AB Background: National prevalence costs of medical care can be key inputs in health policy decisions. Cost estimates vary across data sources, patient populations, and methods, however, the objective of this study was to compare 3 approaches for estimating the prevalence costs of colorectal cancer (CRC) care using different data sources, but similar patient populations and methods. Methods: We identified prevalent CRC patients aged 65 and older from: (1) linked Surveillance Epidemiology and End Results (SEER) registry-Medicare data, (2) Medicare claims only, and (3) the Medical Expenditure Panel Survey (MEPS). Controls were matched by sex, age-group, and geographic location. Mean per person total and net costs, measured as the difference between patients and controls, were compared for each approach during a similar observation period. The SEER-Medicare approach was our reference, and we evaluated the impact of patient selection criteria with sensitivity analyses. Aggregate prevalence estimates were also compared. Results: We found considerable variability across the different approaches to estimating prevalence costs of CRC. Mean net annual per person estimates in the SEER-Medicare reference were $5341 (95% CI: $5243, $5439), compared with $8736 (95% CI: $8203, $9269) for the Medicare claims only and $11,614 (95% CI: $7566, $15,663) for the MEPS. Aggregate national estimates of net prevalence costs of CRC in 2004 ranged from $4524 million, using the SEER-Medicare approach, to $9629 million, using the MEPS approach. Estimates varied by data source based on the payors included and identification of prevalent CRC patients. Conclusions: CRC prevalence cost estimates vary substantially depending on the data sources. Our findings have implications for estimating prevalence costs for other cancers and other diseases without registry systems that can be used to identify newly diagnosed individuals as well as those diagnosed less recently. C1 [Yabroff, K. Robin; Warren, Joan L.; Mariotto, Angela; Brown, Martin L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Banthin, Jessica; Lawrence, William] Agcy Healthcare Res & Qual, Rockville, MD USA. [Schrag, Deborah] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Schrag, Deborah] Harvard Univ, Sch Med, Boston, MA USA. [Meekins, Angela; Topor, Marie] Informat Management Serv Inc, Rockville, MD USA. RP Yabroff, KR (reprint author), Appl Res Program, Hlth Serv & Econ Branch, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 20 TC 35 Z9 36 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUL PY 2009 VL 47 IS 7 BP S64 EP S69 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 463WA UT WOS:000267462500011 PM 19536016 ER PT J AU Gabriel, KP McClain, JJ Lee, CD Swan, PD Alvar, BA Mitros, MR Ainsworth, BE AF Gabriel, Kelley Pettee McClain, James J. Lee, Chong D. Swan, Pamela D. Alvar, Brent A. Mitros, Melanie R. Ainsworth, Barbara E. TI Evaluation of Physical Activity Measures Used in Middle-Aged Women SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE RELIABILITY; VALIDITY; QUESTIONNAIRES; ACCELEROMETERS; FITNESS MEASURES ID ACTIVITY QUESTIONNAIRES; POSTMENOPAUSAL WOMEN; COMPUTER-SCIENCE; ACCELEROMETER; ADULTS; HEALTH; ASSOCIATION; RELIABILITY; CALIBRATION; POPULATION AB PETTEE GABRIEL, K., J. J. MCCLAIN, C. D. LEE, P. D. SWAN, B. A. ALVAR, M. R. MITROS, and B. E. AINSWORTH. Evaluation of Physical Activity Measures Used in Middle-Aged Women. Med. Sci. Sports Exerc., Vol. 41, No. 7, pp. 1403-1412, 2009. Purpose: To evaluate the reliability and validity of five commonly used physical activity questionnaires (PAQ) in women aged 45-65 yr with varying physical activity (PA) levels. Methods: Data were obtained from the Evaluation of Physical Activity Measures in Middle-aged Women (PAW) Study and included 66 women (aged 52.6 +/- 5.4 yr). PAQ evaluated include Modifiable Activity Questionnaire (past week and past month version), Nurses' Health Study PAQ, Active Australia Survey, and Women's Health Initiative PAQ. Intraclass correlation coefficients (ICC) between administrations of the PAQ were used to assess test-retest reliability. Spearman rank-order correlation coefficients were used to examine the associations of PA and physical fitness data with PAQ summary estimates. Results: Accelerometer-determined median (25th, 75th percentiles) times (min.d(-1)) spent in moderate-lifestyle [760-1951 counts (ct)], moderate-walk (1952-5724 ct), vigorous (>= 5725 ct), and combined moderate and vigorous PA (MVPA >= 1952 ct) during the 35 d of observation were 66.0 (5 1.2, 81.3), 23.1 (14.1, 34.6), 0.4 (0.0, 2.3), and 24.3 (15.9, 41.6) min, respectively. The PAQ were shown to be reproducible and relatively stable over time (ICC = 0.32 to 0.91) and were associated with total counts per day (ct.d(-1), 0.46 to 0.60, all P < 0.001), and most were associated with many facets of physical fitness, including cardiorespiratory fitness (0.36 to 0.46, P < 0.01), body composition (-0.27 to -0.34, P < 0.05), and Muscular fatigue (-0.25 to -0.44, P < 0.05). Conclusions: The PAQ evaluated in this study were shown to be reliable and associated with PA and physical fitness measures. Current findings support the utility of these PAQ for PA assessment in research studies of middle-aged women. C1 [Gabriel, Kelley Pettee] Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Hlth Promot Social & Behav Hlth, Omaha, NE 68198 USA. [McClain, James J.] NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Lee, Chong D.; Swan, Pamela D.; Alvar, Brent A.; Mitros, Melanie R.; Ainsworth, Barbara E.] Arizona State Univ, Coll Nursing & Hlth Innovat, Healthy Lifestyles Res Ctr, Program Exercise & Wellness, Mesa, AZ USA. [Alvar, Brent A.] Chandler Gilbert Community Coll, Wellness Hlth Nutr & Phys Educ Div, Mesa, AZ USA. RP Gabriel, KP (reprint author), Univ Nebraska Med Ctr, Coll Publ Hlth, Dept Hlth Promot Social & Behav Hlth, 986075 Nebraska Med Ctr, Omaha, NE 68198 USA. EM kpettee@unmc.edu FU American College of Sports Medicine FX This research was funded by the American College of Sports Medicine, 2007 Paffenbarger-Blair Endowment for Epidemiological Research on Physical Activity that was awarded to Dr. Kelley Pettee Gabriel while working as a postdoctoral research associate at Arizona State University. The results of the present study do not constitute endorsement by the American College of Sports Medicine. NR 37 TC 34 Z9 34 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 2009 VL 41 IS 7 BP 1403 EP 1412 DI 10.1249/MSS.0b013e31819b2482 PG 10 WC Sport Sciences SC Sport Sciences GA 461HY UT WOS:000267256800007 ER PT J AU Feairheller, DL Brown, MD Park, JY Brinkley, TE Basu, S Hagberg, JM Ferrell, RE Fenty-Stewart, NM AF Feairheller, Deborah L. Brown, Michael D. Park, Joon-Young Brinkley, Tina E. Basu, Samar Hagberg, James M. Ferrell, Robert E. Fenty-Stewart, Nicola M. TI Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE OXIDATIVE STRESS; AEROBIC EXERCISE; CYBA GENE; NITRIC OXIDE; ISOPROSTANES ID CORONARY-ARTERY-DISEASE; VASCULAR NAD(P)H OXIDASES; C242T CYBA POLYMORPHISM; OXIDATIVE STRESS; NITRIC-OXIDE; SUPEROXIDE-PRODUCTION; LIPID-PEROXIDATION; NADH/NADPH OXIDASE; DIFFERENT INTENSITIES; ENDOTHELIAL-CELLS AB FEAIRHELLER, D. L., M. D. BROWN, J.-Y. PARK, T. E. BRINKLEY, S. BASU, J. M. HAGBERG, R. E. FERRELL, and N. M. FENTY-STEWART. Exercise Training, NADPH Oxidase p22phox Gene Polymorphisms, and Hypertension. Med. Sci. Sports Exerc., Vol. 41, No. 7, pp. 1421-1428, 2009. Introduction: Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage I hypertensives. Methods: Ninety-four sedentary Pre and Stage I hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% (V)over dotO(2max) to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F(2 alpha) (8-iso-PGF(2 alpha)), urinary nitric oxide metabolites (NO(x)), and plasma total antioxidant capacity (TAC). Results: Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF(2 alpha) levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in (V)over dotO(2max) (P < 0.0001) in the entire Study Population. In addition, there were significant increases in both urinary 8-iso-PGF(2 alpha) (P = 0.002) and plasma TAC (P = 0.03) levels and a significant decrease in endogenous urinary NO(x) (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. Conclusions: We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels Of urinary 8-iso-PGF(2 alpha) but not the aerobic exercise-induced responses. C1 [Feairheller, Deborah L.; Brown, Michael D.; Fenty-Stewart, Nicola M.] Temple Univ, Dept Kinesiol, Hypertens Mol & Appl Physiol Lab, Philadelphia, PA 19122 USA. [Brown, Michael D.; Park, Joon-Young; Brinkley, Tina E.; Hagberg, James M.; Fenty-Stewart, Nicola M.] Univ Maryland, Dept Kinesiol, Sch Publ Hlth, College Pk, MD 20742 USA. [Park, Joon-Young] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. [Brinkley, Tina E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27103 USA. [Basu, Samar] Uppsala Univ, Fac Med, Dept Publ Hlth & Caring Sci, Uppsala, Sweden. [Ferrell, Robert E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. RP Feairheller, DL (reprint author), Temple Univ, Dept Kinesiol, Hypertens Mol & Appl Physiol Lab, 16 Pearson Hall,1800 N Broad St, Philadelphia, PA 19122 USA. EM dlf@temple.edu FU NIH/NIA [KO1AG19640, AG15384, AG17474, AG00268]; AHA [0415444U] FX This work was supported by NIH/NIA grant no. KO1AG19640 (P.I. Michael D. Brown), NIH/NIA grant nos. AG15384, AG17474, and AG00268 (P.I. James M. Hagberg), and AHA predoctoral Fellowship grant no. 0415444U (Joon-Young Park). NR 40 TC 14 Z9 16 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD JUL PY 2009 VL 41 IS 7 BP 1421 EP 1428 DI 10.1249/MSS.0b013e318199cee8 PG 8 WC Sport Sciences SC Sport Sciences GA 461HY UT WOS:000267256800009 PM 19516159 ER PT J AU Rodas, JD Cairo, C Djavani, M Zapata, JC Ruckwardt, T Bryant, J Pauza, CD Lukashevich, IS Salvato, MS AF Rodas, Juan D. Cairo, Cristiana Djavani, Mahmoud Zapata, Juan Carlos Ruckwardt, Tracy Bryant, Joseph Pauza, C. David Lukashevich, Igor S. Salvato, Maria S. TI Circulating natural killer and gamma delta T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus SO MEMORIAS DO INSTITUTO OSWALDO CRUZ LA English DT Article DE NK cells; gamma delta T; rhesus macaque; LCMV; hemorrhagic fever ID EBOLA HEMORRHAGIC-FEVER; VIRAL-INFECTION; LASSA FEVER; NKT CELLS; IN-VITRO; INTERFERON-ALPHA/BETA; CYNOMOLGUS MACAQUES; MEDIATED HEPATITIS; IMMUNE-RESPONSES; GUINEA-PIGS AB Rhesus macaques infected with the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) serve as a model for human infection with Lassa fever virus. To identify the earliest events of acute infection, rhesus macaques were monitored immediately after lethal infection for changes in peripheral blood mononuclear cells (PBMCs). Changes in CD3, CD4, CD8 and CD20 subsets did not vary outside the normal fluctuations of these blood cell populations; however, natural killer (NK) and gamma delta T cells increased slightly on day 1 and then decreased significantly after two days. The NK subsets responsible for the decrease were primarily CD3(-)CD8(+) or CD3(-)CD16(+) and not the NKT (primarily CD3(+)CD56(+)) subset. Macaques infected with a non-virulent arenavirus, LCMV-Armstrong, showed a similar drop in circulating NK and gamma delta T cells, indicating that this is not a pathogenic event. V gamma 9 T cells, representing the majority of circulating gamma delta T cells in rhesus macaques, displayed significant apoptosis when incubated with LCMV in cell culture; however, the low amount of cell death for virus-co-cultured NK cells was insufficient to account for the observed disappearance of this subset. Our observations in primates are similar to those seen in LCMV-infected mice, where decreased circulating NK cells were attributed to margination and cell death. Thus, the disappearance of these cells during acute hemorrhagic fever in rhesus macaques may be a cytokine-induced lymphopenia common to many virus infections. C1 [Cairo, Cristiana; Djavani, Mahmoud; Zapata, Juan Carlos; Bryant, Joseph; Pauza, C. David; Lukashevich, Igor S.; Salvato, Maria S.] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA. [Rodas, Juan D.] Univ Antioquia, Fac Ciencias Agr, Grp Invest Ciencias Vet Centauro, Medellin, Colombia. [Ruckwardt, Tracy] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Salvato, MS (reprint author), Univ Maryland, Inst Human Virol, Sch Med, 725 W Lombard St, Baltimore, MD 21201 USA. EM msalvato@ihv.umaryland.edu FU National Institutes of Health [AI5252367, RR138980, AI53620, AI53619] FX Financial support: National Institutes of Health (AI5252367 to ISL, RR138980 to ISL, AI53620 to MSS, AI53619 to MSS) NR 60 TC 9 Z9 10 U1 0 U2 15 PU FUNDACO OSWALDO CRUZ PI RIO DE JANEIRO, RJ PA AV BRASIL 4365, 21045-900 RIO DE JANEIRO, RJ, BRAZIL SN 0074-0276 J9 MEM I OSWALDO CRUZ JI Mem. Inst. Oswaldo Cruz PD JUL PY 2009 VL 104 IS 4 BP 583 EP 591 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 489ZU UT WOS:000269466900009 PM 19722081 ER PT J AU Brill, LM Motamedchaboki, K Wu, SD Wolf, DA AF Brill, Laurence M. Motamedchaboki, Khatereh Wu, Shuangding Wolf, Dieter A. TI Comprehensive proteomic analysis of Schizosaccharomyces pombe by two-dimensional HPLC-tandem mass spectrometry SO METHODS LA English DT Article DE Multidimensional liquid chromatography; Tandem mass spectrometry; Proteomic profiling; Schizosaccharomyces pombe; Spectrum counting ID PHOSPHORYLATION SITES; SHOTGUN PROTEOMICS; STATISTICAL-MODEL; YEAST; PROTEINS AB We describe a detailed and widely applicable method for comprehensive proteomic profiling of the fission yeast Schizosaccharomyces pombe by 2-dimensional high performance liquid chromatography-electrospray ionization-tandem mass spectrometry that demonstrates high sensitivity and robust operation. Steps ranging from the preparation of total proteins, digestion of proteins to peptides, and separation of peptides by two-dimensional (1. strong cation exchange and 2. reversed-phase) high performance liquid chromatography followed by tandem mass spectrometry and data processing have been optimized for our instrumentation platform. Using this technology, we identify ca. 3400 proteins per sample and have identified an estimated 4600 proteins in vegetative cells (equal to ca. 90% of the predicted S. pombe proteome) at a false discovery rate of <= 0.02. Considering the fact that similar to 500 genes are strongly induced during sexual differentiation, and sexual differentiation was not included in our experiments, the proteomic profiling technique affords what should be virtually complete coverage of the vegetative S. pombe proteome. In addition, these methods are widely applicable, having been used for proteomic profiling of several other organisms. (C) 2009 Elsevier Inc. All rights reserved. C1 [Brill, Laurence M.; Motamedchaboki, Khatereh; Wolf, Dieter A.] NCI, Canc Ctr Proteom Facil, Burnham Med Res Inst, La Jolla, CA 92037 USA. [Wu, Shuangding; Wolf, Dieter A.] Burnham Inst Med Res, Signal Transduct Program, La Jolla, CA 92037 USA. RP Brill, LM (reprint author), NCI, Canc Ctr Proteom Facil, Burnham Med Res Inst, 10901 N Torrey Pines Road, La Jolla, CA 92037 USA. EM lbrill@burnham.org; dwolf@burnham.org OI Wolf, Dieter/0000-0002-3761-1070 FU NIH [R01 GM059780]; Burnham institute for Medical Research NCI Cancer Center [5 P30 CA30199-28]; NINDS [5 P30 NS057096] FX This work was funded by NIH Grant R01 GM059780 to D.A.W., by the Burnham institute for Medical Research NCI Cancer Center Support Grant 5 P30 CA30199-28 and by the La Jolla Interdisciplinary Neuroscience Center Cores Grant 5 P30 NS057096 from NINDS. We thank Kerry Nugent, Peter Kent, Lori Ann Upton and Dave Mintline for custom configuration of the HPLC hardware and systern software, Patrick Chu and David Chang for assistance with Sorcerer-SEQUEST applications, and Dr. Ali Iranli for his efforts in developing QTools. NR 14 TC 27 Z9 27 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD JUL PY 2009 VL 48 IS 3 BP 311 EP 319 DI 10.1016/j.ymeth.2009.02.023 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475LC UT WOS:000268359300014 PM 19272449 ER PT J AU Scott, I AF Scott, Iain TI Mitochondrial factors in the regulation of innate immunity SO MICROBES AND INFECTION LA English DT Review DE MAVS; IPS-1; Cardif; VISA; Mitochondria; Innate Immunity; CARD domain ID HEPATITIS-C VIRUS; NF-KAPPA-B; ANTIVIRAL SIGNALING PROTEIN; INDUCIBLE GENE-I; RIG-I; ADAPTER PROTEIN; RESPONSES; MAVS; IDENTIFICATION; TRANSDUCTION AB Viral infection stimulates multiple signalling pathways in the innate immune system, leading to type I interferon production. Recent research has identified the mitochondrial protein MAVS as a key component of one intracellular pathway, definitively linking mitochondria to the mammalian antiviral defence system for the first time. Published by Elsevier Masson SAS. C1 NHLBI, Mol Biol Sect, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Scott, I (reprint author), NHLBI, Mol Biol Sect, Translat Med Branch, NIH, Bldg 10 CRC,Room 5-3216,9000 Rockville Pike, Bethesda, MD 20892 USA. EM scotti@mail.nih.gov FU National Institute of Neurological Disorders and Stroke; National Heart, Lung and Blood Institute; National Institutes of Health FX The author would like to thank Richard J. Youle (NINDS, NIH) and Michael Sack (NHLBI, NIH) for their support and Damien Arnoult (INSERM U542, Universite Paris-Sud, France) for helpful discussions. This research was supported by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute, National Institutes of Health. NR 43 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD JUL-AUG PY 2009 VL 11 IS 8-9 BP 729 EP 736 DI 10.1016/j.micinf.2009.04.022 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 487QX UT WOS:000269291000002 PM 19427399 ER PT J AU Meysick, KC Seidman, J Falconio, JR AF Meysick, Karen C. Seidman, Jessica Falconio, Jason R. TI The Yersinia pseudotuberculosis YplA phospholipase differs in its activity, regulation and secretion from that of the Yersinia enterocolitica YplA SO MICROBIAL PATHOGENESIS LA English DT Article DE Phospholipases; Yersinia; Enzyme activity; Accessory protein; Secretion; Expression ID SERRATIA-MARCESCENS METALLOPROTEASE; ESCHERICHIA-COLI; ERWINIA-CHRYSANTHEMI; BACTERIAL PHOSPHOLIPASES; EXTRACELLULAR PROTEASES; MEMBRANE PHOSPHOLIPASE; GENOME SEQUENCE; ANKYRIN REPEAT; EXPRESSION; GENE AB Analysis of the Yersinia pseudotuberculosis and Yersinia pestis genomes indicates that both species carry an identical copy of a gene that is predicted to encode a protein which shares 80% similarity to the Yersinia enterocolitica YplA, a secreted phospholipase that has been shown to contribute to virulence. In contrast to well tolerated production of the Y. enterocolitica YplA in Escherichia coli, Y. pseudotuberculosis YplA expression was found to be toxic; however, cell viability could be restored if the Y. pseudotuberculosis YplA was expressed in the presence of its accessory protein YplB. In vitro, Y. pseudotuberculosis YplB was shown to reduce the activity of its cognate phospholipase in a dose-dependent manner. To determine whether the Y. pseudotuberculosis and Y. enterocolitica YplAs were secreted and regulated in a similar manner, secretion and promoter activity assays were performed. Unlike the situation apparent in Y. enterocolitica, expression of the Y. pseudotuberculosis yplA gene did not appear to be controlled by the flagellar regulon, nor did the phospholipase appear to be efficiently exported through the flagellar apparatus. These results indicate that the Yersinia YplAs vary in many of their attributes despite their high degree of amino acid homology. Published by Elsevier Ltd C1 [Meysick, Karen C.; Falconio, Jason R.] US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Lab Resp & Special Pathogens, Bethesda, MD 20892 USA. [Seidman, Jessica] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Meysick, KC (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allergen Prod, Lab Resp & Special Pathogens, HFM 434,8800 Rockville Pike,Bldg 29,Room 430, Bethesda, MD 20892 USA. EM karen.meysick@fda.hhs.gov NR 53 TC 1 Z9 3 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD JUL PY 2009 VL 47 IS 1 BP 24 EP 32 DI 10.1016/j.micpath.2009.04.008 PG 9 WC Immunology; Microbiology SC Immunology; Microbiology GA 467ZZ UT WOS:000267784100004 PM 19397992 ER PT J AU Palmer, RJ AF Palmer, Robert J. TI Oral bacterial biofilms - history in progress SO MICROBIOLOGY-SGM LA English DT Editorial Material C1 NIDCR, NIH, Bethesda, MD 20892 USA. RP Palmer, RJ (reprint author), NIDCR, NIH, Bldg 30,Room 310, Bethesda, MD 20892 USA. EM rjpalmer@dir.nidcr.nih.gov NR 5 TC 3 Z9 5 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-SGM JI Microbiology-(UK) PD JUL PY 2009 VL 155 BP 2113 EP 2114 DI 10.1099/mic.0.030809-0 PG 2 WC Microbiology SC Microbiology GA 473EU UT WOS:000268189600001 PM 19460821 ER PT J AU Sousa, AA Hohmann-Marriott, MF Azari, A Zhang, G Leapman, RD AF Sousa, A. A. Hohmann-Marriott, M. F. Azari, A. Zhang, G. Leapman, R. D. TI BF STEM Tomography for Improved 3D Imaging of Thick Biological Sections SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID RESOLUTION C1 [Sousa, A. A.; Azari, A.; Zhang, G.; Leapman, R. D.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. [Hohmann-Marriott, M. F.] Univ Otago, Dept Biochem, Dunedin, New Zealand. RP Sousa, AA (reprint author), NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. FU NIBIB, NIH FX Research supported by the intramural program of NIBIB, NIH NR 5 TC 1 Z9 1 U1 2 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 572 EP 573 DI 10.1017/S1431927609093659 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100283 ER PT J AU Lin, J Cheng, N Steven, AC Hogle, JM Belnap, DM AF Lin, J. Cheng, N. Steven, A. C. Hogle, J. M. Belnap, D. M. TI Testing a Model of Poliovirus Cell-Entry via Virus-Antibody Interactions SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID RESOLUTION C1 [Lin, J.; Belnap, D. M.] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Cheng, N.; Steven, A. C.; Belnap, D. M.] Natl Inst Arthritis Musculoskeletal & Skin Dis, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Hogle, J. M.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Lin, J (reprint author), Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 584 EP 585 DI 10.1017/S1431927609095634 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100289 ER PT J AU Heymann, JB Nemecek, D Cheng, N Qiao, J Mindich, L Steven, AC AF Heymann, J. B. Nemecek, D. Cheng, N. Qiao, J. Mindich, L. Steven, A. C. TI Expansion of the Bacteriophage phi 6 Procapsid Revealed by Electron Cryo-Microscopy SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID MICROSCOPY C1 [Heymann, J. B.; Nemecek, D.; Cheng, N.; Steven, A. C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Qiao, J.; Mindich, L.] Univ Med & Dent New Jersey, Publ Hlth Res Inst Ctr, Dept Microbiol, Newark, NJ 07103 USA. RP Heymann, JB (reprint author), NIAMSD, NIH, 50 South Dr, Bethesda, MD 20892 USA. FU NIAMS/NIH; NIH [GM34352] FX This work was supported by the Intramural Research Program of NIAMS/NIH and by grant GM34352 to L.M. from the NIH. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 586 EP 587 DI 10.1017/S1431927609098390 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100290 ER PT J AU Nemecek, D Heymann, JB Winkler, DC Qiao, J Mindich, L Steven, AC AF Nemecek, D. Heymann, J. B. Winkler, D. C. Qiao, J. Mindich, L. Steven, A. C. TI Electron Cryo-Tomography Demonstrates Variable Distributions of the Viral NTPase and RNA Polymerase in Bacteriophage phi 6 Procapsids SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract C1 [Nemecek, D.; Heymann, J. B.; Winkler, D. C.; Steven, A. C.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Qiao, J.; Mindich, L.] Univ Med & Dent New Jersey, Dept Microbiol, Publ Hlth Res Inst Ctr, Newark, NJ 07103 USA. RP Nemecek, D (reprint author), NIAMSD, NIH, 50 South Dr, Bethesda, MD 20892 USA. FU NIAMS/NIH; NIH [GM34352] FX This work was supported by the Intramural Research Program of NIAMS/NIH and by grant GM34352 to L.M. from the NIH. NR 5 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 588 EP 589 DI 10.1017/S1431927609098730 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100291 ER PT J AU Wright, ER Datta, SAK Shen, K Ding, HJ Rein, A Jensen, GJ AF Wright, E. R. Datta, S. A. K. Shen, K. Ding, H. J. Rein, A. Jensen, G. J. TI Three Dimensional Analysis of In Vitro Assembled HIV-1 Gag by Electron Cryotomography SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID VIRIONS C1 [Wright, E. R.] Emory Univ, Dept Pediat, Div Infect Dis, Atlanta, GA 30322 USA. [Wright, E. R.; Ding, H. J.; Jensen, G. J.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Datta, S. A. K.; Rein, A.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Shen, K.] Harvard Univ, Cambridge, MA 02138 USA. RP Wright, ER (reprint author), Emory Univ, Dept Pediat, Div Infect Dis, 2015 Uppergate Dr, Atlanta, GA 30322 USA. OI Datta, Siddhartha/0000-0002-4098-7490 NR 5 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 590 EP 591 DI 10.1017/S1431927609098936 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100292 ER PT J AU Meng, X Zhao, GP Mao, QL Wu, XW Zhang, PJ AF Meng, Xin Zhao, Gongpu Mao, Qilong Wu, Xiongwu Zhang, Peijun TI Electron tomography of chemotaxis receptor signaling complex SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID BACTERIAL CHEMORECEPTORS; ARRAYS C1 [Meng, Xin; Zhao, Gongpu; Mao, Qilong; Zhang, Peijun] Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Meng, X (reprint author), Univ Pittsburgh, Dept Biol Struct, Pittsburgh, PA 15260 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 592 EP 593 DI 10.1017/S1431927609099085 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100293 ER PT J AU Northan, BM Sougrat, R de Jonge, N AF Northan, B. M. Sougrat, R. de Jonge, N. TI Guidelines for Adapting Light Microscopy Deconvolution Methods to 3D Biological STEM SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract C1 [Northan, B. M.] Media Cybernet, Bethesda, MD 20814 USA. [Sougrat, R.] NCICHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. [de Jonge, N.] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [de Jonge, N.] Oak Ridge Natl Lab, Mat Sci & Technol Div, Oak Ridge, TN 37831 USA. RP Northan, BM (reprint author), Media Cybernet, 4340 E W Highway,400, Bethesda, MD 20814 USA. RI de Jonge, Niels/B-5677-2008; OI Sougrat, Rachid/0000-0001-6476-1886 FU Oak Ridge National Laboratory (ORNL); U.S. Department of Energy, Office of Energy Efficiency and Renewable Energy, Vanderbilt University Medical Center, NIH [R01GM081801]; NICHD FX We are grateful to L.F. Allard, D. Blom, D.T. Burnette, J.F. Deatherage, J. Lippincott-Schwartz, A.R. Lupini, S.J. Pennycook, D.W. Piston, and J.R. Price. This work was supported by the Laboratory Directed R&D Program of Oak Ridge National Laboratory (ORNL), ORNL's High Temperature Materials Laboratory User Program, sponsored by the U.S. Department of Energy, Office of Energy Efficiency and Renewable Energy, Vehicle Technologies Program, Vanderbilt University Medical Center, NIH grant R01GM081801 (NJ), Intramural Program of NICHD (RS). NR 6 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 628 EP 629 DI 10.1017/S1431927609093532 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100311 ER PT J AU Keller, PW Shaul, OBN Heymann, JB Winkler, DC Oppenheim, A Steven, AC AF Keller, P. W. Shaul, O. Ben-Nun Heymann, J. B. Winkler, D. C. Oppenheim, A. Steven, A. C. TI Analysis of Simian Virus 40 Chromatin Structure by Cryo-Electron Tomography SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID RESOLUTION C1 [Keller, P. W.; Heymann, J. B.; Winkler, D. C.; Steven, A. C.] NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Shaul, O. Ben-Nun; Oppenheim, A.] Hebrew Univ Jerusalem, Dept Hematol, Hadassah Med Sch, IL-91120 Jerusalem, Israel. RP Keller, PW (reprint author), NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. OI Heymann, Bernard/0000-0002-8872-5326 NR 4 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 644 EP 645 DI 10.1017/S1431927609096196 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100319 ER PT J AU Butan, C Lokhandwala, PM Winkler, DC Craven, RC Steven, AC AF Butan, C. Lokhandwala, P. M. Winkler, D. C. Craven, R. C. Steven, A. C. TI Electron-Tomography of a Temperature-Sensitive Morphogenic Mutant of Rous Sarcoma Virus (RSV) SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract C1 [Butan, C.; Winkler, D. C.; Steven, A. C.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. [Lokhandwala, P. M.; Craven, R. C.] Penn State Univ, Dept Microbiol & Immunol, Coll Med, Hershey, PA 17033 USA. RP Butan, C (reprint author), Natl Canc Inst, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 2 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 646 EP 647 DI 10.1017/S1431927609099152 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100320 ER PT J AU de Jonge, N Dukes, MJ Kremers, GJ Northan, BM Peckys, DB Ring, EA Piston, DW Sougrat, R AF de Jonge, N. Dukes, M. J. Kremers, G. J. Northan, B. M. Peckys, D. B. Ring, E. A. Piston, D. W. Sougrat, R. TI Liquid and Three-Dimensional Scanning Transmission Electron Microscopy for Biological Specimen SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract C1 [de Jonge, N.; Dukes, M. J.; Kremers, G. J.; Ring, E. A.; Piston, D. W.] Vanderbilt Univ, Med Ctr, Nashville, TN 37232 USA. [de Jonge, N.; Peckys, D. B.] Oak Ridge Natl Lab, Mat Sci & Technol Div, Oak Ridge, TN 37831 USA. [Northan, B. M.] Media Cybernet, Bethesda, MD 20814 USA. [Sougrat, R.] NCICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP de Jonge, N (reprint author), Vanderbilt Univ, Med Ctr, 2215 Garland Ave, Nashville, TN 37232 USA. RI Peckys, Diana/B-4642-2015; de Jonge, Niels/B-5677-2008; OI Sougrat, Rachid/0000-0001-6476-1886 FU Oak Ridge National Laboratory (ORNL); ORNL's High Temperature Materials Laboratory; US. Department of Energy (DOE), Office of Energy Efficiency and Renewable Energy; Division of Scientific User Facilities, Office of Basic Energy Science, U.S. DOE; Vanderbilt University Medical Center; NIH [R01GM081801, R01-RR018470, P20-GM072048]; NICHD FX We are grateful to L. F. Allard, J. Bentley, D. Blom, D. T. Burnette, J. F. Deatherage, D. C. Joy, T. E. McKnight, A. R. Lupini, K. L. More, S. J. Pennycook, Hummingbird Scientific, and Protochips Inc.. Research supported by the (1) Laboratory Directed R&D Program of Oak Ridge National Laboratory (ORNL), (2) ORNL's High Temperature Materials Laboratory User Program, sponsored by the US. Department of Energy (DOE), Office of Energy Efficiency and Renewable Energy, Vehicle Technologies Program, (3) ORNL's SHaRE User Program, sponsored by the Division of Scientific User Facilities, Office of Basic Energy Science, U.S. DOE, (4) Vanderbilt University Medical Center, (5) NIH grant R01GM081801 (NJ), (6) Intramural Program of NICHD (RS), (7) NIH grant R01-RR018470 (to P. Mazur for DBP), and (8) NIH grant P20-GM072048 (to DWP). NR 6 TC 1 Z9 1 U1 0 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 686 EP 687 DI 10.1017/S1431927609093301 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100340 ER PT J AU Palmer, RJ Egland, PG Kolenbrander, PE AF Palmer, Robert J., Jr. Egland, Paul G. Kolenbrander, Paul E. TI Biofilms of streptococci and veillonellae: interactions in vitro and in the oral cavity SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID GNOTOBIOTIC-RATS; ALCALESCENS; MUTANS C1 [Palmer, Robert J., Jr.; Egland, Paul G.; Kolenbrander, Paul E.] Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Palmer, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 820 EP 821 DI 10.1017/S1431927609092198 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100405 ER PT J AU Aronova, MA Sousa, AA Zhang, G Kruhlak, MJ Lei, EP Leapman, RD AF Aronova, M. A. Sousa, A. A. Zhang, G. Kruhlak, M. J. Lei, E. P. Leapman, R. D. TI Correlative EFTEM, STEM and Fluorescence Microscopy as a Tool for Chromatin Biology SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID TOMOGRAPHY C1 [Aronova, M. A.; Sousa, A. A.; Zhang, G.; Leapman, R. D.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. [Kruhlak, M. J.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Lei, E. P.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Aronova, MA (reprint author), NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. FU NIBIB; NCI; NIDDK FX This research was supported by the intramural programs of NIBIB, NCI and NIDDK. NR 4 TC 1 Z9 1 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 920 EP 921 DI 10.1017/S1431927609093556 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100454 ER PT J AU Swedlow, JR Allan, C Burel, JM Linkert, M Loranger, B MacDonald, D Moore, WJ Patterson, AJ Rueden, C Tarkowska, A Goldberg, IG Eliceiri, KW AF Swedlow, Jason R. Allan, Chris Burel, Jean-Marie Linkert, Melissa Loranger, Brian MacDonald, Donald Moore, William J. Patterson, Andrew J. Rueden, Curtis Tarkowska, Aleksandra Goldberg, Ilya G. Eliceiri, Kevin W. TI The Open Microscopy Environment: Informatics and Quantitative Analysis for Biological Microscopy SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract C1 [Swedlow, Jason R.; Allan, Chris; Burel, Jean-Marie; Loranger, Brian; MacDonald, Donald; Moore, William J.; Patterson, Andrew J.; Tarkowska, Aleksandra] Univ Dundee, Wellcome Trust Ctr Gene Regulat & Express, Coll Life Sci, Dundee DD1 5EH, Scotland. [Linkert, Melissa; Rueden, Curtis; Eliceiri, Kevin W.] Univ Wisconsin, Lab Opt & Computat Instrumentat, Madison, WI USA. [Goldberg, Ilya G.] NIA, Genet Lab, Baltimore, MD 21224 USA. RP Swedlow, JR (reprint author), Univ Dundee, Wellcome Trust Ctr Gene Regulat & Express, Coll Life Sci, Dundee DD1 5EH, Scotland. EM jason@ifesci.dundee.ac.uk RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 NR 0 TC 0 Z9 0 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 1520 EP 1521 DI 10.1017/S1431927609098092 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100747 ER PT J AU Heymann, JB AF Heymann, J. B. TI Image Processing and Interpretation in Structural Electron Microscopy SO MICROSCOPY AND MICROANALYSIS LA English DT Meeting Abstract ID BSOFT C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Heymann, JB (reprint author), NIAMSD, NIH, 50 South Dr, Bethesda, MD 20892 USA. OI Heymann, Bernard/0000-0002-8872-5326 FU NIAMS/NIH FX This work was supported by the Intramural Research Program of NIAMS/NIH. NR 5 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1431-9276 J9 MICROSC MICROANAL JI Microsc. microanal. PD JUL PY 2009 VL 15 SU 2 BP 1536 EP 1537 DI 10.1017/S1431927609098316 PG 2 WC Materials Science, Multidisciplinary; Microscopy SC Materials Science; Microscopy GA V20CW UT WOS:000208119100755 ER PT J AU Schneider, IC Hays, CK Waterman, CM AF Schneider, Ian C. Hays, Cristen K. Waterman, Clare M. TI Epidermal Growth Factor-induced Contraction Regulates Paxillin Phosphorylation to Temporally Separate Traction Generation from De-adhesion SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FLUORESCENT SPECKLE MICROSCOPY; KINASE RHO-KINASE; FOCAL ADHESIONS; TYROSINE PHOSPHORYLATION; CELL-MIGRATION; ACTIN CYTOSKELETON; MATRIX ADHESIONS; PHOSPHOLIPASE-C; CARCINOMA-CELLS; DOWN-REGULATION AB Directed cell migration is mediated by cycles of protrusion, adhesion, traction generation on the extracellular matrix and retraction. However, how the events after protrusion are timed, and what dictates their temporal order is completely unknown. We used acute epidermal growth factor (EGF) stimulation of epidermal keratinocytes to initiate the cell migration cycle to study the mechanism of the timing of adhesion, traction generation, and de-adhesion. Using microscopic and biochemical assays, we surprisingly found that at similar to 2 min after EGF stimulation protrusion, activation of myosin-II, traction generation, adhesion assembly, and paxillin phosphorylation occurred nearly simultaneously, followed by a 10-min delay during which paxillin became dephosphorylated before cell retraction. Inhibition of myosin-II blocked both the EGF-stimulated paxillin phosphorylation and cell retraction, and a paxillin phosphomimic blocked retraction. These results suggest that EGF-mediated activation of myosin-II acts as a mechanical signal to promote a cycle of paxillin phosphorylation/dephosphorylation that mediates a cycle of adhesion strengthening and weakening that delays cell retraction. Thus, we reveal for the first time a mechanism by which cells may temporally segregate protrusion, adhesion, and traction generation from retraction during EGF-stimulated cell migration. C1 [Schneider, Ian C.; Hays, Cristen K.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Schneider, Ian C.] Iowa State Univ, Dept Chem & Biol Engn, Ames, IA 50011 USA. [Schneider, Ian C.] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. [Waterman, Clare M.] NHLBI, Lab Cell & Tissue Morphodynam, NIH, Bethesda, MD 20892 USA. RP Schneider, IC (reprint author), Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. EM ians@iastate.edu; watermancm@nhlbi.nih.gov OI Schneider, Ian/0000-0002-4414-3842; Waterman, Clare/0000-0001-6142-6775 FU Intramural Research Program of the National Institutes of Health; National Heart, Lung, and Blood Institute [GM61804]; Damon Runyon Cancer Research Foundation [19540] FX We thank Robert Fischer, Margaret Gardel, and Ana Pasapera for discussion and technical advice. We thank Rick Horwitz (University of Virginia), David Schlaepfer (University of California, San Diego), Mark Ginsberg (University of California, San Diego), and Velia Fowler (Scripps) for reagents and Gaudenz Danuser (Scripps) for computational algorithms. This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute, Grant GM61804 to C. M. W. and S. L. S. and a fellowship from the Damon Runyon Cancer Research Foundation to I. C. S. The Scripps manuscript number is 19540. NR 51 TC 26 Z9 26 U1 1 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUL 1 PY 2009 VL 20 IS 13 BP 3155 EP 3167 DI 10.1091/mbc.E09-03-0219 PG 13 WC Cell Biology SC Cell Biology GA 464VO UT WOS:000267536400014 PM 19403690 ER PT J AU Rapisarda, A Hollingshead, M Uranchimeg, B Bonomi, CA Borgel, SD Carter, JP Gehrs, B Raffeld, M Kinders, RJ Parchment, R Anver, MR Shoemaker, RH Melillo, G AF Rapisarda, Annamaria Hollingshead, Melinda Uranchimeg, Badarch Bonomi, Carrie A. Borgel, Suzanne D. Carter, John P. Gehrs, Bradley Raffeld, Mark Kinders, Robert J. Parchment, Ralph Anver, Miriam R. Shoemaker, Robert H. Melillo, Giovanni TI Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID DNA TOPOISOMERASE-I; CANCER-THERAPY; TUMOR HYPOXIA; ANTIANGIOGENIC THERAPY; FACTOR 1-ALPHA; SOLID TUMORS; FACTOR-1-ALPHA; GROWTH; CHEMOTHERAPY; XENOGRAFTS AB Inhibition of hypoxia inducible factor-1 (HIF-1) is an attractive therapeutic strategy to target the tumor microenvironment. However, HIF-1 inhibitors may have limited activity as single agents and combination therapies may be required. We tested the hypothesis that HIF-1 inhibition in a hypoxic-stressed tumor microenvironment, which could be generated by administration of antiangiogenic agents, may result in a more pronounced therapeutic effect. The activity of bevacizumab, either alone or in combination with the HIF-1 alpha inhibitor topotecan, was evaluated in U251-HRE xenografts. Tumor tissue was collected at the end of treatment and changes in tumor oxygenation, angiogenesis, proliferation, apoptosis, HIF-1 alpha levels, HIF-1 target genes, and DNA damage were evaluated. Bevacizumab decreased microvessel-density and increased intratumor-hypoxia, but did not induce apoptosis. Moreover, bevacizumab alone caused a significant increase of HIF-1-dependent gene expression in tumor tissue. Addition of a low dose of daily topotecan to bevacizumab significantly inhibited tumor growth, relative to mice treated with topotecan or bevacizumab alone (P < 0.01). The addition of topotecan to bevacizumab was also associated with profound inhibition of HIF-1 transcriptional activity, significant inhibition of proliferation, and induction of apoptosis. Importantly, DNA damage induced by topotecan alone was not augmented by addition of bevacizumab, suggesting that increased cytotoxic activity did not account for the increased antitumor effects observed. These results strongly suggest that combination of anti-vascular endothelial growth factor antibodies with HIF-1 inhibitors is an attractive therapeutic strategy targeting in the hypoxic tumor microenvironment. [Mol Cancer Ther 2009;8(7): 1867-77] C1 [Melillo, Giovanni] NCI, SAIC Frederick Inc, DTP Tumor Hypoxia Lab, Frederick, MD 21702 USA. [Hollingshead, Melinda; Shoemaker, Robert H.] NCI, Dev Therapeut Program, Frederick, MD 21702 USA. [Gehrs, Bradley; Raffeld, Mark] NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. RP Melillo, G (reprint author), NCI, SAIC Frederick Inc, DTP Tumor Hypoxia Lab, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillog@mail.nih.gov FU National Cancer Institute (NCI); NIH [N01-CO-12400]; Developmental Therapeutics Program; Division of Cancer Treatment and Diagnosis, of the National Cancer Institute; NIH FX Federal funds from the National Cancer Institute (NCI), NIH, under Contract no. N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, of the National Cancer Institute, NIH. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the Guide for Care and Use of Laboratory Animals (NIH publication no. 86-23, 1985). NR 40 TC 96 Z9 100 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 1867 EP 1877 DI 10.1158/1535-7163.MCT-09-0274 PG 11 WC Oncology SC Oncology GA 470UG UT WOS:000268005700015 PM 19584228 ER PT J AU Pfister, TD Reinhold, WC Agama, K Gupta, S Khin, SA Kinders, RJ Parchment, RE Tomaszewski, JE Doroshow, JH Pommier, Y AF Pfister, Thomas D. Reinhold, William C. Agama, Keli Gupta, Shalu Khin, Sonny A. Kinders, Robert J. Parchment, Ralph E. Tomaszewski, Joseph E. Doroshow, James H. Pommier, Yves TI Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID COLORECTAL-CANCER; CLEAVAGE COMPLEXES; PROTEIN EXPRESSION; RESISTANCE; TOPOTECAN; CAMPTOTHECIN; DEGRADATION; INHIBITORS; P53 AB Topoisomerase I (Top1) is a proven target for cancer therapeutics, and the level of Top1 in tumors has been used as a biomarker for chemotherapeutic efficacy. In this study, we report the development and validation of a two-site enzyme chemiluminescent immunoassay for Top1, which we used to measure Top1 levels in the NCI-60 cancer cell line panel. Top1 levels ranged from 0.9 to 9.8 ng/mL/mu g protein extract in these cell lines. Levels varied both within and between cancer types but were generally highest in colon cancer and leukemia cell lines and lowest in central nervous system and renal cancer cell lines. Top1 mRNA levels in the NCI-60 cell lines were also measured by microarray; mRNA values generally showed a good correlation with protein levels (Pearson correlation = 0.8). When these expression levels were compared with the activity of the indenoisoquinoline class of Top1 inhibitors across the NCI-60 cell panel, low levels of Top1 were associated with increased resistance to these drugs. The results of our studies indicate that our Top1 assay can be used to quantify Top1 levels in untreated cells as well as cells treated with Top1 inhibitors and that the assay has the potential to be adapted for use in predicting clinical response to Top1-active antineoplastic agents. [Mol Cancer Ther 2009;8(7):1878-84] C1 [Pfister, Thomas D.; Khin, Sonny A.; Kinders, Robert J.; Parchment, Ralph E.] Natl Canc Inst, Sci Applicat Int Corp Frederick Inc, Appl Dev Res Support Directorate, Lab Human Toxicol & Pharmacol, Frederick, MD 21702 USA. [Reinhold, William C.; Agama, Keli; Gupta, Shalu; Doroshow, James H.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Kinders, RJ (reprint author), Natl Canc Inst, Sci Applicat Int Corp Frederick Inc, Appl Dev Res Support Directorate, Lab Human Toxicol & Pharmacol, POB B, Frederick, MD 21702 USA. EM kindersr@mail.nih.gov FU National Cancer Institute; NIH [N01-CO-12400]; Center for Cancer Research; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 27 TC 66 Z9 66 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 EI 1538-8514 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 1878 EP 1884 DI 10.1158/1535-7163.MCT-09-0016 PG 7 WC Oncology SC Oncology GA 470UG UT WOS:000268005700016 PM 19584232 ER PT J AU Trasino, SE Kim, YS Wang, TTY AF Trasino, Steven E. Kim, Young S. Wang, Thomas T. Y. TI Ligand, receptor, and cell type-dependent regulation of ABCA1 and ABCG1 mRNA in prostate cancer epithelial cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID LIVER-X-RECEPTOR; GENE-EXPRESSION; LXR-BETA; NUCLEAR RECEPTOR; LIPID-METABOLISM; CHOLESTEROL; ACTIVATION; ANDROGEN; MICE; MACROPHAGES AB Recent evidence suggests that the liver X receptor (LXR) is a potential anticancer target in prostate carcinoma. There is little characterization, however, of which of the two LXR isoforms, LXR alpha or LXR beta, regulates the LXR-responsive genes ATP-binding cassette subfamily members A1 (ABCA1) and G1 (ABCG1) in transformed prostatic epithelial cells. In this study, small interfering RNA (siRNA) was used to determine whether LXR alpha or LXR beta is involved in regulating ABCA1 and ABCG1 mRNA expression in LNCaP and PC-3 cells. Treatment of both cell lines with the synthetic LXR ligand T0901317 and oxysterols: 25-hydroxycholesterol (25HC) and 24(S), 25-epoxycholesterol (24,25EC), resulted in more than a 10-fold increase of ABCA1 and ABCG1 mRNA expression. Transfection of LNCaP cells with siRNA against either LXR beta or LXR alpha failed to inhibit T0901317 and 25HC-mediated increase of ABCA1 mRNA. siRNA silencing of LXR beta did, however, inhibit ABCA1 mRNA expression in 24,25EC-treated LNCaP cells. In contrast, LXR beta siRNA inhibited T0901317, 25HC, and 24,25EC induction of ABCA1 mRNA in PC-3 cells and ABCG1 mRNA in both LNCaP and PC-3 cells. Additional experiments revealed that T0901317 and 25HC induction of ABCA1 mRNA expression was significantly inhibited by the p38 stress kinase antagonist SB202190 and PKA inhibitor H89. Our study is the first to show that LXR beta, but not LXR alpha, is the major regulatory isoform of ABCG1 mRNA expression in LNCaP and PC-3 cells. Our study also reveals that ABCA1 gene expression is differentially regulated by synthetic and natural LXR ligands, possibly involving kinase mediated signal transduction. [Mol Cancer Ther 2009;8 (7):1934-45] C1 [Trasino, Steven E.; Wang, Thomas T. Y.] USDA ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. [Kim, Young S.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Wang, TTY (reprint author), USDA ARS, Diet Genom & Immunol Lab, Beltsville Human Nutr Res Ctr, Bldg 307C,Room 132, Beltsville, MD 20705 USA. EM tom.wang@ars.usda.gov FU U.S. appropriated funds [1235-51530-052-00]; National Cancer Institute FX U.S. appropriated funds to USDA project number 1235-51530-052-00 (T.T.Y. Wang and S.E. Trasino), and the National Cancer Institute (Y.S. Kim). NR 49 TC 25 Z9 26 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 1934 EP 1945 DI 10.1158/1535-7163.MCT-09-0020 PG 12 WC Oncology SC Oncology GA 470UG UT WOS:000268005700022 PM 19531574 ER PT J AU Guirouilh-Barbat, J Zhang, YW Pommier, Y AF Guirouilh-Barbat, Josee Zhang, Yong-Wei Pommier, Yves TI Induction of glutathione-dependent DNA double-strand breaks by the novel anticancer drug brostallicin SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID I CLEAVAGE COMPLEXES; SOFT-TISSUE SARCOMA; S-TRANSFERASE; UNIQUE MECHANISM; HISTONE H2AX; SINGLE-CELL; PHASE-II; REPLICATION; CANCER; REPAIR AB Brostallicin is a DNA minor groove binder in phase 11 clinical trials. Here, we show that brostallicin induces Y-H2AX nuclear foci that colocalize with 53BP1 and are dependent on glutathione, as shown by inhibition of those Y-H2AX foci by L-buthionine sulfoximine. To differentiate brostallicin from the clinically approved minor groove binder trabectedin (ecteinascidin 743), we tested whether the brostallicin-induced Y-H2AX and anti proliferative responses were dependent on nucleotide excision repair and found that, unlike trabectedin, they are not. Additionally, brostallicin retained activity in the trabectedin-resistant HCT116-ER5 cell line. Induction of Y-H2AX foci by brostallicin was partially dependent on the repair nuclease Well. Pretreatment with aphidicolin partially reduced brostallicin-induced Y-H2AX foci, suggesting that brostallicin induces both replication-associated and replication-independent DNA damage. Replication-associated DNA damage was further shown by the colocalization of Y-H2AX foci with replication foci and by the rapid inhibition of DNA synthesis and accumulation of cells in S phase in response to brostallicin. In addition, brostallicin was able to induce lower intensity Y-H2AX foci in human circulating lymphocytes. Together, our results indicate that brostallicin induces DNA double-strand breaks and suggest Y-H2AX as a pharmacodynamic biomarker for brostallicin. [Mol Cancer Ther 2009;8(7):1985-94] C1 [Guirouilh-Barbat, Josee; Zhang, Yong-Wei; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI ZHANG, YONGWEI/E-6252-2012 FU National Cancer Institute; Center for Cancer Research, Bethesda, Maryland FX National Cancer Institute, Center for Cancer Research, Bethesda, Maryland. NR 49 TC 7 Z9 7 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 1985 EP 1994 DI 10.1158/1535-7163.MCT-09-0320 PG 10 WC Oncology SC Oncology GA 470UG UT WOS:000268005700027 PM 19584235 ER PT J AU Guirouilh-Barbat, J Antony, S Pommier, Y AF Guirouilh-Barbat, Josee Antony, Smitha Pommier, Yves TI Zalypsis (PM00104) is a potent inducer of gamma-H2AX foci and reveals the importance of the C ring of trabectedin for transcription-coupled repair inhibition SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; I CLEAVAGE COMPLEXES; DOUBLE-STRAND BREAKS; CARIBBEAN TUNICATE; ANTITUMOR-ACTIVITY; CRYSTAL-STRUCTURES; ECTEINASCIDIN 743; MINOR-GROOVE; DNA; MECHANISM AB Zalypsis (PM00104) is a novel tetrahydroisoquinoline alkaloid related to trabectedin [ecteinascidin 743 (Et743)]. Et743 and PM00104 have similar A and B rings but differ in their C rings. The present study shows that Et743 and PM00104 differ in at least two ways: in their DNA binding properties and nucleotide excision repair (NER) dependency for cellular targeting. DNase I footprinting shows that the two drugs bind DNA differentially. We also found that, in contrast to Et743, the antiproliferative activity of PM00104 does not depend on transcription-coupled NER. Accordingly, PM00104 induces gamma-H2AX foci with the same efficiency in NER-deficient or NER-proficient cells. Moreover, the formation of gamma-H2AX foci is replication dependent for PM00104, whereas it is both transcription and replication dependent in the case of Et743. These findings show the importance of the C ring structure of tetrahydroisoquinoline ecteinascidin derivatives for NER targeting. Finally, PM00104 exerts antiproliferative activity at nanomolar concentrations and induces gamma-H2AX response in two Ewing's sarcoma cell lines, suggesting that gamma-H2AX could serve as a pharmacodynamic biomarker for the clinical development of PM00104. [Mol Cancer Ther 2009;8(7):2007-14] C1 [Guirouilh-Barbat, Josee; Antony, Smitha; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research; National Cancer Institute, NIH FX Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 27 TC 26 Z9 26 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 2007 EP 2014 DI 10.1158/1535-7163.MCT-09-0336 PG 8 WC Oncology SC Oncology GA 470UG UT WOS:000268005700029 PM 19584237 ER PT J AU Orina, JN Calcagno, AM Wu, CP Varma, S Shih, J Lin, M Eichler, G Weinstein, JN Pommier, Y Ambudkar, SV Gottesman, MM Gillet, JP AF Orina, Josiah N. Calcagno, Anna Maria Wu, Chung-Pu Varma, Sudhir Shih, Joanna Lin, Min Eichler, Gabriel Weinstein, John N. Pommier, Yves Ambudkar, Suresh V. Gottesman, Michael M. Gillet, Jean-Pierre TI Evaluation of current methods used to analyze the expression profiles of ATP-binding cassette transporters yields an improved drug-discovery database SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CANCER CELL-LINE; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; P-GLYCOPROTEIN; MOLECULAR PHARMACOLOGY; ABC TRANSPORTERS; CHEMOSENSITIVITY; CHEMOTHERAPY; PREDICTION; ARRAY AB The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by multiple mechanisms. These mechanisms can act individually or synergistically, leading to MDR, in which the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been successful. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing highly homologous genes from small amounts of tissue is fundamental to achieving any significant enhancement in our understanding of MDR mechanisms and could lead to treatments designed to circumvent it. In this study, we use a previously established database that allows the identification of lead compounds in the early stages of drug discovery that are not ATP-binding cassette (ABC) transporter substrates. We believe this can serve as a model for appraising the accuracy and sensitivity of current methods used to analyze the expression profiles of ABC transporters. We found two platforms to be superior methods for the analysis of expression profiles of highly homologous gene superfamilies. This study also led to an improved database by revealing previously unidentified substrates for ABCB1, ABCC1, and ABCG2, transporters that contribute to MDR. [Mol Cancer Ther 2009;8(7):2057-66] C1 [Orina, Josiah N.; Calcagno, Anna Maria; Wu, Chung-Pu; Ambudkar, Suresh V.; Gottesman, Michael M.; Gillet, Jean-Pierre] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir; Eichler, Gabriel; Weinstein, John N.; Pommier, Yves] NCI, Genom & Bioinformat Branch, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. [Shih, Joanna] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Lin, Min] Fluidigm Corp, San Francisco, CA USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM gottesmanm@mail.nih.gov RI gillet, jean-pierre/A-3714-2012; Calcagno, Anna Maria/A-5617-2012; Varma, Sudhir/N-8763-2014 OI Calcagno, Anna Maria/0000-0002-0804-2753; Varma, Sudhir/0000-0002-4096-4782 FU NIH; National Cancer Institute; Center for Cancer Research; National Institute of General Medical Sciences Pharmacology Research Associate FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. A.M. Calcagno was supported by the National Institute of General Medical Sciences Pharmacology Research Associate Program. NR 37 TC 29 Z9 29 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUL PY 2009 VL 8 IS 7 BP 2057 EP 2066 DI 10.1158/1535-7163.MCT-09-0256 PG 10 WC Oncology SC Oncology GA 470UG UT WOS:000268005700034 PM 19584229 ER PT J AU Virador, VM Flores-Obando, RE Berry, A Patel, R Zakhari, J Lo, YC Strain, K Anders, J Cataisson, C Hansen, LA Yuspa, SH AF Virador, Victoria M. Flores-Obando, Rafael E. Berry, Adam Patel, Rinal Zakhari, Julia Lo, Yu-Chien Strain, Kathryn Anders, Joanna Cataisson, Christophe Hansen, Laura A. Yuspa, Stuart H. TI The Human Promyelocytic Leukemia Protein Is a Tumor Suppressor for Murine Skin Carcinogenesis SO MOLECULAR CARCINOGENESIS LA English DT Article DE transgenic mice; tumor suppressor proteins; nuclear bodies; cytokeratin-10; senescence; keratinocytes ID BLADDER-CANCER CELLS; P53 GENE DOSAGE; MALIGNANT PROGRESSION; TRANSCRIPTION FACTOR; CELLULAR SENESCENCE; CYCLE ARREST; PML PROTEIN; RAR-ALPHA; GROWTH; EXPRESSION AB Expression of the PMLRAR alpha fusion dominant-negative oncogene in the epidermis of transgenic mice resulted in spontaneous skin tumors attributed to changes in both the PML and RAR pathways [Hansen et al., Cancer Res 2003; 63-5257-5265]. To determine the contribution of PML to skin tumor susceptibility, transgenic mice were generated on an FVB/N background, that overexpressed the human PML protein in epidermis and hair follicles under the control of the bovine keratin 5 promoter. PML was highly expressed in the epidermis and hair follicles of these mice and was also increased in cultured keratinocytes where it was confined to nuclear bodies. While an overt skin phenotype was not detected in young transgenic mice, expression of keratin 10 (K10) was increased in epidermis and hair follicles and cultured keratinocytes. As mice aged, they exhibited extensive alopecia that was accentuated on the C57BL/6J background. Following skin tumor induction with 7, 12-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter, papilloma multiplicity and size were decreased in the transgenic mice by 35%, and the conversion of papillomas to carcinomas was delayed. Cultured transgenic keratinocytes underwent premature senescence and upregulated transcripts for p16 and Rb but not p19 and p53. Together, these changes suggest that PML participates in regulating the growth and differentiation of keratinocytes that likely influence its activity as a suppressor for tumor development. Published 2008 Wiley-Liss, Inc. C1 [Virador, Victoria M.; Berry, Adam; Patel, Rinal; Zakhari, Julia; Lo, Yu-Chien; Strain, Kathryn; Anders, Joanna; Cataisson, Christophe; Yuspa, Stuart H.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Flores-Obando, Rafael E.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Hansen, Laura A.] Creighton Univ, Sch Med, Dept Biomed Sci, Omaha, NE 68178 USA. RP Yuspa, SH (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bldg 37,Room 4068, Bethesda, MD 20892 USA. FU National Cancer Institute; Center for Cancer Research of the National Institutes of Health FX The authors thank Henry Hennings, Ulrike Lichti, Michael Gerdes, Rodolfo Murillas and Luowei Li for critical discussions and helpful advice. We also thank Barbara Taylor, Steve Jay, Lionel Feigenbaum, Stephen Wincovitch and Susan Garfield for expert technical assistance. This research was Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the National Institutes of Health. NR 42 TC 4 Z9 4 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD JUL PY 2009 VL 48 IS 7 BP 599 EP 609 DI 10.1002/mc.20498 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 462LJ UT WOS:000267353800005 PM 19058256 ER PT J AU Deroo, BJ Rodriguez, KF Couse, JF Hamilton, KJ Collins, JB Grissom, SF Korach, KS AF Deroo, Bonnie J. Rodriguez, Karina F. Couse, John F. Hamilton, Katherine J. Collins, Jennifer B. Grissom, Sherry F. Korach, Kenneth S. TI Estrogen Receptor beta Is Required for Optimal cAMP Production in Mouse Granulosa Cells SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; PROSTAGLANDIN ENDOPEROXIDE SYNTHASE-2; PROTEIN-KINASE-A; RAT PREOVULATORY FOLLICLES; MESSENGER-RIBONUCLEIC-ACID; PROGESTERONE-RECEPTOR; GENE-EXPRESSION; CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE; IN-VITRO; SIGNALING PATHWAYS AB Granulosa cells of preovulatory follicles differentiate in response to FSH, and this differentiation is augmented by estradiol. We have previously shown that FSH-mediated granulosa cell differentiation requires functional estrogen receptor-beta (ER beta) by demonstrating that the granulosa cells of ER beta(-/-) FSH-treated mice are unable to maximally induce expression of the LH receptor ( an indicator of granulosa cell differentiation) compared with ER beta(+/+) controls. As a result, FSH-primed ER beta(-/-) granulosa cells exhibit a reduced response to a subsequent ovulatory dose of LH. In this study, we further characterized the attenuated response of ER beta(-/-) granulosa cells to stimulation by LH and FSH using isolated mouse granulosa cells and primary granulosa cell cultures. We observed a 50% reduction in cAMP levels in cultured ER beta(-/-) granulosa cells exposed to LH compared with ER beta(+/+) controls. We also observed an attenuated genomic response in granulosa cells isolated from FSH-primed ER beta(-/-) mice compared with ER beta(+/+) controls. Our data indicate that this attenuated response may result from inadequate levels of cAMP, because cAMP levels in cultured ER beta(-/-) granulosa cells exposed to forskolin were approximately 50% lower than in ER beta(+/+) granulosa cells. Phosphorylation of cAMP regulatory element binding protein, an indicator of protein kinase A activity, was also reduced in FSH-treated ER beta(-/-) granulosa cells compared with ER beta(+/+) controls. These are the first data to indicate that ER beta plays a role in the induction of the cAMP pathway in mouse granulosa cells and that disruption of proper ER beta signaling associated with this pathway may cause negative effects on ovulation and fertility. ( Molecular Endocrinology 23: 955-965, 2009) C1 [Korach, Kenneth S.] NIEHS, NIH, Environm Dis Med Program, Receptor Biol Sect, Res Triangle Pk, NC 27709 USA. [Collins, Jennifer B.; Grissom, Sherry F.] NIEHS, NIH, Microarray Grp, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, NIH, Environm Dis Med Program, Receptor Biol Sect, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS NR 46 TC 18 Z9 19 U1 2 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD JUL PY 2009 VL 23 IS 7 BP 955 EP 965 DI 10.1210/me.2008-0213 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 467ZF UT WOS:000267781800002 PM 19324971 ER PT J AU Vincent, LM Adams, D Hess, RA Ziegler, SG Tsilou, E Golas, G O'Brien, KJ White, JG Huizing, M Gahl, WA AF Vincent, Lisa M. Adams, David Hess, Richard A. Ziegler, Shira G. Tsilou, Ekaterini Golas, Gretchen O'Brien, Kevin J. White, James G. Huizing, Marjan Gahl, William A. TI Hermansky-Pudlak syndrome type 1 in patients of Indian descent SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Lysosome-related organelle; Albinism; Indian descent; Splice-site mutation; Bleeding diathesis ID PULMONARY-FIBROSIS; ALBINISM PATIENTS; TYROSINASE GENE; HPS GENE; MUTATIONS; PROTEIN; TRAFFICKING; CELLS; MELANOCYTES; MELANOSOMES AB Hermansky-Pudlak syndrome (HPS) develops from defects in the biogenesis and/or function of lysosome-related organelles essential to membrane and protein trafficking. Of the eight known human sub-types, only HPS-1 and HPS-4 develop pulmonary fibrosis in addition to the general clinical manifestations of oculocutaneous albinism and bleeding diathesis. We identified HPS-1 in three unrelated patients from different regions of India, who presented with iris trans illumination, pale fundi, hypopigmentation, nystagmus, decreased visual acuity, and a bleeding diathesis. Two of these patients carried the homozygous mutation c.398+5G > A (IVS5+5G > A) in HPS1, resulting in skipping of exon 5 in HPS1 nnRNA. The third patient carried a novel homozygous c.988-1G > T mutation that resulted in in-frame skipping of HPS1 exon 12 and removes 56 amino acids from the HPS1 protein. Given the discovery of HPS-1 in an ethnic group where oculocutaneous albinism (OCA) is highly prevalent, it is possible that HPS in India is under-diagnosed. We recommend that unconfirmed OCA patients in this ethic group be considered for mutational screening of known HPS genes, in particular c.398+5G > A and c.980-1G > T, to ensure that patients can be monitored and treated for clinical complications unique to HPS. Published by Elsevier Inc. C1 [Vincent, Lisa M.; Adams, David; Hess, Richard A.; Ziegler, Shira G.; Golas, Gretchen; O'Brien, Kevin J.; Huizing, Marjan; Gahl, William A.] NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Tsilou, Ekaterini] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Golas, Gretchen; O'Brien, Kevin J.; Gahl, William A.] NIH, Intramural Off Rare Dis, Off Director, Bethesda, MD 20892 USA. [White, James G.] Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Vincent, LM (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 10C107,MSC1851, Bethesda, MD 20892 USA. EM vincentl@mail.nih.gov FU National Human Genome Research Institute; National Eye Institute; National Institutes of Health, Bethesda, MD, USA FX Isa Bernardini, Roxanne Fischer, Heidi Dorward, and Wendy Westbroek provided excellent technical assistance. This work was supported by the Intramural Research programs of the National Human Genome Research Institute and National Eye Institute, National Institutes of Health, Bethesda, MD, USA. NR 33 TC 6 Z9 6 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUL PY 2009 VL 97 IS 3 BP 227 EP 233 DI 10.1016/j.ymgme.2009.03.011 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 459IV UT WOS:000267096200010 PM 19398212 ER PT J AU Drgon, T Johnson, C Walther, D Albino, AP Rose, JE Uhl, GR AF Drgon, Tomas Johnson, Catherine Walther, Donna Albino, Anthony P. Rose, Jed E. Uhl, George R. TI Genome-Wide Association for Smoking Cessation Success: Participants in a Trial with Adjunctive Denicotinized Cigarettes SO MOLECULAR MEDICINE LA English DT Article ID SAMPLE-SIZE CALCULATIONS; NICOTINE DEPENDENCE; MOLECULAR-GENETICS; POLYSUBSTANCE ABUSERS; VULNERABILITY LOCI; SUBSTANCE USE; LUNG-CANCER; GENES; TWINS; ADDICTION AB The ability to quit smoking successfully displays substantial heritability in classical and molecular genetic studies. Twin studies suggest that some of the genetics for the ability to quit overlap with genetic components of nicotine dependence, but many do not. Genome-wide association (GWA) studies have demonstrated haplotypes that distinguish successful quitters from individuals who were not able to quit smoking in: i) clinical trials that employed nicotine replacement: ii) clinical trials that employed bupropion: and iii) community quitter samples. We now report novel GWA results from participants in a clinical trial that document the efficacy of adjunctive use of denicotinized cigarettes. These results buttress data from our prior GWA studies of smoking cessation. They suggest that ability to change smoking behavior using denicotinized cigarettes shares substantial underlying genetics with the ability to change this behavior in community settings or in response to treatments with nicotine replacement or bupropion. (C) 2009 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: hffp://www.molmed.org doi: 10.2119/molmed.2009.00040 C1 [Drgon, Tomas; Johnson, Catherine; Walther, Donna; Uhl, George R.] NIDA, Mol Neurobiol Branch, NIH IRP, Baltimore, MD USA. [Albino, Anthony P.] Vector Tobacco Inc, New York, NY USA. [Rose, Jed E.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. RP Uhl, GR (reprint author), Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU Vector Tobacco Inc., New York, NY, USA; NIH Intramural Research Program, NIDA, DHSS FX We are grateful for the careful work on these studies by Karen Becker, Qing-Rong Liu, and colleagues. We appreciate the thoughtful advice and discussion from prior samples obtained from D Hamer, C. Lerman, R. Niaura and S David. This research was supported by Vector Tobacco Inc., New York, NY, USA, and the NIH Intramural Research Program, NIDA, DHSS. NR 24 TC 20 Z9 20 U1 1 U2 4 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD JUL-AUG PY 2009 VL 15 IS 7-8 BP 268 EP 274 DI 10.2119/molmed.2009.00040 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 575CV UT WOS:000276043800009 PM 19593411 ER PT J AU Decker, KB Hinton, DM AF Decker, Kimberly B. Hinton, Deborah M. TI The secret to 6S: regulating RNA polymerase by ribo-sequestration SO MOLECULAR MICROBIOLOGY LA English DT Editorial Material ID ESCHERICHIA-COLI; SIGMA-SUBUNIT; PROMOTER SPECIFICITY; TRANSCRIPTION; PROTEIN; RECOGNITION; DOMAIN AB Regulating transcription under different conditions is vital to all organisms. As Escherichia coli shifts from exponential to stationary growth, regulation of transcription is achieved in large part by the tight binding of 6S RNA to E sigma(70), RNA polymerase with the sigma(70) specificity subunit. Ribo-sequestration of E sigma(70) by 6S RNA serves to downregulate sigma(70)-dependent transcription, which is needed for exponential growth. This facilitates transcription from promoters dependent on stationary phase sigma, sigma(s). Previous work has suggested that the 6S RNA binding to E sigma(70) simply mimics the E sigma(70)/promoter interaction. In this issue of Molecular Microbiology, Klocko and Wassarman demonstrate that many of the contacts between residues within sigma(70) region 4 and 6S RNA are distinct from those between region 4 and promoter DNA. Several residues that interact with 6S RNA are ones previously known to interact with protein activators of E sigma(70). Their work adds 6S RNA to the growing list of factors that can regulate E sigma(70) by interacting with region 4. C1 [Decker, Kimberly B.; Hinton, Deborah M.] NIDDK, Gene Express & Regulat Sect, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. RP Hinton, DM (reprint author), NIDDK, Gene Express & Regulat Sect, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. EM dhinton@helix.nih.gov FU Intramural NIH HHS [Z01 DK057802-20, Z01 DK057813-01] NR 15 TC 10 Z9 10 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUL PY 2009 VL 73 IS 2 BP 137 EP 140 DI 10.1111/j.1365-2958.2009.06759.x PG 4 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 469GK UT WOS:000267883900001 PM 19538446 ER PT J AU Druss, BG Hwang, I Petukhova, M Sampson, NA Wang, PS Kessler, RC AF Druss, B. G. Hwang, I. Petukhova, M. Sampson, N. A. Wang, P. S. Kessler, R. C. TI Impairment in role functioning in mental and chronic medical disorders in the United States: results from the National Comorbidity Survey Replication SO MOLECULAR PSYCHIATRY LA English DT Article DE impairment; disability; disease burden; epidemiology; National Comorbidity Survey Replication ID PSYCHIATRIC-DISORDERS; SELF-REPORTS; HEALTH-CARE; NCS-R; DISABILITY; BURDEN; POPULATION; OUTCOMES; ILLNESS; INFORMATION AB This study presents national data on the comparative role impairments of common mental and chronic medical disorders in the general population. These data come from the National Comorbidity Survey Replication, a nationally representative household survey. Disorder-specific role impairment was assessed with the Sheehan Disability Scales, a multidimensional instrument that asked respondents to attribute impairment to particular conditions. Overall impairment was significantly higher for mental than chronic medical disorders in 74% of pair-wise comparisons between the two groups of conditions, and severe impairment was reported by a significantly higher portion of persons with mental disorders (42.0%) than chronic medical disorders (24.4%). However, treatment was provided for a significantly lower proportion of mental (21.4%) than chronic medical (58.2%) disorders. Although mental disorders were associated with comparable or higher impairment than chronic medical conditions in all domains of function, they showed different patterns of deficits; whereas chronic medical disorders were most likely to be associated with impairment in domains of work and home functioning, mental disorders were most commonly associated with problems in social and close-relation domains. Comorbidity between chronic medical and mental disorders significantly increased the reported impairment associated with each type of disorder. The results indicate a serious mismatch between a high degree of impairment and a low rate of treatment for mental disorders in the United States. Efforts to reduce disability will need to address the disproportionate burden and distinct patterns of deficits of mental disorders and the potentially synergistic impact of comorbid mental and chronic medical disorders. Molecular Psychiatry ( 2009) 14, 728-737; doi:10.1038/mp.2008.13; published online 19 February 2008 C1 [Druss, B. G.] Emory Univ, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. [Hwang, I.; Petukhova, M.; Sampson, N. A.; Kessler, R. C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Wang, P. S.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Druss, BG (reprint author), Emory Univ, Dept Hlth Policy & Management, 1518 Clifton Rd,NE Room 606, Atlanta, GA 30322 USA. EM bdruss@emory.edu FU FIC NIH HHS [R01-TW006481, R03 TW006481, R03 TW006481-03]; NIDA NIH HHS [R01 DA016558, R01 DA016558-06]; NIMH NIH HHS [R01 MH069864-04, K24 MH075867, K24MH075867, R01 MH069864, R01 MH070884, R01 MH070884-04, R01-MH069864, R13 MH066849, R13-MH066849, U01 MH060220, U01 MH060220-08, U01-MH60220, U13 MH066849, U13 MH066849-06] NR 48 TC 62 Z9 62 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD JUL PY 2009 VL 14 IS 7 BP 728 EP 737 DI 10.1038/mp.2008.13 PG 10 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 461QV UT WOS:000267284800009 PM 18283278 ER PT J AU Gorospe, M AF Gorospe, Myriam TI Ribonucleoprotein dynamics connects mRNA networks with drug mechanisms SO MOLECULAR SYSTEMS BIOLOGY LA English DT Editorial Material ID EXPRESSION; MICRORNAS; BINDING; DISEASE; HUR C1 NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov NR 15 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD JUL PY 2009 VL 5 AR 289 DI 10.1038/msb.2009.48 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 480FY UT WOS:000268718900006 PM 19638970 ER PT J AU Berdicevsky, I Kaufman, G Newman, DJ Horwitz, BA AF Berdicevsky, Israela Kaufman, Gil Newman, David J. Horwitz, Benjamin A. TI Preliminary study of activity of the thioredoxin inhibitor pleurotin against Trichophyton mentagrophytes: a novel anti-dermatophyte possibility SO MYCOSES LA English DT Article DE antifungal activity; Trichophyton mentagrophytes; Candida spp; dermatophytes ID PATHOGEN TRICHOPHYTON; STRESS; GROWTH AB Dermatophyte infections, while not life-threatening, are very common, and there is great interest in developing new antifungal agents. Transcriptional profiling of Trichophyton on keratin has identified some antioxidant genes as induced on this host substrate, including a thioredoxin gene TmTRX1. If thioredoxin is a virulence factor, or necessary for the growth on keratin, thioredoxin inhibitors should act as antifungals. As a first evaluation of this hypothesis, we have tested the activity of a thioredoxin-inhibitory natural product, pleurotin, against a clinical isolate of each of two fungal pathogens: the dermatophyte T. mentagrophytes and Candida albicans. Pleurotin inhibited the growth of the dermatophyte in vitro and in an ex vivo skin model, but had no effect on Candida. It may be possible to develop and optimise thioredoxin inhibitors, some of which are already under study in cancer chemotherapy, as antifungals. C1 [Berdicevsky, Israela; Kaufman, Gil] Technion Israel Inst Technol, Fac Med, Dept Mol Microbiol, IL-31096 Haifa, Israel. [Newman, David J.] NCI Frederick, Nat Prod Branch, Frederick, MD USA. [Horwitz, Benjamin A.] Technion Israel Inst Technol, Dept Biol, IL-31096 Haifa, Israel. RP Berdicevsky, I (reprint author), Technion Israel Inst Technol, Fac Med, Dept Mol Microbiol, POB 9649, IL-31096 Haifa, Israel. EM israelab@techunix.technion.ac.il RI Horwitz, Benjamin/I-5056-2013 FU Technion Vice-President for Research (VPR) Fund FX This study was supported by the Technion Vice-President for Research (VPR) Fund. NR 14 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0933-7407 J9 MYCOSES JI Mycoses PD JUL PY 2009 VL 52 IS 4 BP 313 EP 317 DI 10.1111/j.1439-0507.2008.01620.x PG 5 WC Dermatology; Mycology SC Dermatology; Mycology GA 456KK UT WOS:000266844500003 PM 18793260 ER PT J AU Slotta, DJ Barrett, T Edgar, R AF Slotta, Douglas J. Barrett, Tanya Edgar, Ron TI NCBI Peptidome: a new public repository for mass spectrometry peptide identifications SO NATURE BIOTECHNOLOGY LA English DT Letter C1 [Slotta, Douglas J.; Barrett, Tanya; Edgar, Ron] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Slotta, DJ (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM peptidome@ncbi.nlm.nih.gov FU Intramural NIH HHS [NIH0010394446, ]; PHS HHS [NIH0010394446] NR 7 TC 27 Z9 27 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2009 VL 27 IS 7 BP 600 EP 601 DI 10.1038/nbt0709-600 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 469OF UT WOS:000267908500010 PM 19587658 ER PT J AU Addona, TA Abbatiello, SE Schilling, B Skates, SJ Mani, DR Bunk, DM Spiegelman, CH Zimmerman, LJ Ham, AJL Keshishian, H Hall, SC Allen, S Blackman, RK Borchers, CH Buck, C Cardasis, HL Cusack, MP Dodder, NG Gibson, BW Held, JM Hiltke, T Jackson, A Johansen, EB Kinsinger, CR Li, J Mesri, M Neubert, TA Niles, RK Pulsipher, TC Ransohoff, D Rodriguez, H Rudnick, PA Smith, D Tabb, DL Tegeler, TJ Variyath, AM Vega-Montoto, LJ Wahlander, A Waldemarson, S Wang, M Whiteaker, JR Zhao, L Anderson, NL Fisher, SJ Liebler, DC Paulovich, AG Regnier, FE Tempst, P Carr, SA AF Addona, Terri A. Abbatiello, Susan E. Schilling, Birgit Skates, Steven J. Mani, D. R. Bunk, David M. Spiegelman, Clifford H. Zimmerman, Lisa J. Ham, Amy-Joan L. Keshishian, Hasmik Hall, Steven C. Allen, Simon Blackman, Ronald K. Borchers, Christoph H. Buck, Charles Cardasis, Helene L. Cusack, Michael P. Dodder, Nathan G. Gibson, Bradford W. Held, Jason M. Hiltke, Tara Jackson, Angela Johansen, Eric B. Kinsinger, Christopher R. Li, Jing Mesri, Mehdi Neubert, Thomas A. Niles, Richard K. Pulsipher, Trenton C. Ransohoff, David Rodriguez, Henry Rudnick, Paul A. Smith, Derek Tabb, David L. Tegeler, Tony J. Variyath, Asokan M. Vega-Montoto, Lorenzo J. Wahlander, Asa Waldemarson, Sofia Wang, Mu Whiteaker, Jeffrey R. Zhao, Lei Anderson, N. Leigh Fisher, Susan J. Liebler, Daniel C. Paulovich, Amanda G. Regnier, Fred E. Tempst, Paul Carr, Steven A. TI Multi-site assessment of the precision and reproducibility of multiple reaction monitoring-based measurements of proteins in plasma SO NATURE BIOTECHNOLOGY LA English DT Article ID MASS-SPECTROMETRIC QUANTITATION; ABSOLUTE QUANTIFICATION; ISOTOPE-DILUTION; BIOMARKER DISCOVERY; PEPTIDE STANDARDS; SERUM; ASSAYS; LC/MS/MS; PROTEOME; LIMITS AB Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low lg/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma. C1 [Addona, Terri A.; Abbatiello, Susan E.; Mani, D. R.; Keshishian, Hasmik; Blackman, Ronald K.; Carr, Steven A.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Schilling, Birgit; Cusack, Michael P.; Gibson, Bradford W.; Held, Jason M.] Buck Inst Age Res, Novato, CA USA. [Skates, Steven J.; Pulsipher, Trenton C.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Bunk, David M.; Dodder, Nathan G.; Rudnick, Paul A.] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Spiegelman, Clifford H.; Variyath, Asokan M.; Vega-Montoto, Lorenzo J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Zimmerman, Lisa J.; Ham, Amy-Joan L.; Li, Jing; Tabb, David L.; Liebler, Daniel C.] Vanderbilt Univ, Nashville, TN USA. [Hall, Steven C.; Allen, Simon; Johansen, Eric B.; Niles, Richard K.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Borchers, Christoph H.; Jackson, Angela; Smith, Derek] Univ Victoria, Genome BC Prote Ctr, Victoria, BC, Canada. [Buck, Charles; Regnier, Fred E.] Purdue Univ, W Lafayette, IN 47907 USA. [Cardasis, Helene L.; Neubert, Thomas A.; Wahlander, Asa] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY USA. [Cardasis, Helene L.; Neubert, Thomas A.; Wahlander, Asa] NYU, Sch Med, Dept Pharmacol, New York, NY USA. [Hiltke, Tara; Kinsinger, Christopher R.; Mesri, Mehdi; Rodriguez, Henry] NCI, NIH, Bethesda, MD 20892 USA. [Ransohoff, David] Univ N Carolina, Chapel Hill, NC USA. [Tegeler, Tony J.; Wang, Mu] Monarch Life Sci, Indianapolis, IN USA. [Wang, Mu] Indiana Univ, Sch Med, Indianapolis, IN USA. [Whiteaker, Jeffrey R.; Zhao, Lei; Paulovich, Amanda G.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Anderson, N. Leigh] Plasma Proteome Inst, Washington, DC USA. [Tempst, Paul] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Carr, SA (reprint author), Broad Inst MIT & Harvard, Cambridge, MA USA. EM scarr@broad.mit.edu RI Held, Jason/B-1319-2010; Waldemarson, Sofia/C-6377-2012; Dodder, Nathan/C-7971-2015; Vega-Montoto, Lorenzo/B-9035-2017; OI Dodder, Nathan/0000-0001-5913-1767; Vega-Montoto, Lorenzo/0000-0002-4096-1100; Tempst, Paul/0000-0002-6680-3987; Held, Jason/0000-0001-8024-2736; Liebler, Daniel/0000-0002-7873-3031 FU NCI NIH HHS [U24 CA126480-01, U24 CA126476, U24 CA126476-03, U24 CA126480, U24 CA126485]; PHS HHS [U24 126477, U24 126479, U24 126480] NR 38 TC 588 Z9 595 U1 9 U2 102 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2009 VL 27 IS 7 BP 633 EP U85 DI 10.1038/nbt.1546 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 469OF UT WOS:000267908500020 PM 19561596 ER PT J AU Chanock, S AF Chanock, Stephen TI High marks for GWAS SO NATURE GENETICS LA English DT Editorial Material ID ETIOLOGY; DISEASE; CANCER; RISK AB Two genome-wide association studies for testicular cancer report associations at three new loci, including two candidate genes previously implicated in testicular development, KITLG (ligand for the receptor tyrosine kinase) and SPRY4 (sprouty 4). These studies are notable for the high effect sizes detected and the biological plausibility of the candidate genes. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chanock, S (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov NR 10 TC 18 Z9 18 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2009 VL 41 IS 7 BP 765 EP 766 DI 10.1038/ng0709-765 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 468AS UT WOS:000267786200002 PM 19557077 ER PT J AU Henneke, M Diekmann, S Ohlenbusch, A Kaiser, J Engelbrecht, V Kohlschutter, A Kratzner, R Madruga-Garrido, M Mayer, M Opitz, L Rodriguez, D Ruschendorf, F Schumacher, J Thiele, H Thoms, S Steinfeld, R Nurnberg, P Gartner, J AF Henneke, Marco Diekmann, Simone Ohlenbusch, Andreas Kaiser, Jens Engelbrecht, Volkher Kohlschuetter, Alfried Kraetzner, Ralph Madruga-Garrido, Marcos Mayer, Michele Opitz, Lennart Rodriguez, Diana Rueschendorf, Franz Schumacher, Johannes Thiele, Holger Thoms, Sven Steinfeld, Robert Nuernberg, Peter Gaertner, Jutta TI RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection SO NATURE GENETICS LA English DT Article ID EPITHELIAL OVARIAN-CANCER; TUMOR-SUPPRESSOR GENE; HUMAN MEMBER; RNASET2; 6Q27; REGION; FAMILY; RIBONUCLEASES; CLONING AB Congenital cytomegalovirus brain infection without symptoms at birth can cause a static encephalopathy with characteristic patterns of brain abnormalities. Here we show that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. Congenital cytomegalovirus infection and RNASET2 deficiency may both interfere with brain development and myelination through angiogenesis or RNA metabolism. C1 [Henneke, Marco; Diekmann, Simone; Ohlenbusch, Andreas; Kaiser, Jens; Kraetzner, Ralph; Thoms, Sven; Steinfeld, Robert; Gaertner, Jutta] Univ Gottingen, Dept Pediat & Pediat Neurol, Gottingen, Germany. [Engelbrecht, Volkher] Hosp St Marien, Inst Diagnost & Intervent Radiol, Amberg, Germany. [Kohlschuetter, Alfried] Univ Med Ctr, Dept Pediat, Hamburg, Germany. [Madruga-Garrido, Marcos] Univ Hosp Virgen del Rocio, Dept Neuropediat, Seville, Spain. [Mayer, Michele; Rodriguez, Diana] Armand Trousseau Hosp, Dept Neuropediat, AP HP, Paris, France. [Opitz, Lennart] Univ Gottingen, DNA Microarray Facil, Gottingen, Germany. [Rodriguez, Diana] INSERM, UMR S546, Paris, France. [Rodriguez, Diana] Univ Paris 06, Paris, France. [Rueschendorf, Franz] Max Delbruck Ctr Mol Med, Berlin, Germany. [Schumacher, Johannes] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Schumacher, Johannes] NIH, Bethesda, MD 20892 USA. [Thiele, Holger; Nuernberg, Peter] Univ Cologne, CCG, D-5000 Cologne, Germany. [Thiele, Holger; Nuernberg, Peter] Univ Cologne, Inst Genet, D-5000 Cologne 41, Germany. [Nuernberg, Peter] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-5000 Cologne 41, Germany. RP Gartner, J (reprint author), Univ Gottingen, Dept Pediat & Pediat Neurol, Gottingen, Germany. EM gaertnj@med.uni-goettingen.de RI Thoms, Sven/B-5763-2013; Schumacher, Johannes/F-4970-2015 OI Schumacher, Johannes/0000-0001-9217-6457 FU Deutsche Forschungsgemeinschaft [GA354/6-1]; Bundesministerium fur Bildung and Forschung (BMBF) through the German Leukodystrophy Network FX We thank the subjects and their families for participating in the study, C. Becker, L. Florin, M. Grapp, R. Hitt, J. Landgrebe and G. Nurnberg for expert technical assistance, and A. Fuchs, T. V. O. Hansen, R. Sedlmeier, O. Shoseyov and G. Tretter for collaborative efforts. This work has been supported by the Deutsche Forschungsgemeinschaft Grant GA354/6-1 (J. G. and M. H.) and the Bundesministerium fur Bildung and Forschung (BMBF) through the German Leukodystrophy Network (M. H. and J. S.). NR 15 TC 52 Z9 56 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2009 VL 41 IS 7 BP 773 EP 775 DI 10.1038/ng.398 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 468AS UT WOS:000267786200005 PM 19525954 ER PT J AU Gregersen, PK Amos, CI Lee, AT Lu, Y Remmers, EF Kastner, DL Seldin, MF Criswell, LA Plenge, RM Holers, VM Mikuls, TR Sokka, T Moreland, LW Bridges, SL Xie, G Begovich, AB Siminovitch, KA AF Gregersen, Peter K. Amos, Chistopher I. Lee, Annette T. Lu, Yue Remmers, Elaine F. Kastner, Daniel L. Seldin, Michael F. Criswell, Lindsey A. Plenge, Robert M. Holers, V. Michael Mikuls, Ted R. Sokka, Tuulikki Moreland, Larry W. Bridges, S. Louis, Jr. Xie, Gang Begovich, Ann B. Siminovitch, Katherine A. TI REL, encoding a member of the NF-kappa B family of transcription factors, is a newly defined risk locus for rheumatoid arthritis SO NATURE GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; C-REL; INCEPTION COHORT; CELLS; ASSOCIATION; EXPRESSION; VARIANTS; ITGAM AB We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR 1.25 (P = 3.08 x 10(-14)) for marker rs13031237 and an allelic OR 1.21 (P = 2.60 x 10(-11)) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappa B family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ(1,2). C1 [Gregersen, Peter K.; Lee, Annette T.] N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Amos, Chistopher I.; Lu, Yue] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Remmers, Elaine F.; Kastner, Daniel L.] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. [Seldin, Michael F.] Univ Calif Davis, Rowe Program Genet, Davis, CA 95616 USA. [Criswell, Lindsey A.] Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA 94143 USA. [Plenge, Robert M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Holers, V. Michael] Univ Colorado, Denver Sch Med, Denver, CO 80202 USA. [Sokka, Tuulikki] Univ Nebraska, Med Ctr, Omaha, NE USA. [Sokka, Tuulikki] Jyvaskyla Cent Hosp, Jyvaskyla, Finland. [Moreland, Larry W.] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. [Bridges, S. Louis, Jr.] Univ Alabama, Birmingham, AL USA. [Xie, Gang; Siminovitch, Katherine A.] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Xie, Gang; Siminovitch, Katherine A.] Univ Hlth Network, Toronto, ON M5G 1X5, Canada. [Begovich, Ann B.] Celera, Alameda, CA USA. RP Gregersen, PK (reprint author), N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. EM peterg@nshs.edu; ksimin@mshri.on.ca RI Siminovitch, Katherine/K-1475-2013 FU US National Institutes of Health [NO1-AR-2-2263, RO1 AR44422]; Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation; Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; Canadian Institutes for Health Research [MOP79321]; Ontario Research Fund [RE01061]; Canada Research Chair FX This work was supported by grants from the US National Institutes of Health NO1-AR-2-2263 (P. K. G.), RO1 AR44422 (P. K. G.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis and the Muriel Fusfeld Foundation. The work was also supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and by grants from the Canadian Institutes for Health Research (MOP79321) and Ontario Research Fund (RE01061) and a Canada Research Chair to K. A. S. NR 30 TC 189 Z9 194 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUL PY 2009 VL 41 IS 7 BP 820 EP U77 DI 10.1038/ng.395 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 468AS UT WOS:000267786200013 PM 19503088 ER PT J AU Augustine, AD Hall, BF Leitner, WW Mo, AX Wali, TM Fauci, AS AF Augustine, Alison Deckhut Hall, B. Fenton Leitner, Wolfgang W. Mo, Annie X. Wali, Tonu M. Fauci, Anthony S. TI NIAID workshop on immunity to malaria: addressing immunological challenges SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CELL EXHAUSTION; RESISTANCE; INFECTION; RESPONSES AB The US National Institute of Allergy and Infectious Diseases convened a workshop of malaria investigators and immunologists to foster collaborations and attract more immunologists into malaria research. Discussions highlighted research gaps and underscored the incomplete understanding of basic immune mechanisms that contribute to the pathogenesis of or protection against malaria. C1 [Augustine, Alison Deckhut; Hall, B. Fenton; Leitner, Wolfgang W.; Mo, Annie X.; Wali, Tonu M.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Augustine, AD (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fauci@niaid.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 17 TC 8 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2009 VL 10 IS 7 BP 673 EP 678 DI 10.1038/ni0709-673 PG 6 WC Immunology SC Immunology GA 459WF UT WOS:000267142600002 PM 19536188 ER PT J AU Wynn, TA AF Wynn, Thomas A. TI Basophils trump dendritic cells as APCs for T(H)2 responses SO NATURE IMMUNOLOGY LA English DT Editorial Material ID CD8(+) T-CELLS; IN-VIVO; MESSENGER-RNA; IL-4; CD8-ALPHA(+); EOSINOPHILS; ACTIVATION; PRODUCT AB Dendritic cells are best known as antigen-presenting cells that initiate adaptive immune responses. Three new papers suggest that basophils initiate allergen-and helminth-driven CD4(+) T helper type 2 responses by functioning as antigen-presenting cells in draining lymph nodes. C1 NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS [Z01 AI001019-01] NR 17 TC 33 Z9 33 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2009 VL 10 IS 7 BP 679 EP 681 DI 10.1038/ni0709-679 PG 4 WC Immunology SC Immunology GA 459WF UT WOS:000267142600003 PM 19536189 ER PT J AU McVicar, DW Trinchieri, G AF McVicar, Daniel W. Trinchieri, Giorgio TI CSF-1R, DAP12 and beta-catenin: a menage a trois SO NATURE IMMUNOLOGY LA English DT Editorial Material ID ACTIVATION AB DAP12-coupled receptors influence signals emanating from Toll-like receptors, integrins and receptors for cytokines and growth factors. New findings indicate that DAP12 also facilitates the ability of CSF-1R, the receptor for M-CSF, to induce the stabilization and nuclear translocation of beta-catenin. C1 [McVicar, Daniel W.; Trinchieri, Giorgio] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP McVicar, DW (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. EM trinchig@mail.nih.gov RI McVicar, Daniel/G-1970-2015 NR 12 TC 6 Z9 6 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2009 VL 10 IS 7 BP 681 EP 683 DI 10.1038/ni0709-681 PG 3 WC Immunology SC Immunology GA 459WF UT WOS:000267142600004 PM 19536190 ER PT J AU Liu, GW Burns, S Huang, GH Boyd, K Proia, RL Flavell, RA Chi, HB AF Liu, Guangwei Burns, Samir Huang, Gonghua Boyd, Kelli Proia, Richard L. Flavell, Richard A. Chi, Hongbo TI The receptor S1P(1) overrides regulatory T cell-mediated immune suppression through Akt-mTOR SO NATURE IMMUNOLOGY LA English DT Article ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; TOLL-LIKE; FUNCTIONAL-ACTIVITY; LYMPHOCYTE EGRESS; FOXP3 EXPRESSION; SPHINGOSINE-1-PHOSPHATE; FTY720; TRAFFICKING; TOLERANCE; REVERSAL AB Regulatory T cells (T-reg cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P(1)) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T-reg cells. Combining loss-and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T-reg precursors and function of mature T-reg cells and affected T-reg cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T-reg cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T-reg cell-mediated immune suppression, the lipid-activated S1P(1)-Akt-mTOR pathway orchestrates adaptive immune responses. C1 [Liu, Guangwei; Burns, Samir; Huang, Gonghua; Chi, Hongbo] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Boyd, Kelli] St Jude Childrens Hosp, Anim Resources Ctr, Memphis, TN 38105 USA. [Proia, Richard L.] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Flavell, Richard A.; Chi, Hongbo] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06510 USA. RP Chi, HB (reprint author), St Jude Childrens Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM hongbo.chi@stjude.org RI Proia, Richard/A-7908-2012 FU Intramural NIH HHS; NIAMS NIH HHS [K01 AR053573, K01 AR053573-01A1, K01 AR053573-02, K01 AR053573-03]; NINDS NIH HHS [R01 NS064599] NR 49 TC 171 Z9 179 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUL PY 2009 VL 10 IS 7 BP 769 EP U132 DI 10.1038/ni.1743 PG 11 WC Immunology SC Immunology GA 459WF UT WOS:000267142600017 PM 19483717 ER PT J AU Hansen, AM Caspi, RR AF Hansen, Anna M. Caspi, Rachel R. TI Targeting lymphotoxin depletes pathogenic T cells SO NATURE MEDICINE LA English DT Editorial Material C1 [Hansen, Anna M.; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Hansen, AM (reprint author), NEI, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS [Z01 EY000184-25] NR 7 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2009 VL 15 IS 7 BP 732 EP 733 DI 10.1038/nm0709-732 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 468HE UT WOS:000267806900022 PM 19584860 ER PT J AU Weaver, TA Charafeddine, AH Agarwal, A Turner, AP Russell, M Leopardi, FV Kampen, RL Stempora, L Song, MQ Larsen, CP Kirk, AD AF Weaver, Tim A. Charafeddine, Ali H. Agarwal, Avinash Turner, Alexandra P. Russell, Maria Leopardi, Frank V. Kampen, Robert L. Stempora, Linda Song, Mingqing Larsen, Christian P. Kirk, Allan D. TI Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates SO NATURE MEDICINE LA English DT Article ID DONOR-SPECIFIC TRANSFUSION; CHRONIC PLAQUE PSORIASIS; T-CELL MEMORY; TRANSPLANTATION TOLERANCE; BARRIER; IMMUNITY AB Memory T cells promote allograft rejection particularly in co-stimulation blockade-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function-associated antigen-3-Ig; LFA-3-Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade-based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan-T cell depletion. C1 [Weaver, Tim A.; Charafeddine, Ali H.; Agarwal, Avinash; Turner, Alexandra P.; Russell, Maria; Leopardi, Frank V.; Kampen, Robert L.; Stempora, Linda; Song, Mingqing; Kirk, Allan D.] NIDDK, Transplantat Branch, US NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Weaver, Tim A.; Charafeddine, Ali H.; Leopardi, Frank V.; Kampen, Robert L.; Larsen, Christian P.; Kirk, Allan D.] Emory Univ, Emory Transplant Ctr, Atlanta, GA 30322 USA. RP Kirk, AD (reprint author), NIDDK, Transplantat Branch, US NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM adkirk@emory.edu RI Kirk, Allan/B-6905-2012; Larsen, Christian/B-6906-2012 OI Larsen, Christian/0000-0001-6573-2649 FU Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Disease, NIH [Z01 DK062007-06]; National Institutes of Health [1U01AI079223-01A1]; Georgia Research Alliance; McKelvey Foundation FX This study was funded in part by the Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Disease, NIH (Z01 DK062007-06). Salary support for T. A. W. was provided by the Howard Hughes Medical Institute through the NIH Research Scholars Program. A. D. K. is supported by the National Institutes of Health (1U01AI079223-01A1), the Georgia Research Alliance and the McKelvey Foundation. We gratefully acknowledge the expert assistance of J. Bacher and the staff of the NIH Veterinary Pathology Department. NR 14 TC 116 Z9 119 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2009 VL 15 IS 7 BP 746 EP 749 DI 10.1038/nm.1993 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 468HE UT WOS:000267806900026 PM 19584865 ER PT J AU Gattinoni, L Zhong, XS Palmer, DC Ji, Y Hinrichs, CS Yu, ZY Wrzesinski, C Boni, A Cassard, L Garvin, LM Paulos, CM Muranski, P Restifo, NP AF Gattinoni, Luca Zhong, Xiao-Song Palmer, Douglas C. Ji, Yun Hinrichs, Christian S. Yu, Zhiya Wrzesinski, Claudia Boni, Andrea Cassard, Lydie Garvin, Lindsay M. Paulos, Chrystal M. Muranski, Pawel Restifo, Nicholas P. TI Wnt signaling arrests effector T cell differentiation and generates CD8(+) memory stem cells SO NATURE MEDICINE LA English DT Article ID BETA-CATENIN; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; TRANSCRIPTION FACTORS; SELF-RENEWAL; LONG-TERM; IMMUNITY; CANCER; PROLIFERATION; MAINTENANCE AB Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways(1). The Wnt-beta-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation(2,3), but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt-beta-catenin signaling by inhibitors of glycogen sythase kinase-3 beta or the Wnt protein family member Wnt3a arrested CD8(+) T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44(low)CD62L(high)Sca-1(high)CD122(high)Bcl-2(high) self-renewing multipotent CD8(+) memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory CD8(+) T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies. C1 [Gattinoni, Luca; Zhong, Xiao-Song; Palmer, Douglas C.; Ji, Yun; Hinrichs, Christian S.; Yu, Zhiya; Wrzesinski, Claudia; Boni, Andrea; Cassard, Lydie; Garvin, Lindsay M.; Paulos, Chrystal M.; Muranski, Pawel; Restifo, Nicholas P.] NCI, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gattinoni, L (reprint author), NCI, Ctr Canc Res, US Natl Inst Hlth, Bethesda, MD 20892 USA. EM gattinol@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Ji, Yun/B-7245-2009; Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010; Palmer, Douglas/B-9454-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Ji, Yun/0000-0001-6340-7009; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU US National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. We would like to thank S. A. Rosenberg, C. A. Klebanoff and S. Kerkar for critical review of the manuscript and A. Mixon and S. Farid of the Flow Cytometry Unit for Flow Cytometry analyses and sorting. This study was done in partial fulfillment of a PhD in Biochemistry (to D.C.P.) at the George Washington University, Washington, DC. NR 40 TC 307 Z9 316 U1 2 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2009 VL 15 IS 7 BP 808 EP U129 DI 10.1038/nm.1982 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 468HE UT WOS:000267806900036 PM 19525962 ER PT J AU Dobrovolskaia, MA Germolec, DR Weaver, JL AF Dobrovolskaia, Marina A. Germolec, Dori R. Weaver, James L. TI Evaluation of nanoparticle immunotoxicity SO NATURE NANOTECHNOLOGY LA English DT Review ID VACCINES; ISSUES; SIZE AB The pharmaceutical industry is developing increasing numbers of drugs and diagnostics based on nanoparticles, and evaluating the immune response to these diverse formulations has become a challenge for scientists and regulatory agencies alike. An international panel of scientists and representatives from various agencies and companies reviewed the limitations of current tests at a workshop held at the National Cancer Institute in Frederick, Maryland. This article outlines practical strategies for identifying and controlling interferences in common evaluation methods and the implications for regulation. C1 [Dobrovolskaia, Marina A.] NCI, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. [Germolec, Dori R.] Natl Inst Environm Hlth Sci, Toxicol Branch, Natl Toxicol Program, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Weaver, James L.] US FDA, CDER, Div Appl Pharmacol Res, Silver Spring, MD 20993 USA. RP Dobrovolskaia, MA (reprint author), NCI, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU PHS HHS [HHSN261200800001E] NR 12 TC 157 Z9 158 U1 3 U2 73 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD JUL PY 2009 VL 4 IS 7 BP 411 EP 414 DI 10.1038/NNANO.2009.175 PG 4 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 478OJ UT WOS:000268597300009 PM 19581891 ER PT J AU Rochman, Y Spolski, R Leonard, WJ AF Rochman, Yrina Spolski, Rosanne Leonard, Warren J. TI New insights into the regulation of T cells by gamma(c) family cytokines SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID THYMIC STROMAL LYMPHOPOIETIN; IL-7 RECEPTOR-ALPHA; SEVERE COMBINED IMMUNODEFICIENCY; FOLLICULAR-HELPER-CELLS; RESPONSES IN-VIVO; DENDRITIC CELLS; CUTTING EDGE; HOMEOSTATIC PROLIFERATION; INTERLEUKIN-7 RECEPTOR; DIFFERENTIAL REGULATION AB Common cytokine receptor gamma-chain (gamma(c)) family cytokines have crucial roles in the development, proliferation, survival and differentiation of multiple cell lineages of both the innate and adaptive immune systems. In this Review, we focus on our current understanding of the distinct and overlapping effects of interleukin-2 (IL-2), IL-7, IL-9, IL-15 and IL-21, as well as the IL-7-related cytokine thymic stromal lymphopoietin (TSLP), on the survival and proliferation of conventional alpha beta T cells, gamma delta T cells and regulatory T cells. This knowledge potentially allows for the therapeutic manipulation of immune responses for the treatment of cancer, autoimmunity, allergic diseases and immunodeficiency, as well as for vaccine development. C1 [Rochman, Yrina; Spolski, Rosanne; Leonard, Warren J.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 149 TC 416 Z9 426 U1 9 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD JUL PY 2009 VL 9 IS 7 BP 480 EP 490 DI 10.1038/nri2580 PG 11 WC Immunology SC Immunology GA 462HR UT WOS:000267342300011 PM 19543225 ER PT J AU Velikovsky, CA Deng, L Tasumi, S Iyer, LM Kerzic, MC Aravind, L Pancer, Z Mariuzza, RA AF Velikovsky, C. Alejandro Deng, Lu Tasumi, Satoshi Iyer, Lakshminarayan M. Kerzic, Melissa C. Aravind, L. Pancer, Zeev Mariuzza, Roy A. TI Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID MOLECULAR RECOGNITION; ALIGNMENT ALGORITHM; CRYSTAL-STRUCTURE; ANTIBODIES; DIVERSITY; BINDING; DOMAIN; DIVERSIFICATION; MATURATION; EVOLUTION AB Variable lymphocyte receptors (VLRs) are leucine-rich repeat proteins that mediate adaptive immunity in jawless vertebrates. VLRs are fundamentally different from the antibodies of jawed vertebrates, which consist of immunoglobulin (Ig) domains. We determined the structure of an anti-hen egg white lysozyme (HEL) VLR, isolated by yeast display, bound to HEL. The VLR, whose affinity resembles that of IgM antibodies, uses nearly all its concave surface to bind the protein, in addition to a loop that penetrates into the enzyme active site. The VLR-HEL structure combined with sequence analysis revealed an almost perfect match between ligand-contacting positions and positions with highest sequence diversity. Thus, it is likely that we have defined the generalized antigen-binding site of VLRs. We further demonstrated that VLRs can be affinity-matured by 13-fold to affinities as high as those of IgG antibodies, making VLRs potential alternatives to antibodies for biotechnology applications. C1 [Tasumi, Satoshi; Pancer, Zeev] Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, Baltimore, MD 21202 USA. [Velikovsky, C. Alejandro; Deng, Lu; Kerzic, Melissa C.; Mariuzza, Roy A.] Univ Maryland, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Inst Biotechnol, Rockville, MD USA. [Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Pancer, Z (reprint author), Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, 600 E Lombard St, Baltimore, MD 21202 USA. EM pancer@comb.umbi.umd.edu; mariuzza@carb.nist.gov FU US National Institutes of Health [AI065612, AI036900]; US National Science Foundation [(MCB-0614672]; University of Maryland Biotechnology Institute; US Department of Energy; National Institutes of Health; Cancer Research Institute FX This study was supported by the US National Institutes of Health (AI065612 and AI036900 to R. A. M.) and the US National Science Foundation (MCB-0614672 to Z. P.). R. A. M. and Z. P. were also supported by an Intercenter Collaboration Grant from the University of Maryland Biotechnology Institute. We thank H. Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Support for beamline X29 comes from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. L. M. I. and L. A. were supported by the National Library of Medicine of the National Institutes of Health. L. D. is supported by the Cancer Research Institute. NR 39 TC 56 Z9 57 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD JUL PY 2009 VL 16 IS 7 BP 725 EP U44 DI 10.1038/nsmb.1619 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 467TB UT WOS:000267764500010 PM 19543291 ER PT J AU Schiffmann, R Warnock, DG Banikazemi, M Bultas, J Linthorst, GE Packman, S Sorensen, SA Wilcox, WR Desnick, RJ AF Schiffmann, Raphael Warnock, David G. Banikazemi, Maryam Bultas, Jan Linthorst, Gabor E. Packman, Seymour Sorensen, Sven Asger Wilcox, William R. Desnick, Robert J. TI Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy SO NEPHROLOGY DIALYSIS TRANSPLANTATION LA English DT Article DE albuminuria; arrhythmia; Fabry disease; nephropathy; proteinuria; stroke ID GLOMERULAR-FILTRATION-RATE; AGALSIDASE-BETA THERAPY; CLINICAL-MANIFESTATIONS; ALPHA-GALACTOSIDASE; OUTCOME SURVEY; CONTROLLED TRIAL; RENAL-FUNCTION; FEMALES; KIDNEY; PROTEINURIA AB Background. In Fabry disease, progressive glycolipid accumulation leads to organ damage and early demise, but the incidence of renal, cardiac and cerebrovascular events has not been well characterized. Methods. We conducted a retrospective chart review of 279 affected males and 168 females from 27 sites (USA, Canada, Europe). The pre-defined study endpoints included progression of renal, cardiac and cerebrovascular involvement and/or death before the initiation of enzyme replacement therapy. Results. The mean rate of estimated glomerular filtration rate (eGFR) decline for patients was -2.93 for males, and -1.02 ml/min/1.73 m(2)/year for females. Prevalence and severity of proteinuria, baseline eGFR <60 ml/min/1.73 m(2) and hypertension were associated with more rapid loss of eGFR. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events (mainly arrhythmias), strokes and transient ischaemic attacks occurred in 49, 11, 6% of males, and in 35, 8, 4% of females, respectively. The mean age at death for 20 male patients was 49.9 years. Conclusions. Baseline proteinuria, reduced baseline eGFR, hypertension and male gender were associated with more rapid progression of Fabry nephropathy. The eGFR progression rate may increase with advancing nephropathy, and may differ between subgroups of patients with Fabry disease. C1 [Banikazemi, Maryam; Desnick, Robert J.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Schiffmann, Raphael] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. [Warnock, David G.] Univ Alabama, Div Nephrol, Birmingham, AL USA. [Bultas, Jan] Charles Univ Hosp, Fac Med 3, Dept Pharmacol, Prague, Czech Republic. [Linthorst, Gabor E.] Univ Amsterdam, Acad Med Ctr, Dept Endocrinol & Metab, NL-1105 AZ Amsterdam, Netherlands. [Packman, Seymour] Univ Calif San Francisco, Dept Pediat, Div Med Genet, San Francisco, CA 94143 USA. [Sorensen, Sven Asger] Univ Copenhagen, Dept Med Biochem & Genet, Neurogenet Sect, Copenhagen, Denmark. [Wilcox, William R.] Univ Calif Los Angeles, Sch Med, Dept Pediat, Cedars Sinai Med Ctr, Los Angeles, CA 90024 USA. [Wilcox, William R.] Univ Calif Los Angeles, Sch Med, Inst Med Genet, Los Angeles, CA 90024 USA. RP Desnick, RJ (reprint author), Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. EM robert.desnick@mssm.edu FU National Center for Research Resources of the National Institutes of Health (NIH); General Clinical Research Centers at the Mount Sinai School of Medicine [5 M01 RR00071]; Cedars-SinaiMedical Center [5 M01 RR00032] FX The authors are indebted to the patients whose data were included in this study, and to the physicians, nursing staffs and study coordinators who provided the patients' care at all the investigational sites. The authors would like to acknowledge the efforts of Hans Ebels (Genzyme Corporation) in assisting with the preparation of the manuscript for submission. In particular, the authors would like to acknowledge the principal investigators at the study sites for their contributions: United States of America - J. Barranger, Pittsburgh, PA; K. Brandspiegel, Elizabeth City, NC; D. Brennan, St Louis, MO; J. Charrow, Chicago, IL; C. M. Eng, Houston, TX; R. W. Erbe, Buffalo, NY; P. Fernhoff, Atlanta, GA; R. Finkel, Philadelphia, PA; R. Hopkin, Cincinnati, OH; M. C. Leary, Boston, MA; C. Schmitt, Everett, WA; K. B. Sims, Boston, MA; R. Steiner, Portland, OR; J. Thomas, Denver CO; N. Weinreb, Coral Springs, FL; Czech Republic - S. Magage, Prague; Canada - D. G. Bichet, Montreal, QC; A. Chan, Edmonton, Alberta; J. Clarke, Toronto, Ontario; S. Dyack, Halifax, Novo Scotia; P. Wyatt, Toronto, Ontario. Furthermore, the authors wish to thank the nursing staffs of the general clinical research centres at our institutions for their assistance with this study. Genzyme Corporation supported data collection by Abt Associates Clinical Trials. This work was funded in part by grants from the National Center for Research Resources of the National Institutes of Health (NIH) grants to the General Clinical Research Centers at the Mount Sinai School of Medicine (5 M01 RR00071), Cedars-SinaiMedical Center (5 M01 RR00032), University of California, San Francisco (5 M01 RR01271), and University of Alabama at Birmingham (5 M01 RR00032). These studies also were supported in part by the research program of the National Institute of Neurological Disorders and Stroke, and an NIH research grant (MERIT Award, 5 R37 DK34045) to R. J. D. WW was supported by the Winnick Family Clinical Development Scholar Award. The authors wish to thank Fanny O'Brien, PhD (senior director of Biostatistics, NR 38 TC 121 Z9 134 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0931-0509 J9 NEPHROL DIAL TRANSPL JI Nephrol. Dial. Transplant. PD JUL PY 2009 VL 24 IS 7 BP 2102 EP 2111 DI 10.1093/ndt/gfp031 PG 10 WC Transplantation; Urology & Nephrology SC Transplantation; Urology & Nephrology GA 460XR UT WOS:000267226500018 PM 19218538 ER PT J AU Wang, Y Greig, NH Yu, QS Mattson, MP AF Wang, Yue Greig, Nigel H. Yu, Qian-sheng Mattson, Mark P. TI Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices SO NEUROBIOLOGY OF AGING LA English DT Article DE NMDA; PS1KI mice; LTP; Butyrylcholinesterase; Alzheimer disease ID LONG-TERM POTENTIATION; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; TRANSGENIC MICE; IN-VIVO; RYANODINE RECEPTOR; RAT HIPPOCAMPUS; A-BETA; ACETYLCHOLINE-RECEPTORS; INTRACELLULAR CALCIUM AB Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid beta-peptide (A beta). However, A beta-independent effects of mutant PS1 on neuronal Ca(2+) homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances UP at CA1 synapses of normal mice, it impairs UP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenscrine to enhance UP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca(2+) chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies. Published by Elsevier Inc. C1 [Wang, Yue; Greig, Nigel H.; Yu, Qian-sheng; Mattson, Mark P.] Natl Inst Aging Intramural Res Program, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Aging Intramural Res Program, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wangyu@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural Research Program of the National Institute on Aging, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 51 TC 30 Z9 30 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2009 VL 30 IS 7 BP 1061 EP 1068 DI 10.1016/j.neurobiolaging.2007.10.009 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 453OI UT WOS:000266619800006 PM 18068871 ER PT J AU Strozyk, D Launer, LJ Adlard, PA Cherny, RA Tsatsanis, A Volitakis, I Blennow, K Petrovitch, H White, LR Bush, AI AF Strozyk, Dorothea Launer, Lenore J. Adlard, Paul A. Cherny, Robert A. Tsatsanis, Andrew Volitakis, Irene Blennow, Kai Petrovitch, Helen White, Lon R. Bush, Ashley I. TI Zinc and copper modulate Alzheimer A beta levels in human cerebrospinal fluid SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyloid; Alzheimer's disease; Metalloproteinase; Cerebrospinal fluid; Zinc; Copper; Iron; Manganese; Chromium ID AMYLOID-BETA; HYDROGEN-PEROXIDE; DISEASE; PROTEIN; CLIOQUINOL; PEPTIDE; AGGREGATION; MICE; IRON; DEGRADATION AB Abnormal interaction of beta-amyloid 42 (A beta 42) with copper, zinc and iron induce peptide aggregation and oxidation in Alzheimer's disease (AD). However, in health, A beta degradation is mediated by extracellular metalloproteinases, neprilysin, insulin degrading enzyme (IDE) and matrix metalloproteinases. We investigated the relationship between levels of A beta and biological metals in CSF. We assayed CSF copper, zinc, other metals and A beta 42 in ventricular autopsy samples of Japanese American men (N=131) from the population-based Honolulu Asia Aging Study. There was a significant inverse correlation of CSF A beta 42 with copper, zinc, iron, manganese and chromium. The association was particularly strong in the subgroup with high levels of both zinc and copper. Selenium and aluminum levels were not associated to CSF A beta 42. In vitro, the degradation of synthetic A beta substrate added to CSF was markedly accelerated by low levels (2 mu M) of exogenous zinc and copper. While excessive interaction with copper and zinc may induce neocortical A beta precipitation in AD, soluble A beta degradation is normally promoted by physiological copper and zinc concentrations. (C) 2007 Elsevier Inc. All rights reserved. C1 [Strozyk, Dorothea; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA. [Strozyk, Dorothea] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. [Adlard, Paul A.; Cherny, Robert A.; Tsatsanis, Andrew; Volitakis, Irene; Bush, Ashley I.] Univ Melbourne, Dept Pathol, Mental Hlth Res Inst Victoria, Melbourne, Vic 3010, Australia. [Blennow, Kai] Sahlgrens Univ Hosp, Dept Clin Neurosci, Molndal, Sweden. [Petrovitch, Helen; White, Lon R.] Kuakini Med Ctr, Pacific Hlth Res Inst, Honolulu, HI USA. [Bush, Ashley I.] Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol Demog & Biometry, Neuroepidemiol Sect, NIH, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov; abush@mhri.edu.au RI Bush, Ashley/A-1186-2007; OI Bush, Ashley/0000-0001-8259-9069; Volitakis, Irene/0000-0003-0766-817X FU NIH (National Institute on Aging) [1RO1 AG12686, 1 U01 AG19349-01, 5 R01 AG017155-04]; Intramural Research Program of the NIH; National Institute on Aging; Australian Research Council Federation Fellowship; National health and Medical Research Council of Australia; American Health Assistance Foundation; University of Melbourne; Mental Health Research Institute of Victoria, Victorian Forensic Institute of Medicine; Neurosciences Australia and the National Health & Medical Research Council FX This study was supported by NIH (National Institute on Aging); Grant Numbers 1RO1 AG12686 (to AIB), 1 U01 AG19349-01, 5 R01 AG017155-04, and in part by the Intramural Research Program of the NIH, National Institute on Aging, as well as (to AIB) the Australian Research Council Federation Fellowship, the National health and Medical Research Council of Australia, the Alzheimer Association Zenith Award and the American Health Assistance Foundation. The Victorian Brain Bank Network is supported by The University of Melbourne, The Mental Health Research Institute of Victoria, Victorian Forensic Institute of Medicine and funded by Neurosciences Australia and the National Health & Medical Research Council. NR 43 TC 68 Z9 71 U1 6 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL PY 2009 VL 30 IS 7 BP 1069 EP 1077 DI 10.1016/j.neurobiolaging.2007.10.012 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 453OI UT WOS:000266619800007 PM 18068270 ER PT J AU Nalls, MA Guerreiro, RJ Simon-Sanchez, J Bras, JT Traynor, BJ Gibbs, JR Launer, L Hardy, J Singleton, AB AF Nalls, M. A. Guerreiro, R. J. Simon-Sanchez, J. Bras, J. T. Traynor, B. J. Gibbs, J. R. Launer, L. Hardy, J. Singleton, A. B. TI Extended tracts of homozygosity identify novel candidate genes associated with late-onset Alzheimer's disease SO NEUROGENETICS LA English DT Article DE Alzheimer's disease; Homozygous regions; APOE; Genetics ID HUMAN GENOME; POPULATION; ALLELE; EPSILON-4; LOCI; APOE; INSULIN; RISK; RUNS AB Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer's disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD. C1 [Nalls, M. A.; Guerreiro, R. J.; Simon-Sanchez, J.; Bras, J. T.; Gibbs, J. R.; Singleton, A. B.] NIA, Mol Genet Sect, NIH, Bethesda, MD 20892 USA. [Nalls, M. A.; Guerreiro, R. J.; Simon-Sanchez, J.; Bras, J. T.; Gibbs, J. R.; Singleton, A. B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Guerreiro, R. J.; Bras, J. T.] Univ Coimbra, Ctr Neurosci & Cell Biol, Fac Med, P-3004504 Coimbra, Portugal. [Traynor, B. J.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Launer, L.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Hardy, J.] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Hardy, J.] UCL, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London WC1N 3BG, England. RP Singleton, AB (reprint author), NIA, Mol Genet Sect, NIH, Bldg 35,Room 1A1014,35 Convent Dr, Bethesda, MD 20892 USA. EM Singleta@mail.nih.gov RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Bras, Jose/D-3366-2009; Bras, Jose/A-1428-2011; Gibbs, J. Raphael/A-3984-2010; Guerreiro, Rita/A-1327-2011; Traynor, Bryan/G-5690-2010 FU National Institute on Aging; National Institutes of Health; Department of Health and Human Services [Z01 AG000950-06]; Portuguese Fundacao para a Ciencia e Tecnologia [SFRH/BD/29647/2006, SFRH/BD/27442/2006] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (Z01 AG000950-06) and the Portuguese Fundacao para a Ciencia e Tecnologia grants (SFRH/BD/29647/2006 and SFRH/BD/27442/2006). The experiments presented here comply with the current laws of the United States of America. The authors would like to thank the Translational Genomics Research Institute (TGen), in particular Dr. Eric Reiman and collaborators for publicly releasing the data that made this study possible. NR 32 TC 43 Z9 45 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD JUL PY 2009 VL 10 IS 3 BP 183 EP 190 DI 10.1007/s10048-009-0182-4 PG 8 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 457FL UT WOS:000266913800002 PM 19271249 ER PT J AU Hanna, MC Blackstone, C AF Hanna, Michael C. Blackstone, Craig TI Interaction of the SPG21 protein ACP33/maspardin with the aldehyde dehydrogenase ALDH16A1 SO NEUROGENETICS LA English DT Article DE Aldehyde dehydrogenase; ACP33; CD4; Spastic paraplegia; Endocytosis ID HEREDITARY SPASTIC PARAPLEGIA; SJOGREN-LARSSON-SYNDROME; GENE FAMILY; DEFICIENCY; ACID; HYDROLASE; LOCALIZATION; PATHOGENESIS; ASSOCIATION; SUPERFAMILY AB Mast syndrome (SPG21) is an autosomal-recessive complicated form of hereditary spastic paraplegia characterized by dementia, thin corpus callosum, white matter abnormalities, and cerebellar and extrapyramidal signs in addition to spastic paraparesis. A nucleotide insertion resulting in premature truncation of the SPG21 gene product acidic cluster protein 33 (ACP33)/maspardin underlies this disorder, likely causing loss of protein function. However, little is known about the function of maspardin. Here, we report that maspardin localizes prominently to cytoplasm as well as to membranes, possibly at trans-Golgi network/late endosomal compartments. Immunoprecipitation of maspardin with identification of coprecipitating proteins by mass spectrometry revealed the aldehyde dehydrogenase ALDH16A1 as an interacting protein. This interaction was confirmed using overexpressed proteins as well as by fusion protein pull down experiments, and these proteins colocalized in cells. Further studies of the function of ALDH16A1 and the role of the maspardin-ALDH16A1 interaction in neuronal cells may clarify the cellular pathogenesis of Mast syndrome. C1 [Hanna, Michael C.] Texas A&M Univ Commerce, Dept Biol & Environm Sci, Commerce, TX 75428 USA. [Hanna, Michael C.; Blackstone, Craig] Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Hanna, MC (reprint author), Texas A&M Univ Commerce, Dept Biol & Environm Sci, Commerce, TX 75428 USA. EM michael_hanna@tamu-commerce.edu; blackstc@ninds.nih.gov FU NIH; National Institutes of Neurological Disorders and Stroke FX The authors wish to thank Dr. Howard Jaffe (NINDS Protein/Peptide Sequencing Facility) for mass spectrometry, James Nagle and Debbie Kauffman (NINDS DNA Sequencing Facility) for DNA sequencing, and Henri Jupille and Julia Stadler for technical assistance. This study was supported by the Intramural Research Program of the NIH, National Institutes of Neurological Disorders and Stroke. NR 34 TC 20 Z9 24 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD JUL PY 2009 VL 10 IS 3 BP 217 EP 228 DI 10.1007/s10048-009-0172-6 PG 12 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 457FL UT WOS:000266913800006 PM 19184135 ER PT J AU Spiller, K Xi, ZX Li, X Ashby, CR Callahan, PM Tehim, A Gardner, EL AF Spiller, Krista Xi, Zheng-Xiong Li, Xia Ashby, Charles R., Jr. Callahan, Patrick M. Tehim, Ashok Gardner, Eliot L. TI Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of alpha 4 beta 2 nicotinic receptors in rats SO NEUROPHARMACOLOGY LA English DT Article DE Nicotine; Varenicline; Dopamine; alpha 4 beta 2 receptors; Reward; Addiction ID CONDITIONED PLACE PREFERENCE; DIHYDRO-BETA-ERYTHROIDINE; ACETYLCHOLINE-RECEPTOR; SMOKING-CESSATION; PARTIAL AGONIST; SUBUNIT COMPOSITION; DOPAMINE RELEASE; MICE; ALPHA-7; ANTAGONIST AB Varenicline, a partial alpha 4 beta 2 and full alpha 7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25-1.0 mg/kg, i.p.) or varenicline (0.03-3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03-1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-erythroicline (a relatively selective nicotinic alpha 4-containing receptor antagonist), but not methyllycaconitine (a selective alpha 7 receptor antagonist), suggesting an effect mediated by activation of alpha 4 beta 2 receptors. This suggestion is supported by findings that the alpha 4 beta 2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective alpha 7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of alpha 4 beta 2, but not alpha 7, receptors. Published by Elsevier Ltd. C1 [Spiller, Krista; Xi, Zheng-Xiong; Li, Xia; Gardner, Eliot L.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Ashby, Charles R., Jr.] St Johns Univ, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [Callahan, Patrick M.; Tehim, Ashok] Memory Pharmaceut, Montvale, NJ 07645 USA. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM zxi@mail.nih.gov FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH), U.S.A FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), U.S.A. NR 57 TC 32 Z9 32 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD JUL PY 2009 VL 57 IS 1 BP 60 EP 66 DI 10.1016/j.neuropharm.2009.04.006 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 467BO UT WOS:000267711400008 PM 19393252 ER PT J AU Fitzgerald, PJ AF Fitzgerald, Paul J. TI Neuromodulating mice and men: Are there functional species differences in neurotransmitter concentration? SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Serotonin; Norepinephrine; Dopamine; Acetylcholine; GABA; Glutamate; Prefrontal cortex; Microdialysis; Rodent; Macaque ID IN-VIVO MICRODIALYSIS; CAPILLARY LIQUID-CHROMATOGRAPHY; DOPAMINE SYSTEM REGULATION; MEDIAL PREFRONTAL CORTEX; DORSAL RAPHE; AMINO-ACIDS; HUMAN BRAIN; NOREPINEPHRINE RELEASE; FOOTSHOCK STRESS; RHESUS-MONKEY AB I examine evidence that the concentration of certain modulatory neurotransmitters varies across species, including differences between rodents and primates. Microdialysis Studies indicate that the baseline concentration of serotonin, norepinephrine, dopamine, and acetylcholine, as measured in the prefrontal cortex of awake animals, may differ between rats and macaque monkeys. These differences may extend to mice and humans, as well. if there are differences in the tonic concentration of these neurotransmitters, this may affect the functioning of these transmitter systems in multiple ways, including potential effects on neuropsychiatric conditions such as the various mental illnesses and modeling of them in animals. Species differences in transmitter concentration may also have neuropharmacological implications, and may be relevant to the phenomenon of differences in speed of drug response between humans and rodents. This paper is divided into three sections that address related questions about the potential concentration differences: (1) Are there species differences in baseline neurotransmitter concentration? (2) Are the Putative differences functional? (3) What might the functional differences be? Consideration of the existing evidence indicates that there may indeed be functional species differences in the modulatory transmitter systems. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Fitzgerald, Paul J.] Johns Hopkins Univ, Dept Neurosci, Zanvyl Krieger Mind Brain Inst, Baltimore, MD 21218 USA. RP Fitzgerald, PJ (reprint author), NIAAA, 5625 Fishers Lane,Room TS20, Rockville, MD 20852 USA. EM pfitz@mbi.mb.jhu.edu NR 66 TC 10 Z9 10 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD JUL PY 2009 VL 33 IS 7 BP 1037 EP 1041 DI 10.1016/j.neubiorev.2009.04.003 PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 475QM UT WOS:000268375300005 PM 19580916 ER PT J AU Pancrazio, JJ AF Pancrazio, Joseph J. TI National Institute of Neurological Disorders and Stroke support for brain-machine interface technology SO NEUROSURGICAL FOCUS LA English DT Article DE brain-machine interface; National Institute of Neurological Disorders and Stroke ID MOVEMENT AB Brain-machine interfaces (BMIs) offer the promise of restoring communication, enabling control of assistive devices, and allowing volitional control of extremities in paralyzed individuals. Working in multidisciplinary teams, neurosurgeons can play an invaluable role in the design, development, and demonstration of novel BMI technology. At the National Institutes of Health, the National Institute of Neurological Disorders and Stroke has a long history of supporting neural engineering and prosthetics efforts including BMI, and these research opportunities continue today. The author provides a brief overview of the opportunities and programs currently available to support BMI projects. (DOI:10.3171/2009.3.FOCUS0989) C1 NINDS, NIH, Rockville, MD 20892 USA. RP Pancrazio, JJ (reprint author), NINDS, NIH, NSC 2205,6001 Execut Blvd, Rockville, MD 20892 USA. EM pancrazj@ninds.nih.gov RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 FU Intramural NIH HHS [NIH0011642045]; PHS HHS [NIH0011642045] NR 8 TC 2 Z9 2 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1092-0684 J9 NEUROSURG FOCUS JI Neurosurg. Focus PD JUL PY 2009 VL 27 IS 1 AR E14 DI 10.3171/2009.3.FOCUS0989 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 478JI UT WOS:000268583300014 PM 19569889 ER PT J AU Gohlke, JM Stockton, P Sieber, S Foley, J Portier, CJ AF Gohlke, J. M. Stockton, P. Sieber, S. Foley, J. Portier, C. J. TI AhR-mediated gene expression in the developing mouse telencephalon SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the Neurobehavioral-Teratology-Society/49th Annual Meeting of the Teratology-Society/22nd Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 28-JUL 01, 2009 CL Rio Grande, PR SP Neurobehav Teratol Soc, Teratol Soc, Org Teratol Informat Specialists C1 [Gohlke, J. M.; Portier, C. J.] Natl Inst Environm Hlth Sci, Environm Syst Biol Grp, Mol Toxicol Lab, Res Triangle Pk, NC USA. [Stockton, P.; Foley, J.] Natl Inst Environm Hlth Sci, Lab Environm Pathol, Res Triangle Pk, NC USA. [Sieber, S.] Natl Inst Environm Hlth Sci, Microarray Grp, Mol Toxicol Lab, Res Triangle Pk, NC USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-SEP PY 2009 VL 31 IS 4 MA NBTS17 BP 241 EP 241 DI 10.1016/j.ntt.2009.04.021 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 461GY UT WOS:000267253900024 ER PT J AU Patterson, T Li, M Morris, S Rodriguez, J Slikker, W Mattison, D Paule, M AF Patterson, Tucker Li, Mi Morris, Suzanne Rodriguez, Jesse Slikker, William Mattison, Donald, Jr. Paule, Merle TI The effects of chronic methylphenidate treatment on the performance of rhesus monkeys in the NCTR operant test battery SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the Neurobehavioral-Teratology-Society/49th Annual Meeting of the Teratology-Society/22nd Annual Meeting of the Organization-of-Teratology-Information-Specialists CY JUN 28-JUL 01, 2009 CL Rio Grande, PR SP Neurobehav Teratol Soc, Teratol Soc, Org Teratol Informat Specialists C1 [Patterson, Tucker; Li, Mi; Rodriguez, Jesse; Paule, Merle] US FDA, Natl Ctr Toxicol Res, Div Neurotoxicol, Jefferson, AR 72079 USA. [Morris, Suzanne] US FDA, Natl Ctr Toxicol Res, Div Genet & Reprod Toxicol, Jefferson, AR 72079 USA. [Slikker, William] US FDA, Natl Ctr Toxicol Res, Off Director, Jefferson, AR 72079 USA. [Mattison, Donald, Jr.] NICHHD, Rockville, MD USA. RI Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD JUL-SEP PY 2009 VL 31 IS 4 MA NBTS45 BP 248 EP 248 DI 10.1016/j.ntt.2009.04.049 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 461GY UT WOS:000267253900052 ER PT J AU Botello-Harbaum, MT Haynie, DL Iannotti, RJ Wang, J Gase, L Simons-Morton, B AF Botello-Harbaum, Maria T. Haynie, Denise L. Iannotti, Ronald J. Wang, Jing Gase, Lauren Simons-Morton, Bruce TI Tobacco control policy and adolescent cigarette smoking status in the United States SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID INDOOR AIR LAWS; YOUTH-ACCESS; SOCIOECONOMIC-STATUS; RATING SYSTEM; PROGRESSION; BEHAVIOR; SCHOOL; RESTRICTIONS; INITIATION; LOCATIONS AB Tobacco policies that limit the sale of cigarettes to minors and restrict smoking in public places are important strategies to deter youth from accessing and consuming cigarettes. We examined the relationship of youth cigarette smoking status to state-level youth access and clean indoor air laws, controlling for sociodemographic characteristics and cigarette price. Data were analyzed from the 2001 to 2002 U.S. Health Behavior in School-Aged Children survey, a cross-sectional survey conducted with a nationally representative sample of 13,339 students in the United States. Compared with students living in states with strict regulations, those living in states with no or minimal restrictions, particularly high school students, were more likely to be daily smokers. These effects were somewhat reduced when logistic regressions were adjusted for sociodemographic characteristics and cigarette price, suggesting that higher cigarette prices may discourage youth to access and consume cigarettes independent of other tobacco control measures. Strict tobacco control legislation could decrease the potential of youth experimenting with cigarettes or becoming daily smokers. The findings are consistent with the hypothesis that smoking policies, particularly clean indoor air provisions, reduce smoking prevalence among high school students. C1 [Botello-Harbaum, Maria T.] Consumer Reports Best Buy Drugs, Washington, DC 20036 USA. [Haynie, Denise L.; Iannotti, Ronald J.; Wang, Jing; Gase, Lauren; Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. RP Botello-Harbaum, MT (reprint author), Consumer Reports Best Buy Drugs, 1101 17th St NW,Suite 500, Washington, DC 20036 USA. EM mbotello@consumer.org OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 FU National Institutes of Health; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Health Resources and Services Administration FX This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Health Resources and Services Administration NR 52 TC 30 Z9 30 U1 2 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUL PY 2009 VL 11 IS 7 BP 875 EP 885 DI 10.1093/ntr/ntp081 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 463OR UT WOS:000267442000015 PM 19443786 ER PT J AU Parascandola, M Augustson, E O'Connell, ME Marcus, S AF Parascandola, Mark Augustson, Erik O'Connell, Mary E. Marcus, Stephen TI Consumer awareness and attitudes related to new potential reduced-exposure tobacco product brands SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID HARM REDUCTION; HEALTH INFORMATION; PERCEPTIONS; PREPS; RISK; CIGARETTES; BELIEFS; SCIENCE; SMOKER; THINK AB In recent years, there has been a proliferation of potential reduced-exposure tobacco products (PREPs) marketed that claim to be less harmful or less addictive, compared with conventional cigarettes. Tobacco control scientists have raised concerns about the potential adverse impact of marketing of these products for smoking prevention and cessation efforts. Although these products have not been widely used among smokers, there are few data available on consumers' awareness and attitudes toward these products. Data were obtained from the 2003 and 2005 Health Information National Trends Survey, a nationally representative telephone survey of adults 18 years and older regarding health communication and associated beliefs and behaviors. Our study population consisted of 6,369 respondents in 2003 and 5,586 respondents in 2005, of whom 19% were current smokers and 28% were former smokers. In 2005, 45% of respondents had heard of at least one PREP product, while only 4.8% had actually tried one. Awareness and use were substantially higher among current smokers (55.6% and 12.7%). Awareness was highest for Marlboro Ultra Smooth (MUS) (30.2%), Eclipse (18.2%), Quest (7.8%), and Ariva (5.4%), while less than 2% for any other product. Of respondents who had tried a PREP, 50% cited harm reduction or assistance in quitting as a reason for trying the product and 30% believed that the product was less harmful than their usual brand. In the combined 2003 and 2005 dataset, 54.4% of current smokers stated that they would be "very" or "somewhat" interested in trying a cigarette advertised as less harmful, while only 3.2% of former smokers and 1.1% of never-smokers were interested. Among current smokers, interest was higher in females and non-Hispanic Whites, and among daily smokers, those who smoked 20 or more cigarettes per day and those who were not considering quitting. Smokers interested in PREPs were substantially more likely to rate their perceived lung cancer risk as high (40.3% vs. 8.3%) and to worry frequently about developing lung cancer (19.7% vs. 4%). These results suggest that there is a substantial level of interest among current smokers in cigarettes marketed with claims of reduced exposure or harm. Of particular concern is that "health conscious" smokers and heavy smokers not planning to quit may be especially vulnerable to PREP marketing messages and view such products as an alternative to smoking cessation. C1 [Parascandola, Mark] NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. [O'Connell, Mary E.] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Bethesda, MD 20892 USA. RP Parascandola, M (reprint author), NCI, Tobacco Control Res Branch, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,Room 4039, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov FU NCI NIH HHS [N01CO12400] NR 35 TC 10 Z9 10 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUL PY 2009 VL 11 IS 7 BP 886 EP 895 DI 10.1093/ntr/ntp082 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 463OR UT WOS:000267442000016 PM 19541949 ER PT J AU Kumari, D Somma, V Nakamura, AJ Bonner, WM D'Ambrosio, E Usdin, K AF Kumari, Daman Somma, Valentina Nakamura, Asako J. Bonner, William M. D'Ambrosio, Ettore Usdin, Karen TI The role of DNA damage response pathways in chromosome fragility in Fragile X syndrome SO NUCLEIC ACIDS RESEARCH LA English DT Article ID LINKED MENTAL-RETARDATION; SITE STABILITY; CGG-REPEAT; MOLECULAR CHARACTERIZATION; ATAXIA-TELANGIECTASIA; TRINUCLEOTIDE REPEATS; MACRO-ORCHIDISM; OVARIAN-CANCER; POTENTIAL ROLE; GENE AB FRAXA is one of a number of fragile sites in human chromosomes that are induced by agents like fluorodeoxyuridine (FdU) that affect intracellular thymidylate levels. FRAXA coincides with a > 200 CGG center dot CCG repeat tract in the 5' UTR of the FMR1 gene, and alleles prone to fragility are associated with Fragile X (FX) syndrome, one of the leading genetic causes of intellectual disability. Using siRNA depletion, we show that ATR is involved in protecting the genome against FdU-induced chromosome fragility. We also show that FdU increases the number of gamma-H2AX foci seen in both normal and patient cells and increases the frequency with which the FMR1 gene colocalizes with these foci in patient cells. In the presence of FdU and KU55933, an ATM inhibitor, the incidence of chromosome fragility is reduced, suggesting that ATM contributes to FdU-induced chromosome fragility. Since both ATR and ATM are involved in preventing aphidicolin-sensitive fragile sites, our data suggest that the lesions responsible for aphidicolin-induced and FdU-induced fragile sites differ. FRAXA also displays a second form of chromosome fragility in absence of FdU, which our data suggest is normally prevented by an ATM-dependent process. C1 [Kumari, Daman; Usdin, Karen] NIDDKD, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. [Somma, Valentina; D'Ambrosio, Ettore] CNR, Ist Neurobiol & Med Mol, I-00143 Rome, Italy. [Nakamura, Asako J.; Bonner, William M.] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDKD, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU National Institutes of Health FX Funding for open access charge: Intramural program of the NIDDK, National Institutes of Health. NR 54 TC 8 Z9 8 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL PY 2009 VL 37 IS 13 BP 4385 EP 4392 DI 10.1093/nar/gkp391 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 475BW UT WOS:000268331800026 PM 19465392 ER PT J AU Cer, RZ Mudunuri, U Stephens, R Lebeda, FJ AF Cer, R. Z. Mudunuri, U. Stephens, R. Lebeda, F. J. TI IC50-to-K-i: a web-based tool for converting IC50 to K-i values for inhibitors of enzyme activity and ligand binding SO NUCLEIC ACIDS RESEARCH LA English DT Article ID FLUORESCENCE POLARIZATION; PRUSOFF; EQUATIONS; AFFINITY; SCHILD; ASSAY AB A new web-server tool estimates K-i values from experimentally determined IC50 values for inhibitors of enzymes and of binding reactions between macromolecules (e.g. proteins, polynucleic acids) and ligands. This converter was developed to enable end users to help gauge the quality of the underlying assumptions used in these calculations which depend on the type of mechanism of inhibitor action and the concentrations of the interacting molecular species. Additional calculations are performed for nonclassical, tightly bound inhibitors of enzyme-substrate or of macromolecule-ligand systems in which free, rather than total concentrations of the reacting species are required. Required user-defined input values include the total enzyme (or another target molecule) and substrate (or ligand) concentrations, the K-m of the enzyme-substrate (or the K-d of the target-ligand) reaction, and the IC50 value. Assumptions and caveats for these calculations are discussed along with examples taken from the literature. The host database for this converter contains kinetic constants and other data for inhibitors of the proteolytic clostridial neurotoxins (http://botdb. abcc.ncifcrf.gov/toxin/kiConverter.jsp). C1 [Lebeda, F. J.] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Cer, R. Z.; Mudunuri, U.; Stephens, R.] NCI, SAIC Frederick Inc, Adv Technol Program, Adv Biomed Comp Ctr, Ft Detrick, MD 21702 USA. RP Lebeda, FJ (reprint author), USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. EM frank.lebeda@amedd.army.mil FU Defense Threat Reduction Agency Joint Science and Technology Office-Chemical Biological Defense [3.10043_07_RD_B]; National Cancer Institute; National Institutes of Health [HHSN261200800001E]; Defense Threat Reduction Agency FX The Defense Threat Reduction Agency Joint Science and Technology Office-Chemical Biological Defense (project 3.10043_07_RD_B to F. J. L.); and by the National Cancer Institute, National Institutes of Health (contract No. HHSN261200800001E). Funding for open access charge: Defense Threat Reduction Agency. NR 18 TC 101 Z9 101 U1 1 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2009 VL 37 SU S BP W441 EP W445 DI 10.1093/nar/gkp253 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469IG UT WOS:000267889100077 PM 19395593 ER PT J AU Wang, YL Xiao, JW Suzek, TO Zhang, J Wang, JY Bryant, SH AF Wang, Yanli Xiao, Jewen Suzek, Tugba O. Zhang, Jian Wang, Jiyao Bryant, Stephen H. TI PubChem: a public information system for analyzing bioactivities of small molecules SO NUCLEIC ACIDS RESEARCH LA English DT Article ID BINDING AFFINITIES; NIH ROADMAP; DATABASE; TOOL AB PubChem (http://pubchem.ncbi.nlm.nih.gov) is a public repository for biological properties of small molecules hosted by the US National Institutes of Health (NIH). PubChem BioAssay database currently contains biological test results for more than 700 000 compounds. The goal of PubChem is to make this information easily accessible to biomedical researchers. In this work, we present a set of web servers to facilitate and optimize the utility of biological activity information within PubChem. These web-based services provide tools for rapid data retrieval, integration and comparison of biological screening results, exploratory structure-activity analysis, and target selectivity examination. This article reviews these bioactivity analysis tools and discusses their uses. Most of the tools described in this work can be directly accessed at http://pubchem.ncbi.nlm.nih.gov/assay/. URLs for accessing other tools described in this work are specified individually. C1 [Wang, Yanli; Xiao, Jewen; Suzek, Tugba O.; Zhang, Jian; Wang, Jiyao; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Bryant, SH (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM bryant@ncbi.nlm.nih.gov RI Suzek, Tugba/B-6943-2015; OI Suzek, Tugba/0000-0002-3243-1759 FU Intramural Research program (National Institutes of Health) FX Intramural Research program (National Institutes of Health). Funding for open access charge: National Institutes of Health. NR 15 TC 440 Z9 450 U1 1 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2009 VL 37 BP W623 EP W633 DI 10.1093/nar/gkp456 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469IG UT WOS:000267889100108 PM 19498078 ER PT J AU Xu, ZL Taylor, JA AF Xu, Zongli Taylor, Jack A. TI SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GENOME-WIDE ASSOCIATION; EXONIC SPLICING ENHANCERS; FACTOR-BINDING SITES; PROSTATE-CANCER; SEQUENCES; SINGLE; DNA AB We have developed a set of web-based SNP selection tools (freely available at http://www.niehs.nih.gov/snpinfo) where investigators can specify genes or linkage regions and select SNPs based on GWAS results, linkage disequilibrium (LD), and predicted functional characteristics of both coding and non-coding SNPs. The algorithm uses GWAS SNP P-value data and finds all SNPs in high LD with GWAS SNPs, so that selection is from a much larger set of SNPs than the GWAS itself. The program can also identify and choose tag SNPs for SNPs not in high LD with any GWAS SNP. We incorporate functional predictions of protein structure, gene regulation, splicing and miRNA binding, and consider whether the alternative alleles of a SNP are likely to have differential effects on function. Users can assign weights for different functional categories of SNPs to further tailor SNP selection. The program accounts for LD structure of different populations so that a GWAS study from one ethnic group can be used to choose SNPs for one or more other ethnic groups. Finally, we provide an example using prostate cancer and demonstrate that this algorithm can select a small panel of SNPs that include many of the recently validated prostate cancer SNPs. C1 [Xu, Zongli; Taylor, Jack A.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Taylor, Jack A.] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Taylor, JA (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. EM xuz@niehs.nih.gov; taylor@niehs.nih.gov OI xu, zongli/0000-0002-9034-8902; taylor, jack/0000-0001-5303-6398 FU NIH FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. Funding for open access charge: National Institute of Environmental Health Sciences. NR 26 TC 265 Z9 274 U1 6 U2 23 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUL 1 PY 2009 VL 37 BP W600 EP W605 DI 10.1093/nar/gkp290 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 469IG UT WOS:000267889100104 PM 19417063 ER PT J AU Yeum, KJ Beretta, G Krinsky, NI Russell, RM Aldini, G AF Yeum, Kyung-Jin Beretta, Giangiacomo Krinsky, Norman I. Russell, Robert M. Aldini, Giancarlo TI Synergistic interactions of antioxidant nutrients in a biological model system SO NUTRITION LA English DT Article DE Antioxidant network; Synergistic interaction; Total antioxidant performance ID LOW-DENSITY-LIPOPROTEIN; CAROTENOID RADICAL CATIONS; ALPHA-TOCOPHEROL; VITAMIN-C; BETA-CAROTENE; LIPID-PEROXIDATION; SINGLET OXYGEN; URIC-ACID; PLASMA; OXIDATION AB Objective: The antioxidant activity of fat- and water-soluble antioxidant nutrients and their interactions in physiologic concentrations were determined in an in vitro biological model system. Methods: Reconstituted human serum consisting of delipidized human serum (DHS) combined with phosphatidylcholine liposomes (PCL) was used to determine antioxidant activities of physiologic concentrations of antioxidant nutrients. Radicals were initiated with 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (2 mmol/L), and oxidation was monitored by 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid. Fat-soluble antioxidant nutrients were incorporated into the PCL prepared by sonication and suspended in DHS to avoid any interference by the endogenous fat-soluble antioxidants. Water-soluble antioxidants were added directly into the DHS. The oxidation kinetics were monitored every 5 min up to 2 10 min using a microplate reader (excitation wavelength 500 nm, emission wavelength 520 nm). Results: We confirmed the synergistic protective effect of the combination of ascorbic acid (1-5 mu M) and a-tocopherol (1-5 mu M) against the oxidation of DHS with PCL. Furthermore, physiologic concentrations of 1) beta-carotene (0.1, 0.5 mu M) and alpha-tocopherol (2.5, 5.0 mu M), 2) beta-carotene (0.1, 0.5 mu M) and ascorbic acid (2.5 mu M), and 3) uric acid (10 uM) and a-tocopherol (2.5, 5.0 mu M) synergistically protected oxidation of reconstituted human serum. Conclusion: The present study results suggest a wide antioxidant network between water- and fat-soluble antioxidant nutrients in a biological system, although their actions in vivo warrant further study. (C) 2009 Elsevier Inc. All rights reserved. C1 [Yeum, Kyung-Jin; Krinsky, Norman I.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Beretta, Giangiacomo; Aldini, Giancarlo] Univ Milan, Fac Pharm, Dept Pharmaceut Sci, Milan, Italy. [Krinsky, Norman I.; Russell, Robert M.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Russell, Robert M.] NIH, Off Director, Washington, DC USA. RP Yeum, KJ (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM kyungjin.yeum@tufts.edu RI Beretta, Giangiacomo/D-3861-2011; OI Beretta, Giangiacomo/0000-0003-0987-0857; aldini, giancarlo/0000-0002-2355-6744 FU National Eye Institute [R03EY015674]; BioGreen 21 Program [20070301034009]; Rural Development Administration, Korea; U.S. Department of Agriculture [581950-9-001] FX This research was supported in part by grant R03EY015674 from the National Eye Institute, BioGreen 21 Program (Code, 20070301034009), the Rural Development Administration, Korea, and the U.S. Department of Agriculture, under agreement 581950-9-001. NR 37 TC 25 Z9 26 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD JUL-AUG PY 2009 VL 25 IS 7-8 BP 839 EP 846 DI 10.1016/j.nut.2009.01.011 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 465II UT WOS:000267576100016 PM 19398299 ER PT J AU Brownawell, AM Harris, WS Hibbeln, JR Klurfeld, DM Newton, I Yates, A AF Brownawell, Amy M. Harris, William S. Hibbeln, Joseph R. Klurfeld, David M. Newton, Ian Yates, Allison TI Assessing the environment for regulatory change for eicosapentaenoic acid and docosahexaenoic acid nutrition labeling SO NUTRITION REVIEWS LA English DT Review DE cardiovascular disease (CVD); dietary reference intake (DRI); docosahexaenoic acid (DHA); eicosapentaenoic acid (EPA); mood-stabilizing effects ID ESSENTIAL FATTY-ACIDS; CORONARY-HEART-DISEASE; LINOLENIC ACID; N-3; DEFICIENCY; OMEGA-3-FATTY-ACIDS; TRIACYLGLYCEROL; SECRETION; FISH AB This review examines issues related to the development of a recommended daily allowance or adequate intake, two of the categories of dietary reference intakes, for the long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3). Although some have suggested a dietary intake of two servings of fatty fish per week or supplement intake of 500 mg/day EPA plus DHA, based on evidence from epidemiologic and clinical studies of cardiovascular benefit from regular fish or fish-oil consumption, supplementation with EPA and/or DHA may also have antidepressant and mood-stabilizing effects. Omega-3 PUFA biology is complex and chronic disease outcomes are sometimes difficult to prove, yet the possibility of benefit for a substantial portion of the population from increased omega-3 PUFA intake is a public health issue that must be addressed responsibly and be based on significant scientific evidence. C1 [Brownawell, Amy M.] Life Sci Res Off, Bethesda, MD 20814 USA. [Harris, William S.] Univ S Dakota, Sch Med, Sioux Falls, SD USA. [Hibbeln, Joseph R.] NIAAA, Bethesda, MD USA. [Klurfeld, David M.; Yates, Allison] USDA ARS, Beltsville, MD USA. [Newton, Ian] Ceres Consulting, Markham, ON, Canada. RP Brownawell, AM (reprint author), Life Sci Res Off, 9650 Rockville Pike, Bethesda, MD 20814 USA. EM brownawella@lsro.org FU Global Organization for EPA and DHA Omega-3 (GOED) FX The Life Sciences Research Office Workshop held on May, 1 2008, in Bethesda, Maryland, and this manuscript have been supported by funding from the Global Organization for EPA and DHA Omega-3 (GOED). Workshop details and speaker presentations can be found at http://www.LSRO.org. NR 41 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD JUL PY 2009 VL 67 IS 7 BP 391 EP 397 DI 10.1111/j.1753-4887.2009.00212.x PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 463JG UT WOS:000267427600003 PM 19566599 ER PT J AU Sacks, FM Bray, GA Carey, VJ Smith, SR Ryan, DH Anton, SD McManus, K Champagne, CM Bishop, LM Laranjo, N Leboff, MS Rood, JC de Jonge, L Greenway, FL Loria, CM Obarzanek, E Williamson, DA AF Sacks, Frank M. Bray, George A. Carey, Vincent J. Smith, Steven R. Ryan, Donna H. Anton, Stephen D. McManus, Katherine Champagne, Catherine M. Bishop, Louise M. Laranjo, Nancy Leboff, Meryl S. Rood, Jennifer C. de Jonge, Lilian Greenway, Frank L. Loria, Catherine M. Obarzanek, Eva Williamson, Donald A. TI Comparison of Weight-Loss Diets With Different Compositions of Fat, Protein, and Carbohydrates EDITORIAL COMMENT SO OBSTETRICAL & GYNECOLOGICAL SURVEY LA English DT Editorial Material C1 [Sacks, Frank M.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Channing Labs, Boston, MA USA. Div Endocrine, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Nutr, Boston, MA 02115 USA. Louisiana State Univ Syst, Pennington Biomed Res Ctr, Baton Rouge, LA USA. NHLBI, Bethesda, MD 20892 USA. RP Sacks, FM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7828 J9 OBSTET GYNECOL SURV JI Obstet. Gynecol. Surv. PD JUL PY 2009 VL 64 IS 7 BP 460 EP 462 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 463AQ UT WOS:000267401100017 ER PT J AU Fonseca, L Ramin, SM Mele, L Wapner, RJ Johnson, F Peaceman, AM Sorokin, Y Dudley, DJ Spong, CY Leveno, KJ Caritis, SN Miodovnik, M Mercer, B Thorp, JM O'Sullivan, MJ Carpenter, MW Rouse, DJ Sibai, B AF Fonseca, Linda Ramin, Susan M. Mele, Lisa Wapner, Ronald J. Johnson, Francee Peaceman, Alan M. Sorokin, Yoram Dudley, Donald J. Spong, Catherine Y. Leveno, Kenneth J. Caritis, Steve N. Miodovnik, Menachem Mercer, Brian Thorp, John M. O'Sullivan, Mary Jo Carpenter, Marshall W. Rouse, Dwight J. Sibai, Baha CA NICHD MFMU TI Bone Metabolism in Fetuses of Pregnant Women Exposed to Single and Multiple Courses of Corticosteroids SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 14-17, 2007 CL Reno, NV SP Soc Gynecol Invest ID I COLLAGEN; GESTATIONAL-AGE; CARBOXYTERMINAL PROPEPTIDE; ANTENATAL CORTICOSTEROIDS; GLUCOCORTICOID TREATMENT; BIOCHEMICAL MARKERS; PRETERM INFANTS; SERUM MARKERS; THERAPY; DEGRADATION AB OBJECTIVE: To estimate the effect of single and recurrent doses of antenatal corticosteroids on fetal bone metabolism. METHODS: This was a secondary analysis of a cohort of pregnant women from a previously reported randomized, placebo-controlled, multicenter trial of women at risk for preterm delivery who received weekly courses of betamethasone (active) or placebo after an initial course of corticosteroids. Umbilical cord serum levels of carboxy-terminal carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I procollagen were measured to assess the rate of fetal bone formation and resorption, respectively. Analysis was stratified according to number of repeat antenatal study courses of betamethasone or placebo (one to three compared with at least four courses, not including the initial course). RESULTS: Of the 251 umbilical cord serum samples, the median serum carboxy-terminal telopeptide of type I procollagen levels, but not carboxy-terminal propeptide of type I procollagen levels, was significantly lower with repeat betamethasone exposure (55.0 compared with 57.9 micrograms/L, P=.01). In the fetuses exposed to at least four repeat study courses, there was a significant decrease in median carboxy-terminal telopeptide of type-l procollagen levels between repeat betamethasone exposure and placebo (53.4 compared with 58.6 micrograms/L, respectively, P=.04), but there was no difference between groups in the fetuses exposed to 1-3 repeat study courses (57.4 compared with 56.7 micrograms/L, respectively, P=.29). CONCLUSION: Levels of umbilical cord serum markers of bone resorption but not formation are reduced in fetuses exposed to repeat courses of antenatal betamethasone. Up to four courses of antenatal betamethasone do not seem to affect fetal bone metabolism. (Obstet Gynecol 2009;114:38-44) C1 [Fonseca, Linda] Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Drexel Univ, Dept Obstet & Gynecol, Coll Med, Philadelphia, PA 19104 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. NICHHD, Bethesda, MD 20892 USA. Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA USA. Columbia Univ, Dept Obstet & Gynecol, New York, NY USA. Univ Cincinnati, Cincinnati, OH USA. Case Western Reserve Univ, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Miami, Dept Obstet & Gynecol, Miami, FL USA. Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. RP Fonseca, L (reprint author), Univ Texas Hlth Sci Ctr Houston, Dept Obstet Gynecol & Reprod Sci, Houston, TX USA. EM l-fonseca@northwestern.edu OI caritis, steve/0000-0002-2169-0712; Peaceman, Alan/0000-0002-4515-4850 FU NCRR NIH HHS [M01 RR000080, M01 RR000080-45]; NICHD NIH HHS [U10 HD027915, R24 HD050924, U01 HD036801, U10 HD021410, U10 HD021410-22, U10 HD021414-15, U10 HD027860, U10 HD027860-15, U10 HD027861-10, U10 HD027869, U10 HD027869-10, U10 HD027905, U10 HD027905-10, U10 HD027915-18, U10 HD027917, U10 HD027917-18, U10 HD034116, U10 HD034116-13, U10 HD034122, U10 HD034122-05, U10 HD034136, U10 HD034136-07, U10 HD034208, U10 HD034208-12, U10 HD036801, U10 HD036801-11, U10 HD040485, U10 HD040485-09, U10 HD040500, U10 HD040500-08, U10 HD040512, U10 HD040512-09, U10 HD040544, U10 HD040544-09, U10 HD040545, U10 HD040545-09, U10 HD040560, U10 HD040560-09, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 22 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2009 VL 114 IS 1 BP 38 EP 44 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 463BX UT WOS:000267404500007 PM 19546756 ER PT J AU Castle, P AF Castle, Philip TI Cervical Cancers After Human Papillomavirus Vaccination SO OBSTETRICS AND GYNECOLOGY LA English DT Letter ID WOMEN C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Castle, P (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 6 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUL PY 2009 VL 114 IS 1 BP 174 EP 174 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 463BX UT WOS:000267404500041 PM 19546791 ER PT J AU Li, QDQ Wang, GD Zhang, MC Cuff, CF Huang, L Reed, E AF Li, Qingdi Q. Wang, Gangduo Zhang, Manchao Cuff, Christopher F. Huang, Lan Reed, Eddie TI beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis SO ONCOLOGY REPORTS LA English DT Article DE beta-elemene; plant drug; Chinese medicine; cisplatin; lung cancer; apoptosis ID BREAST-CANCER CELLS; CYTOCHROME-C; POLY(ADP-RIBOSE) POLYMERASE; INHIBITORY PROTEIN; BCL-2 PROTEIN; CYCLE ARREST; ANNEXIN-V; DEATH; CHEMOTHERAPY; CLEAVAGE AB beta-Elemene, a new plant-derived anticancer agent with low toxicity, has been reported to be effective in the treatment of leukemia and solid tumors. In the current study, we explored the therapeutic application of beta-elemene in sensitizing lung cancer cells to cisplatin. beta-Elemene considerably enhanced the inhibitory effect of cisplatin on cell proliferation in a time- and dose-dependent manner in the human non-small cell lung cancer (NSCLC) cell lines H460 and A549. Furthermore, this effect of beta-elemene on cisplatin activity occurred through the induction of apoptosis in NSCLC cells, as assessed by an ELISA-based assay, TUNEL assay and annexin V binding assay. Consistent with these results, the protein levels of Bax and phospho-Bcl-2 increased and those of Bcl-2 and XIAP decreased in cells treated with beta-elemene in combination with cisplatin, compared with the levels in cells treated with either agent alone. Finally, beta-elemene augmented the cisplatin-induced increases in caspase-3, -7, -9 and -10 activities and cleaved caspase-3, -9 and poly(ADP-ribose) polymerase levels in NSCLC cells. These observations suggest that beta-elemene sensitizes NSCLC cells to cisplatin via a mitochondria-mediated intrinsic apoptosis pathway involving Bcl-2 family proteins and IAPs (inhibitor of apoptosis proteins). Our data provide a rationale for developing a combination of beta-elemene and cisplatin as a regimen for the treatment of lung carcinoma and other cisplatin-resistant tumors. C1 [Li, Qingdi Q.] NIH, Bethesda, MD 20892 USA. [Li, Qingdi Q.; Wang, Gangduo; Zhang, Manchao; Cuff, Christopher F.] W Virginia Univ, Sch Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Li, Qingdi Q.; Wang, Gangduo; Zhang, Manchao; Cuff, Christopher F.] W Virginia Univ, Sch Med, Robert C Byrd Hlth Sci Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. [Huang, Lan] HYWE Pharmaceut Corp, Berkeley Hts, NJ 07922 USA. [Reed, Eddie] Univ S Alabama, Mitchell Canc Inst, Mobile, AL 36604 USA. RP Li, QDQ (reprint author), NIH, Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM liquenti@mail.nih.gov FU National Institutes of Health [P20RR16440-010003]; Long Range International Ltd USA, Inc. FX We thank Dr Cynthia Cunningham for technical assistance during the FACS measurements. This study was partly supported by grants from the National Institutes of Health (No. P20RR16440-010003 to Q.Q.L.) and Long Range International Ltd USA, Inc. (to Q.Q.L.). NR 56 TC 45 Z9 51 U1 2 U2 17 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUL PY 2009 VL 22 IS 1 BP 161 EP 170 DI 10.3892/or_00000420 PG 10 WC Oncology SC Oncology GA 461IQ UT WOS:000267259100023 PM 19513519 ER PT J AU Ding, XY Patel, M Herzlich, AA Sieving, PC Chan, CC AF Ding, Xiaoyan Patel, Mrinali Herzlich, Alexandra A. Sieving, Pamela C. Chan, Chi-Chao TI Ophthalmic Pathology of Nance-Horan Syndrome: Case Report and Review of the Literature SO OPHTHALMIC GENETICS LA English DT Article DE Nance-Horan syndrome; eye pathology; cataract; glaucoma; retinal cystoid retinopathy ID X-LINKED CATARACT; LINKAGE ANALYSIS; CONGENITAL CATARACT; BILATERAL CATARACT; MENTAL-RETARDATION; DENTAL ANOMALIES; CANDIDATE GENES; 4 FAMILIES; NHS GENE; EXPRESSION AB Background: Nance-Horan syndrome (NHS) is a rare X-linked disorder typified by dense congenital central cataracts, microcornea, anteverted and simplex pinnae, brachymetacarpalia, and numerous dental anomalies due in most cases to a mutation in the NHS gene. Material and Methods: We present a case of clinical manifestation and ocular pathology in a patient with NHS. This article also reviews and discusses the relevant literature. Results: Classic and novel ocular pathological findings of a young male with NHS are described, including congenital cataracts, infantile glaucoma, scleral staphyloma, and severe retinal cystoid degeneration. Conclusions: We report a new pathological finding of severe retinal cystoid degeneration in this NHS patient and confirm abnormal development of the anterior chamber angle structure. These findings, coupled with our analysis of the available NHS literature, provide new understanding of the histopathological basis of ocular abnormalities and vision loss in NHS. C1 [Chan, Chi-Chao] NEI, NIH, Immunopathol Sect, Immunol Lab, Bethesda, MD 20892 USA. [Ding, Xiaoyan] Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510275, Guangdong, Peoples R China. [Patel, Mrinali] Howard Hughes Med Inst, Chevy Chase, MD USA. [Sieving, Pamela C.] Natl Inst Hlth Lib, NIH, Bethesda, MD USA. RP Chan, CC (reprint author), NEI, NIH, Immunopathol Sect, Immunol Lab, 10 Ctr Dr,10-10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov OI Sieving, Pamela/0000-0003-3794-5000 FU NEI intramural research program FX The study was supported by the NEI intramural research program. Sincere appreciation is extended to the families described here for their willing and continuing cooperation in these investigations. Dr. Richard A. Lewis reviewed the manuscript. NR 37 TC 7 Z9 7 U1 0 U2 4 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1381-6810 J9 OPHTHALMIC GENET JI Ophthalmic Genet. PD JUL-AUG PY 2009 VL 30 IS 3 BP 127 EP 135 DI 10.1080/13816810902822021 PG 9 WC Genetics & Heredity; Ophthalmology SC Genetics & Heredity; Ophthalmology GA 497DG UT WOS:000270034000003 PM 19941417 ER PT J AU Patel, V Hood, BL Molinolo, AA Lee, NL Veenstra, TD Gutkind, JS AF Patel, V. Hood, B. L. Molinolo, A. A. Lee, N. L. Veenstra, T. D. Gutkind, J. S. TI Proteomic analysis of laser-captured paraffin-embedded tissues: A molecular portrait of head and neck cancer progression SO ORAL ONCOLOGY LA English DT Meeting Abstract CT 2nd World Congress of the International-Academy-of-Oral-Oncology CY JUL 08-11, 2009 CL Toronto, CANADA SP Int Acad Oral Oncol C1 [Hood, B. L.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. [Lee, N. L.] George Washington Univ, Med Ctr, Washington, DC 20052 USA. [Veenstra, T. D.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2009 BP 68 EP 69 DI 10.1016/j.oos.2009.06.123 PG 5 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 509KJ UT WOS:000271015100079 ER PT J AU Czerninski, RC Amornphimoltham, P Patel, V Molinolo, AA Gutkind, SJ AF Czerninski, R. C. Amornphimoltham, P. Patel, V. Molinolo, A. A. Gutkind, S. J. TI Optimizing the 4NQO oral carcinogenesis model for rapamycin chemoprevention SO ORAL ONCOLOGY LA English DT Meeting Abstract CT 2nd World Congress of the International-Academy-of-Oral-Oncology CY JUL 08-11, 2009 CL Toronto, CANADA SP Int Acad Oral Oncol C1 [Czerninski, R. C.] Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Dept Oral Med, Jerusalem, Israel. [Amornphimoltham, P.; Patel, V.; Molinolo, A. A.; Gutkind, S. J.] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD JUL PY 2009 BP 189 EP 190 DI 10.1016/j.oos.2009.06.493 PG 6 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 509KJ UT WOS:000271015100446 ER PT J AU Looker, AC Melton, LJ Harris, T Borrud, L Shepherd, J McGowan, J AF Looker, A. C. Melton, L. J., III Harris, T. Borrud, L. Shepherd, J. McGowan, J. TI Age, gender, and race/ethnic differences in total body and subregional bone density SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Cross-sectional age patterns; Gender differences; Race/ethnic differences; Total body bone mineral density ID MINERAL DENSITY; AFRICAN-AMERICAN; SKELETAL-MUSCLE; OLDER MEN; WOMEN; OSTEOPOROSIS; HEALTHY; MASS; DXA; PREVALENCE AB Total body bone density of adults from National Health and Nutrition Examination Survey (NHANES) 1999-2004 differed as expected for some groups (men > women and blacks > whites) but not others (whites > Mexican Americans). Cross-sectional age patterns in bone mineral density (BMD) of older adults differed at skeletal sites that varied by degree of weight-bearing. Total body dual-energy X-ray absorptiometry (DXA) data offer the opportunity to compare bone density of demographic groups across the entire skeleton. The present study uses total body DXA data (Hologic QDR 4500A, Hologic, Bedford MA, USA) from the NHANES 1999-2004 to examine BMD of the total body and selected skeletal subregions in a wide age range of adult men and women from three race/ethnic groups. Total body, lumbar spine, pelvis, right leg, and left arm BMD and lean mass from 13,091 adults aged 20 years and older were used. The subregions were chosen to represent sites with different degrees of weight-bearing. Mean BMD varied in expected ways for some demographic characteristics (men > women and non-Hispanic blacks > non-Hispanic whites) but not others (non-Hispanic whites > Mexican Americans). Differences in age patterns in BMD also emerged for some characteristics (sex) but not others (race/ethnicity). Differences in cross-sectional age patterns in BMD and lean mass by degree of weight-bearing in older adults were observed for the pelvis, leg, and arm. This information may be useful for generating hypotheses about age, race, and sex differences in fracture risk in the population. C1 [Looker, A. C.; Borrud, L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Melton, L. J., III] Mayo Clin, Div Epidemiol, Coll Med, Rochester, MN USA. [Harris, T.] NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. [Shepherd, J.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [McGowan, J.] Natl Inst Musculoskeletal & Skin Dis, Div Musculoskeletal Dis, Bethesda, MD USA. RP Looker, AC (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Room 4310,3311 Toledo Rd, Hyattsville, MD 20782 USA. EM Alooker@cdc.gov FU Intramural NIH HHS [ZIA AG004050-02] NR 36 TC 38 Z9 40 U1 0 U2 9 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X EI 1433-2965 J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUL PY 2009 VL 20 IS 7 BP 1141 EP 1149 DI 10.1007/s00198-008-0809-6 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 454ES UT WOS:000266665800005 PM 19048179 ER PT J AU Dumitrescu, CE Kelly, MH Khosravi, A Hart, TC Brahim, J White, KE Farrow, EG Nathan, MH Murphey, MD Collins, MT AF Dumitrescu, C. E. Kelly, M. H. Khosravi, A. Hart, T. C. Brahim, J. White, K. E. Farrow, E. G. Nathan, M. H. Murphey, M. D. Collins, M. T. TI A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Dental; FGF23; GALNT3; KLOTHO; Phosphorus; Vitamin D ID HOMOZYGOUS MISSENSE MUTATION; O-GLYCOSYLATION; CALCINOSIS; FIBROBLAST-GROWTH-FACTOR-23; FGF23; HOMEOSTASIS; DISORDER AB A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology. FTC and HHS are caused by mutations in FGF23, GALNT3, or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D(3) (1,25-D(3)); FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis. A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment. Serum phosphorus was 7.3 mg/dL (2.5-4.8), TmP/GFR 6.99 mg/100 mL (2.97-4.45), 1,25-D(3) 35 pg/mL (22-67). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (20-108), but intact FGF23 was 7.4 pg/mL (10-50). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23. This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23. C1 [Dumitrescu, C. E.; Kelly, M. H.; Khosravi, A.; Hart, T. C.; Collins, M. T.] NIDCR, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. [Khosravi, A.] Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD USA. [White, K. E.; Farrow, E. G.] Indiana Univ, Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Nathan, M. H.] Univ Vermont, Coll Med, Dept Diabet Endocrinol & Metab, Burlington, VT USA. [Murphey, M. D.] AFIP, Dept Radiol Pathol, Washington, DC USA. RP Collins, MT (reprint author), NIDCR, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228,MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov FU NIH, National Institute of Dental and Craniofacial Research; NIH [DK063934] FX This research was supported, in part, by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. KEW and EGF are supported by NIH DK063934. NR 23 TC 26 Z9 27 U1 0 U2 1 PU SPRINGER LONDON LTD PI ARTINGTON PA ASHBOURNE HOUSE, THE GUILDWAY, OLD PORTSMOUTH ROAD, ARTINGTON GU3 1LP, GUILDFORD, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUL PY 2009 VL 20 IS 7 BP 1273 EP 1278 DI 10.1007/s00198-008-0775-z PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 454ES UT WOS:000266665800021 PM 18982401 ER PT J AU Pronczuk, J Krotoski, D AF Pronczuk, Jenny Krotoski, Danuta TI Preface SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Editorial Material C1 [Pronczuk, Jenny] WHO, CH-1211 Geneva 27, Switzerland. [Krotoski, Danuta] NICHHD, Eunice Kennedy Shriver Ctr, NIH, Bethesda, MD 20892 USA. RP Pronczuk, J (reprint author), WHO, CH-1211 Geneva 27, Switzerland. EM pronczukj@who.int NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2009 VL 23 BP IV EP V DI 10.1111/j.1365-3016.2009.01012.x PG 2 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 448DX UT WOS:000266244400002 ER PT J AU Haberg, SE Stigum, H London, SJ Nystad, W Nafstad, P AF Haberg, Siri E. Stigum, Hein London, Stephanie J. Nystad, Wenche Nafstad, Per TI Maternal obesity in pregnancy and respiratory health in early childhood SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE maternal obesity; maternal body mass index; infant respiratory infection; infant wheezing; MoBa ID BODY-MASS INDEX; 10-YEAR FOLLOW-UP; UNITED-STATES; ATOPIC DISEASE; BIRTH COHORT; ASTHMA; CHILDREN; PREVALENCE; OVERWEIGHT; RISK AB Obesity is associated with systemic inflammation, immunological changes, increased risk of respiratory infections and chronic respiratory illness. Maternal obesity in pregnancy increases the risk of pregnancy complications, caesarean sections and adverse birth outcomes, which have in turn been associated with respiratory illness in children. To our knowledge, the possible influence of maternal obesity in pregnancy on respiratory illness in early childhood beyond the newborn period has not been explored. We examined the relationship between a high maternal body mass index (BMI) in pregnancy and lower respiratory tract infections and wheeze up to 18 months of age in the Norwegian Mother and Child Study (MoBa), a population-based cohort study that includes 100 000 pregnant women, conducted at the Norwegian Institute of Public Health. We analysed data from the first 33 192 children, born between 1999 and 2005. In unadjusted analyses maternal obesity in pregnancy was related to both respiratory infections and wheeze in the children. In multivariable analyses, only an effect on wheeze remained. The risk of wheeze increased linearly with maternal BMI in pregnancy, and was 3.3% higher [95% CI 1.2, 5.3] for children with mothers who were obese during pregnancy, than for children of mothers with normal BMI. This effect was not mediated through obesity-related pregnancy complications, low birthweight, preterm birth or caesarean section. C1 [Haberg, Siri E.; Stigum, Hein; Nystad, Wenche; Nafstad, Per] Norwegian Inst Publ Hlth, Div Epidemiol, NO-0403 Oslo, Norway. [Nafstad, Per] Univ Oslo, Dept Gen Practice & Community Med, Fac Med, Oslo, Norway. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Durham, NC USA. [London, Stephanie J.] Natl Inst Environm Hlth Sci, Lab Resp Biol, NIH, Dept Hlth & Human Serv, Durham, NC USA. RP Haberg, SE (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, POB 4404 Nydalen, NO-0403 Oslo, Norway. EM siri.haberg@fhi.no OI London, Stephanie/0000-0003-4911-5290 FU Norwegian Foundation for Health and Rehabilitation; Division of Intramural Research; National Institute of Environmental Health Sciences; National Institutes of Health, USA [HHSN291200775558C, Z01-ES-85433, 1 UO1 NS 047537-01]; Norwegian Ministry of Health; Norwegian Research Council/FUGE [151918/S10] FX We gratefully acknowledge the participation of the MoBa parents. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, USA (Contract no. HHSN291200775558C and Project no. Z01-ES-85433), NIH/NINDS (grant no. 1 UO1 NS 047537-01) and the Norwegian Research Council/FUGE (grant no. 151918/S10). NR 64 TC 39 Z9 40 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD JUL PY 2009 VL 23 IS 4 BP 352 EP 362 DI 10.1111/j.1365-3016.2009.01034.x PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 453HO UT WOS:000266601700008 PM 19523082 ER PT J AU McPherson, M Thaniel, L Minniti, CP AF McPherson, Marianne Thaniel, Lisa Minniti, Caterina P. TI Transition of Patients With Sickle Cell Disease From Pediatric to Adult Care: Assessing Patient Readiness SO PEDIATRIC BLOOD & CANCER LA English DT Article DE adolescent; psychosocial; sickle cell disease; transition ID HEALTH-CARE; CHILDREN AB Background. Transfer of care from pediatric to adult-oriented providers is challenging for adolescents with sickle cell disease (SCD). The need for transition programs is known, however many SCD patients leave pediatric care without adequate preparation. This Study has two aims: to assess adolescent SCD patients' preparation for transition and to identify variables that predict patient readiness. Procedure. Adolescent patients receiving care at a pediatric SCD center received a survey regarding essential steps of the transition process. Patients' level of prior thought, interest, anticipated difficulty, and perceived importance of transition were graded on a scale of 0 to 3. Knowledge of individual transition plans was scaled 0 to 4. Responses were analyzed according to age, sex, and disease severity. Results. Seventy patients ages 14 to 20 years (median 16.7 years) were assessed. Mean readiness scores were low, with greatest deficiencies in prior thought (mean 0.88 [0.66-1.09]), knowledge (mean 0.85 [0.61-1.09]), anticipated difficulty (mean 1.42 [1.231-1.61]), and interest (mean 1.71 [1.47-1.95]). Perceived importance of transition received the highest score (mean 2.71 [2.58-2.84]). Younger age (<= 16 years) was associated with less knowledge (P=0.003) and interest (P=0.023); disease severity (>= 3 crises/year) was associated with lower interest (P=0.043) but greater anticipated difficulty (P=0.001). Anticipated difficulty trended higher among females (P=0.028). Conclusions. Adolescents with SCD acknowledge the importance but demonstrate poor preparation for transition to adult-oriented care. Readiness improves with age but remains insufficient. This analysis highlights the need for improvements in anticipatory guidance for transition during adolescence. Pediatr Blood Cancer 2009;52:838-841. (C) 2009 Wiley-Liss, Inc. C1 [Minniti, Caterina P.] NHLBI, NIH, Pulm & Vasc Med Branch, Bethesda, MD 20892 USA. [Thaniel, Lisa] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Minniti, CP (reprint author), NHLBI, NIH, Pulm & Vasc Med Branch, 9000 Rockville Pike,Bldg 10CRC,Room 5-5140, Bethesda, MD 20892 USA. EM minnitic@mail.nih.gov NR 11 TC 60 Z9 60 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2009 VL 52 IS 7 BP 838 EP 841 DI 10.1002/pbc.21974 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 435LT UT WOS:000265346100019 PM 19229973 ER PT J AU Rao, VK Price, S Perkins, K Aldridge, P Tretler, J Davis, J Dale, JK Gill, F Hartman, KR Stork, LC Gnarra, DJ Krishnamurti, L Newburger, PE Puck, J Fleisher, T AF Rao, V. Koneti Price, Susan Perkins, Katie Aldridge, Patricia Tretler, Jean Davis, Joie Dale, Janet K. Gill, Fred Hartman, Kip R. Stork, Linda C. Gnarra, David J. Krishnamurti, Lakshmanan Newburger, Peter E. Puck, Jennifer Fleisher, Thomas TI Use of Rituximab for Refractory Cytopenias Associated With Autoimmune Lymphoproliferative Syndrome (ALPS) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE ALPS; cytopenias; lymphadenopathy; rituximab; splenomegaly ID IMMUNE THROMBOCYTOPENIC PURPURA; COMMON VARIABLE IMMUNODEFICIENCY; LYMPHOCYTE APOPTOSIS; MYCOPHENOLATE-MOFETIL; FAS MUTATIONS; CHILDREN; DISEASE; DISORDERS; FAMILIES; FEATURES AB Background. ALPS is a disorder Of apoptosis resulting ill accumulation of autoreactive lymphocytes, leading to marked lymphadenopthy, hepatosplenomegaly, and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in 12 patients, 9children, and 3 adults out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health. Method;. Refractory immune thrombocytopenia (platelet Count <20,000) in nine patients and autoimmune hemolytic anemia (AIHA) in three patients led to treatment with rituximab. Among them, seven patients had undergone prior surgical splenectomy; three had significant splenomegaly; and two had no palpable spleen. Results. In seven out of nine patients with ALPS and thrombocyto-penia, rituximab therapy led to median response duration of 21 months (range 14-36 months). In contrast, none of the three children treated with rituximab for AIHA responded. Noted toxicities included profound and prolonged hypogammaglobulinemia in three patients requiring replacement IVIG, total absence of antibody response to polysaccharide vaccines lasting Up to 4 years after rituximab infusions in one patient and prolonged neutropenia in one patient. Conclusion. Toxicities including hypogammaglobulinemia and neutropenia constitute all additional infection risk burden, especially in asplenic individuals, and may warrant avoidance of rituximab until other immunosupprressive medication options are exhausted. Long-term follow-up of ALPS patients with cytopenias after any treatment is necessary to determine relative risks and benefits. Pediatr Blood Cancer 2009;52:847-852. (C) 2009 Wiley-Liss, Inc. C1 [Rao, V. Koneti] NIAID, ALPS Unit, LCID, NIH, Bethesda, MD 20892 USA. [Rao, V. Koneti; Price, Susan; Aldridge, Patricia; Tretler, Jean; Davis, Joie; Dale, Janet K.; Gill, Fred; Fleisher, Thomas] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Perkins, Katie] NCI, LCID, SAIC Frederick Inc, Frederick, MD 21701 USA. [Hartman, Kip R.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Stork, Linda C.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Gnarra, David J.] Childrens Hosp, Omaha, NE USA. [Krishnamurti, Lakshmanan] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Newburger, Peter E.] Univ Massachusetts, Worcester, MA 01605 USA. [Puck, Jennifer] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Rao, VK (reprint author), NIAID, ALPS Unit, LCID, NIH, 10 Ctr Dr,Room 11N234, Bethesda, MD 20892 USA. EM krao@niaid.nih.gov RI Krishnamurti, Lakshmanan/F-7637-2011; OI Newburger, Peter/0000-0002-8615-673X FU NIH; NIAID; Bethesda, MD; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX Grant sponsor: NIH, NIAID, Bethesda, MD: Grant sponsor: National Cancer Institute, National Institutes of Health; Grant number: HHSN261200800001E. NR 37 TC 37 Z9 39 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUL 1 PY 2009 VL 52 IS 7 BP 847 EP 852 DI 10.1002/pbc.21965 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 435LT UT WOS:000265346100021 PM 19214977 ER PT J AU Holubkov, R Dean, JM Berger, J Anand, KJS Carcillo, J Meert, K Zimmerman, J Newth, C Harrison, R Willson, DF Nicholson, C AF Holubkov, Richard Dean, J. Michael Berger, John Anand, Kanwaljeet J. S. Carcillo, Joseph Meert, Kathleen Zimmerman, Jerry Newth, Christopher Harrison, Rick Willson, Douglas F. Nicholson, Carol CA Eunice Kennedy Shriver Natl TI Is "rescue" therapy ethical in randomized controlled trials? SO PEDIATRIC CRITICAL CARE MEDICINE LA English DT Article DE randomized clinical trials; critical care; corticosterone; equipoise; ethics; placebos; septic shock; rescue therapy ID RESPIRATORY-DISTRESS-SYNDROME; SEPTIC SHOCK; CLINICAL-RESEARCH; EQUIPOISE; PLACEBO; METHYLPREDNISOLONE; CHILDREN; BENEFIT; SEPSIS AB Objective: There is a commonly held belief that randomized, placebo-controlled trials in pediatric critical care should incorporate "rescue" therapy (open-label administration of active drug) when a child's condition is deteriorating. The ethical, conceptual, and analytic challenges related to rescue therapy in randomized trials can be misrepresented. Design: Narrative review. Methods: The ethical basis of rescue therapy, the equipoise concept, and intention-to-treat analysis are examined in the setting of a hypothetical randomized trial comparing corticosteroids vs. placebo in pediatric septic shock. Findings: The perceived need for rescue therapy may be partly motivated by the moral imperative to save a child's life. However, allowing rescue therapy in a trial is misconceived and inconsistent with equipoise regarding the efficacy of the study drug. If rescue therapy is permitted, intention-to-treat analysis can only compare immediate vs. delayed use of the study drug. When rescue therapy is beneficial, the observed treatment effect is substantially diminished from true effect of the study drug, leading to increased sample size and thereby placing more children at risk (18 "excess" placebo-arm deaths occur in our hypothetical example). Analysis of a trial incorporating rescue therapy cannot definitively assess overall efficacy of the agent, or distinguish beneficial or harmful treatment effects related to timing of drug use. Conclusions: Although a rescue therapy component in a randomized trial may be perceived as ethically desirable, inconsistency of rescue therapy with full equipoise may itself raise significant ethical concerns. Increased sample sizes expose more children to the risks of study participation, including death. Researchers should be aware that clinical trials designed with rescue therapy cannot definitively determine the beneficial or harmful effects of a treatment per se, and can only assess the effects of delayed vs. immediate provision of the treatment. (Pediatr Crit Care Med 2009; 10:431-438) C1 [Holubkov, Richard; Dean, J. Michael] Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA. [Berger, John] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Anand, Kanwaljeet J. S.] Arkansas Childrens Hosp, Little Rock, AR 72202 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Meert, Kathleen] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Seattle, WA USA. [Newth, Christopher] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Harrison, Rick] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Willson, Douglas F.] Univ Virginia, Dept Pediat, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Holubkov, R (reprint author), Univ Utah, Dept Pediat, Salt Lake City, UT 84112 USA. EM rich.holubkov@hsc.utah.edu OI Anand, Kanwaljeet/0000-0001-6498-1483 FU Eunice Kennedy Shriver National Institute; National Institutes of Health; Department of Health and Human Services [U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012, U01HD049934] FX Supported, in part, by the following cooperative agreements from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and Department of Health and Human Services: U10HD050096, U10HD049981, U10HD500009, U10HD049945, U10HD049983, U10HD050012,and U01HD049934. NR 35 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1529-7535 J9 PEDIATR CRIT CARE ME JI Pediatr. Crit. Care Med. PD JUL PY 2009 VL 10 IS 4 BP 431 EP 438 DI 10.1097/PCC.0b013e318198bd13 PG 8 WC Critical Care Medicine; Pediatrics SC General & Internal Medicine; Pediatrics GA 468SI UT WOS:000267840500001 PM 19307815 ER PT J AU Read, JS Brogly, S Basar, M Scott, G AF Read, Jennifer S. Brogly, Susan Basar, Michael Scott, Gwendolyn TI Human Immunodeficiency Virus Diagnostic Testing of Infants at Clinical Sites in North America 2002-2006 SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the European-Society-for-Paediatric-Infectious-Diseases CY JUN 09-13, 2009 CL Brussels, BELGIUM SP European Soc Paediat Infect Dis DE HIV; diagnostic testing; infants; North America ID POLYMERASE CHAIN-REACTION; HIV-1 INFECTION; UNITED-STATES; RNA DETECTION; TRANSMISSION; DNA; TYPE-1; WOMEN; CULTURE; ASSAYS AB Background: Our objectives were to assess the timing of testing, the types of diagnostic assays used, and the costs associated with the diagnosis of HIV-1 infection among infants born to HIV-1-infected women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group Protocol 1025 (P1025). Methods: P1025 is a prospective cohort study of HIV-1-infected women and their infants at clinical sites in the United States and Puerto Rico. Enrollment began in 2002 and is ongoing. Follow-up of infants continued for at least 6 months after delivery/birth. The study population for this analysis comprised all live born infants of known HIV-1 infection status, born by December 31, 2006 to enrolled women. Results: Nine hundred eighty-eight infants had 5147 HIV-1 diagnostic test results reported. The median number of HIV-1 diagnostic assays performed per infant was 5 (10th, 90th percentiles: 3, 7), and the greatest number of tests reported per infant was 13. The median ages at the time of the first, second, third, and fourth HIV-1 diagnostic assay were 0.1, 2.3, 7.0, and 17.6 weeks, respectively. Nucleic acid amplification tests (NAATs) represented 86.9% of all diagnostic assays (HIV-1 DNA PCR assays: n = 4082 [79.3%]; other NAATs: n = 389 [7.6%]). The median cost per infant for HIV-1 diagnostic testing was $1168 (10th 90th percentiles: $762, $1642). Conclusions: Most assays reported for HIV-1-exposed infants at clinical sites in the United States and Puerto Rico were NAATs, but the number of HIV-1 diagnostic assays performed per infant, and the cost associated with HIV-1 diagnostic testing per infant, varied greatly. C1 [Read, Jennifer S.] NICHHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, DHHS,NIH, Bethesda, MD 20892 USA. [Brogly, Susan] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Basar, Michael] Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. [Scott, Gwendolyn] Univ Miami, Sch Med, Dept Pediat, Miami, FL USA. RP Read, JS (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, CRMC, DHHS,NIH, Execut Bldg,Room 4B11C,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. EM jennifer_read@nih.gov FU NIAID NIH HHS [1 U01 AI068616, U01AI068632]; NICHD NIH HHS [N01-HD-3-3365]; NIDDK NIH HHS [N01-DK-8-0001]; PHS HHS [HHSN267200800001C, HHSN272200800014C] NR 21 TC 3 Z9 3 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2009 VL 28 IS 7 BP 614 EP 618 DI 10.1097/INF.0b013e31819ac33b PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 463DS UT WOS:000267409900010 PM 19478686 ER PT J AU Morens, DM AF Morens, David M. TI Dengue Fever and Dengue Hemorrhagic Fever SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Editorial Material DE dengue; arboviruses; flaviviruses C1 NIAID, Off Director, CAPT, US Publ Hlth Serv,NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, Off Director, CAPT, US Publ Hlth Serv,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 12 TC 6 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD JUL PY 2009 VL 28 IS 7 BP 635 EP 636 DI 10.1097/INF.0b013e3181afcd5b PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 463DS UT WOS:000267409900014 PM 19561427 ER PT J AU Gargus, RA Vohr, BR Tyson, JE High, P Higgins, RD Wrage, LA Poole, K AF Gargus, Regina A. Vohr, Betty R. Tyson, Jon E. High, Pamela Higgins, Rosemary D. Wrage, Lisa A. Poole, Kenneth TI Unimpaired Outcomes for Extremely Low Birth Weight Infants at 18 to 22 Months SO PEDIATRICS LA English DT Article DE extremely low birth weight; outcomes; neurodevelopmental impairment ID NEONATAL INTENSIVE-CARE; EXTREMELY PRETERM; PROACTIVE MANAGEMENT; EXTREMELY PREMATURE; NATIONAL-INSTITUTE; GROWTH OUTCOMES; CHILD-HEALTH; 800 GRAMS; AGE; 1990S AB OBJECTIVE: The goal was to identify, among extremely low birth weight (<= 1000 g) live births, the proportion of infants who were unimpaired at 18 to 22 months of corrected age. METHODS: Unimpaired outcome was defined as Bayley Scales of Infant Development II scores of >= 85, normal neurologic examination findings, and normal vision, hearing, swallowing, and walking. Outcomes were determined for 5250 (86%) of 6090 extremely low birth weight inborn infants. RESULTS: Of the 5250 infants whose outcomes were known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 ( 22%) had moderate/severe neurodevelopmental impairments, and 2100 (40%) had died. Unimpaired survival rates varied according to birth weight, from <1% for infants <= 500 g to 24% for infants 901 to 1000 g. The regression model to predict unimpaired survival versus death or impairment for live births (N = 5250) indicated that 25.3% of the variance was derived from infant factors present at birth, including female gender, higher birth weight, singleton birth. The regression model to predict unimpaired survival for discharged infants indicated that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographic features (15.7%) and only 8.5% was derived from infant factors present at birth. CONCLUSIONS: Although <1% of live-born infants of <= 500 g survive free of impairment at 18 months, this increases to almost 24% for infants of 901 to 1000 g. Female gender, singleton birth, higher birth weight, absence of neonatal morbidities, private health insurance, and white race increase the likelihood of unimpaired status. Pediatrics 2009;124:112-121 C1 [Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. [Gargus, Regina A.] Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. [Vohr, Betty R.; High, Pamela] Brown Univ, Dept Pediat, Warren Alpert Med Sch, Providence, RI 02912 USA. [Tyson, Jon E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [High, Pamela] Hasbro Childrens Hosp, Div Dev Behav Pediat, Providence, RI USA. [Higgins, Rosemary D.] NICHHD, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. [Wrage, Lisa A.; Poole, Kenneth] RTI Int, Dept Stat & Epidemiol, Res Triangle Pk, NC USA. RP Vohr, BR (reprint author), Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. EM betty_vohr@brown.edu FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [M01RR54, M01 RR001032, M01 RR002172, M01 RR002635, M01 RR006022, M01 RR007122, M01 RR008084, M01 RR1032, M01 RR125, M01 RR2172, M01 RR2635, M01 RR59, M01 RR6022, M01 RR7122, M01 RR750, M01 RR8084, M01RR39, M01RR44, M01RR633, M01RR64, M01RR80, KL2 RR024149, KL2 RR24149, M01 RR016587, M01 RR16587, M01 RR2588, M01 RR30, M01 RR32, M01 RR997, M01RR70, UL1 RR024128, UL1 RR024139, UL1 RR024148, UL1 RR025008, UL1 RR24139, UL1 RR24148, UL1RR24128]; NICHD NIH HHS [U10 HD27880, U10 HD021364, U10 HD021373, U10 HD021397, U10 HD027856, U10 HD027904, U10 HD027904-18, U10 HD034216, U10 HD040521, U10 HD053109, U10 HD21364, U10 HD21373, U10 HD21397, U10 HD27856, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40521, U10 HD53109, U01 HD036790, U01 HD36790, U10 HD021385, U10 HD027851, U10 HD027853, U10 HD027871, U10 HD027880, U10 HD034167, U10 HD040461, U10 HD040492, U10 HD040498, U10 HD040689, U10 HD053089, U10 HD053119, U10 HD053124, U10 HD21385, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27871, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40689, U10 HD53089, U10 HD53119, U10 HD53124] NR 43 TC 48 Z9 50 U1 5 U2 10 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP 112 EP 121 DI 10.1542/peds.2008-2742 PG 10 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100015 PM 19564290 ER PT J AU Reddy, UM Ko, CW Raju, TNK Willinger, M AF Reddy, Uma M. Ko, Chia-Wen Raju, Tonse N. K. Willinger, Marian TI Delivery Indications at Late-Preterm Gestations and Infant Mortality Rates in the United States SO PEDIATRICS LA English DT Article DE infant mortality; preterm; preterm infants ID BIRTH CERTIFICATE DATA; TERM; VALIDATION; COMPLICATIONS; EPIDEMIOLOGY; ACCURACY; RECORDS; LABOR; AGE AB OBJECTIVE: The rate of preterm births has been increasing in the United States, especially for births 34 to 36 weeks of gestation ( late preterm), which now constitute 71% of all preterm births. The causes for these trends remain unclear. We characterized the delivery indications for late preterm births and their potential impact on neonatal and infant mortality rates. PATIENTS AND METHODS: Using the 2001 US Birth Cohort Linked birth/death files of 3 483 496 singleton births, we categorized delivery indications as follows: ( 1) maternal medical conditions; ( 2) obstetric complications; ( 3) major congenital anomalies; ( 4) isolated spontaneous labor: vaginal delivery without induction and without associated medical/obstetric factors; and ( 5) no recorded indication. RESULTS: Of the 292 627 late-preterm births, the first 4 categories ( those with indications and isolated spontaneous labor) accounted for 76.8%. The remaining 23.2% ( 67 909) were classified as deliveries with no recorded indication. Factors significantly increasing the chance of no recorded indication were older maternal age; non-Hispanic, white mother; >= 13 years of education; Southern, Midwestern, and Western region; multiparity; or previous infant with a >= 4000-g birth weight. The neonatal and infant mortality rates were significantly higher among deliveries with no recorded indication compared with deliveries secondary to isolated spontaneous labor but lower compared with deliveries with an obstetric indication or congenital anomaly. CONCLUSIONS: A total of 23% of late preterm births had no recorded indication for delivery noted on birth certificates. Patient factors may be playing a role in these deliveries. It is concerning that these infants had higher mortality rates compared with those born after spontaneous labor at similar gestational ages. Given the excess risk of mortality, patients and providers need to discuss the risks of delivering a preterm infant in the absence of medical indications at 34 to 36 weeks. Pediatrics 2009; 124: 234-240 C1 [Reddy, Uma M.; Ko, Chia-Wen; Raju, Tonse N. K.; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Reddy, UM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 28 TC 81 Z9 89 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP 234 EP 240 DI 10.1542/peds.2008-3232 PG 7 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100030 PM 19564305 ER PT J AU Kafulafula, G Mwatha, A Chen, YQ Aboud, S Martinson, F Hoffman, I Fawzi, W Read, JS Valentine, M Mwinga, K Goldenberg, R Taha, TE AF Kafulafula, George Mwatha, Anthony Chen, Ying Qing Aboud, Said Martinson, Francis Hoffman, Irving Fawzi, Wafaie Read, Jennifer S. Valentine, Megan Mwinga, Kasonde Goldenberg, Robert Taha, Taha E. TI Intrapartum Antibiotic Exposure and Early Neonatal, Morbidity, and Mortality in Africa SO PEDIATRICS LA English DT Article DE antibiotic resistance; antibiotics; neonatal morbidity; neonatal mortality; neonatal sepsis ID CHORIOAMNIONITIS; TRANSMISSION; TRIAL; HIV-1 AB BACKGROUND: Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants. OBJECTIVE: Our goal was to determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality. METHODS: We performed secondary analysis of data from a multisite randomized, placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intention-to-treat (ITT) analysis, infants born to women randomly assigned to antibiotics or placebo were compared. In addition, non-ITT analysis was performed because some women received nonstudy antibiotics for various clinical indications. RESULTS: Overall, 2659 pregnant women were randomly assigned. Of these, 2466 HIV-1-infected and HIV-1-uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs 8.6%, P = .03) and more admissions to the special care infant unit (12.6% vs 9.8%, P = .04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Additional analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received nonstudy antibiotics than of mothers who received study antibiotics. CONCLUSIONS: There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive nonstudy antibiotics. Pediatrics 2009; 124: e137-e144 C1 [Kafulafula, George] Univ Malawi, Coll Med, Dept Obstet & Gynecol, Blantyre 3, Malawi. [Mwatha, Anthony; Chen, Ying Qing] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. [Aboud, Said] Muhimbili Univ Hlth & Allied Sci, Dept Microbiol & Immunol, Dar Os Salaam, Tanzania. [Martinson, Francis; Hoffman, Irving] Univ N Carolina, Ctr Infect Dis, Chapel Hill, NC USA. [Fawzi, Wafaie] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Valentine, Megan] Family Hlth Int, Res Triangle Pk, NC 27709 USA. [Mwinga, Kasonde] Univ Teaching Hosp, Dept Pediat & Child Hlth, Lusaka, Zambia. [Goldenberg, Robert] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Kafulafula, G (reprint author), Univ Malawi, Coll Med, Dept Obstet & Gynecol, Private Bag 360, Blantyre 3, Malawi. EM gkafulafula@jhu.medcol.mw FU NIAID NIH HHS [N01 AI045200, N01 AI035173, N01-AI-35173-117/412, U01 AI047972, U01 AI047972-05, U01 AI048005, U01 AI048005-05, U01 AI048006] NR 12 TC 6 Z9 6 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP E137 EP E144 DI 10.1542/peds.2008-1873 PG 8 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100074 PM 19564260 ER PT J AU Lateef, TM Grewal, M McClintock, W Chamberlain, J Kaulas, H Nelson, KB AF Lateef, Tarannum M. Grewal, Mandeep McClintock, William Chamberlain, James Kaulas, Himanshu Nelson, Karin B. TI Headache in Young Children in the Emergency Department: Use of Computed Tomography SO PEDIATRICS LA English DT Article DE headache; child; emergency department; computed tomography ID PEDIATRIC EMERGENCY; MIGRAINE; ADOLESCENTS; PREVALENCE; ETIOLOGY; SEIZURE; CANCER; RISKS; CT AB OBJECTIVE: The goal was to determine whether computed tomographic (CT) scans led to better acute care of young children with headache presenting the emergency department (ED). METHODS: We examined the records of 364 children 2 to 5 years of age who presented with headache to a large urban ED between July 1, 2003, and June 30, 2006. By reviewing initial history and examination findings, we first identified patients with secondary headaches (ie, with readily identifiable explanations such as ventriculoperitoneal shunts, known brain tumors, or acute illnesses, such as viral syndromes, fever, probable meningitis, or trauma). Charts for the remaining patients were reviewed for headache history, neurologic examination findings, laboratory and neuroimaging results, final diagnosis, and disposition. RESULTS: On the basis of initial history and physical examination results, 306 children (84%) had secondary headaches. For 72% of those children, acute febrile illnesses and viral respiratory syndromes accounted for the headaches. Among the 58 children (16%) who had no recognized central nervous system disease or systemic illness at presentation, 28% had CT scans performed. Of those, 1 scan yielded abnormal results, showing a brainstem glioma; the patient demonstrated abnormal neurologic examination findings on the day of presentation. For 15 (94%) of 16 patients, the CT scans did not contribute to diagnosis or management. For 59% of children with apparently primary headaches, no family history was recorded. CONCLUSION: For young children presenting to the ED with headache but normal neurologic examination findings and nonworrying history, CT scans seldom lead to diagnosis or contribute to immediate management. Pediatrics 2009; 124: e12-e17 C1 [Lateef, Tarannum M.; Grewal, Mandeep; McClintock, William; Kaulas, Himanshu; Nelson, Karin B.] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Lateef, Tarannum M.; Grewal, Mandeep; McClintock, William; Kaulas, Himanshu; Nelson, Karin B.] Childrens Natl Med Ctr, Dept Emergency Med, Washington, DC 20010 USA. George Washington Univ, Sch Med, Washington, DC USA. [Nelson, Karin B.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Lateef, TM (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave, Washington, DC 20010 USA. EM tlateef@cnmc.org FU National Institute of Neurological Disorders and Stroke FX This work was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 29 TC 11 Z9 12 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP E12 EP E17 DI 10.1542/peds.2008-3150 PG 6 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100058 PM 19564257 ER PT J AU Pollack, MM Holubkov, R Glass, P Dean, JM Meert, KL Zimmerman, J Anand, KJS Carcillo, J Newth, CJL Harrison, R Willson, DF Nicholson, C AF Pollack, Murray M. Holubkov, Richard Glass, Penny Dean, J. Michael Meert, Kathleen L. Zimmerman, Jerry Anand, Kanwaljeet J. S. Carcillo, Joseph Newth, Christopher J. L. Harrison, Rick Willson, Douglas F. Nicholson, Carol CA Eunice Kennedy Shriver Natl Inst TI Functional Status Scale: New Pediatric Outcome Measure SO PEDIATRICS LA English DT Article DE functional status; outcome assessment; activities of daily living; adaptive behavior; health status indicators; health utilities index; treatment outcome; child ID INTENSIVE-CARE-UNIT; MORTALITY; ASSESSMENTS; PREDICTION; SEVERITY AB OBJECTIVE: The goal was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments. METHODS: Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (score = 1) to very severe dysfunction (score = 5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II. Statistical analyses were performed. RESULTS: A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of >= 10, 14% had FSS scores of >= 15, and 6% had FSS scores of >= 20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction ( ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively. CONCLUSIONS: The FSS met our objectives and is well suited for large outcome studies. Pediatrics 2009; 124: e18-e28 C1 [Pollack, Murray M.; Glass, Penny] Childrens Natl Med Ctr, Dept Pediat, Washington, DC 20010 USA. [Holubkov, Richard; Dean, J. Michael] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Meert, Kathleen L.] Childrens Hosp Michigan, Dept Pediat, Detroit, MI 48201 USA. [Zimmerman, Jerry] Seattle Childrens Hosp, Dept Pediat, Seattle, WA USA. [Anand, Kanwaljeet J. S.] Arkansas Childrens Hosp, Dept Pediat, Little Rock, AR 72202 USA. [Carcillo, Joseph] Childrens Hosp Pittsburgh, Dept Pediat, Pittsburgh, PA 15213 USA. [Harrison, Rick] Childrens Hosp Los Angeles, Dept Pediat, Los Angeles, CA 90027 USA. [Harrison, Rick] Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. [Willson, Douglas F.] Univ Virginia, Dept Pediat, Childrens Hosp, Charlottesville, VA USA. [Nicholson, Carol] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Pediat, Bethesda, MD USA. RP Pollack, MM (reprint author), Childrens Hosp, 1919 E Thomas Rd, Phoenix, AZ 85016 USA. EM mpollack@phoenixchildrens.com OI Anand, Kanwaljeet/0000-0001-6498-1483 FU NICHD NIH HHS [U10 HD063114, U01 HD049934, U01-HD049934, U10 HD049945, U10 HD049981, U10 HD049983, U10 HD050012, U10 HD050096, U10-HD049983, U10HD049945, U10HD049981, U10HD050012, U10HD050096, U10HD500009, UG1 HD049981, UG1 HD050096] NR 16 TC 36 Z9 37 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2009 VL 124 IS 1 BP E18 EP E28 DI 10.1542/peds.2008-1987 PG 11 WC Pediatrics SC Pediatrics GA 463QY UT WOS:000267448100059 PM 19564265 ER PT J AU Uhl, GR AF Uhl, George R. TI Promise of pharmacogenomics in smoking cessation SO PHARMACOGENOMICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; NICOTINE DEPENDENCE; MOLECULAR-GENETICS; GENES; TWINS; SNPS C1 NIH, Mol Neurobiol Res Branch, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIH, Mol Neurobiol Res Branch, POB 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU Intramural NIH HHS NR 13 TC 6 Z9 6 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUL PY 2009 VL 10 IS 7 BP 1123 EP 1125 DI 10.2217/PGS.09.87 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 478WX UT WOS:000268620500007 PM 19604085 ER PT J AU Jones, JD Hall, FS Uhl, GR Rice, K Riley, AL AF Jones, Jermaine D. Hall, F. Scott Uhl, George R. Rice, Kenner Riley, Anthony L. TI Differential involvement of the norepinephrine, serotonin and dopamine reuptake transporter proteins in cocaine-induced taste aversion SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Preexposure; Cocaine; Taste-aversion; Dopamine; Norepinephrine; Serotonin; Monoamine-transporter; Nisoxetine; Fluoxetine; Vanoxerine ID STIMULUS PROPERTIES; MORPHINE PREEXPOSURE; RATS; AMPHETAMINE; DRUGS; SUPPRESSION; HYPOTHESIS; GBR-12909; ABUSE; FLUVOXAMINE AB Despite the impact of cocaine's aversive effects on its abuse potential, the neurochemical basis of these aversive effects remains poorly understood. By blocking the reuptake of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT) into the presynaptic terminal, cocaine acts as a potent indirect agonist of each of these systems. The following studies attempted to assess the extent of monoaminergic mediation of cocaine's aversive effects using conditioned taste aversion (CTA) learning [Garcia.J., Kimeldorf, D.J., Koelling, R.A., Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 1955:122:157-158.]. Specifically, Experiment I assessed the ability of selective monoamine transporter inhibitors, e.g., DAT (vanoxerine), NET (nisoxetine) and SERT (fluoxetine), to induce taste aversions (relative to cocaine). Only the NET inhibitor approximated the aversive strength of cocaine. Experiment 2 compared the effects of pretreatment of each of these transport inhibitors on the development of a cocaine-induced CTA. Pretreatment with nisoxetine and fluoxetine both attenuated cocaine-induced aversions in a manner comparable to that produced by cocaine itself. The DAT inhibitor was without effect. Combined. the results of these investigations indicate little or no involvement of dopaminergic systems in cocaine's aversive effects while NE appears to contribute most substantially, with a possible modulatory involvement by serotonin. (C) 2009 Elsevier Inc. All rights reserved. C1 [Jones, Jermaine D.] Columbia Univ, New York State Psychiat Inst, Substance Use Res Ctr, New York, NY 10032 USA. [Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Hall, F. Scott; Uhl, George R.] NIDA, IRP, NIH, DHHS,Mol Neurobiol Branch, Baltimore, MD 21224 USA. [Rice, Kenner] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner] NIAAA, Bethesda, MD 20892 USA. RP Jones, JD (reprint author), Columbia Univ, New York State Psychiat Inst, Substance Use Res Ctr, 1051 Riverside Dr, New York, NY 10032 USA. EM JermaineDJones@gmail.com RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Mellon Foundations; National Institute on Drug Abuse; NIH/DHHS FX This research was supported, in part, by a grant from the Mellon Foundations to ALR and the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS (FSH, GRU). Requests for reprints should be sent to Jermaine Jones, New York State Psychiatric Institute/Columbia University, 1051 Riverside Drive, New York, NY 10032. NR 61 TC 13 Z9 13 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUL PY 2009 VL 93 IS 1 BP 75 EP 81 DI 10.1016/j.pbb.2009.04.009 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 464SF UT WOS:000267526100011 PM 19376154 ER PT J AU Coelho, SG Koo, E Hearing, VJ AF Coelho, Sergio G. Koo, Eubee Hearing, Vincent J. TI Standardization of In Vitro Macrophotography for Assessment of Cutaneous Responses SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID HUMAN-SKIN; DNA-DAMAGE; PIGMENTATION; COLOR; MELANOGENESIS; MECHANISMS; RADIATION; APOPTOSIS; PROTECTS; ERYTHEMA AB The increased popularity of commercially available three-dimensional human skin equivalents in recent years has allowed for assessment of melanogenesis modulated by compounds topically applied to the skin or directly incorporated from the medium. These skin equivalents provide a suitable model for elucidating the mechanisms of action of various factors that modulate skin pigmentation or other properties of the skin. As such, researchers need to objectively quantify cutaneous responses at the macroscopic level. A simple method to standardize macrophotography images is reported that can quantify cutaneous responses in human skin equivalents of Asian, Black or African American, and Caucasian or White racial/ethnic origin. Macrophotographs are analyzed using the Commission Internationale de l'Eclairage L*a*b* color space system in combination with a personal computer and image editing software. Pigmentation changes monitored over a 9 day period showed a high correlation with melanin content evaluated in Fontana-Masson-stained sections. These results indicate the feasibility of using a macrophotography setup in a sterile tissue culture environment to objectively assess in vitro cutaneous responses in human skin equivalents. This serves as an adjunct tool to biochemical and morphological methods to effectively quantify changes in pigmentation over time. C1 [Coelho, Sergio G.; Koo, Eubee; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM coelhos@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 27 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD JUL-AUG PY 2009 VL 85 IS 4 BP 1032 EP 1037 DI 10.1111/j.1751-1097.2009.00549.x PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 461QS UT WOS:000267284300026 PM 19320841 ER PT J AU Grothaus, PG Newman, DJ AF Grothaus, P. G. Newman, D. J. TI Anti-cancer Agents from Plants, Current and Future Prospects SO PLANTA MEDICA LA English DT Meeting Abstract CT 55th International Congress and Annual Meeting of the Society-for-Medicinal-Plant-Research-and-Natural-Product-Research CY AUG 16-20, 2009 CL Geneva, SWITZERLAND SP Soc Medicinal Plant & Nat Prod Res C1 [Grothaus, P. G.; Newman, D. J.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 J9 PLANTA MED JI Planta Med. PD JUL PY 2009 VL 75 IS 9 BP 879 EP 879 PG 1 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 481JQ UT WOS:000268806600009 ER PT J AU Jin, J Sherer, NM Heidecker, G Derse, D Mothes, W AF Jin, Jing Sherer, Nathan M. Heidecker, Gisela Derse, David Mothes, Walther TI Assembly of the Murine Leukemia Virus Is Directed towards Sites of Cell-Cell Contact SO PLOS BIOLOGY LA English DT Article ID ENVELOPE PROTEIN; VIROLOGICAL SYNAPSES; CYTOPLASMIC TAIL; HIV-1 VIRIONS; LIVING CELLS; ENV PROTEIN; R-PEPTIDE; T-CELLS; TYPE-1; TRANSMISSION AB We have investigated the underlying mechanism by which direct cell-cell contact enhances the efficiency of cell-to-cell transmission of retroviruses. Applying 4D imaging to a model retrovirus, the murine leukemia virus, we directly monitor and quantify sequential assembly, release, and transmission events for individual viral particles as they happen in living cells. We demonstrate that de novo assembly is highly polarized towards zones of cell-cell contact. Viruses assembled approximately 10-fold more frequently at zones of cell contact with no change in assembly kinetics. Gag proteins were drawn to adhesive zones formed by viral Env glycoprotein and its cognate receptor to promote virus assembly at cell-cell contact. This process was dependent on the cytoplasmic tail of viral Env. Env lacking the cytoplasmic tail while still allowing for contact formation, failed to direct virus assembly towards contact sites. Our data describe a novel role for the viral Env glycoprotein in establishing cell-cell adhesion and polarization of assembly prior to becoming a fusion protein to allow virus entry into cells. C1 [Jin, Jing; Sherer, Nathan M.; Mothes, Walther] Yale Univ, Sch Med, Sect Microbial Pathogenesis, New Haven, CT 06520 USA. [Heidecker, Gisela; Derse, David] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Jin, J (reprint author), Yale Univ, Sch Med, Sect Microbial Pathogenesis, New Haven, CT 06520 USA. EM walther.mothes@yale.edu FU National Cancer Institute [ROI CA098727]; amfAR Foundation FX The work is supported by a grant from the National Cancer Institute ROI CA098727 to WM and a fellowship from amfAR Foundation for AIDS research to JJ. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 57 Z9 57 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD JUL PY 2009 VL 7 IS 7 AR e1000163 DI 10.1371/journal.pbio.1000163 PG 15 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 475ZE UT WOS:000268405700013 PM 19636361 ER PT J AU Zhang, LQ Button, B Gabriel, SE Burkett, S Yan, Y Skiadopoulos, MH Dang, YL Vogel, LN McKay, T Mengos, A Boucher, RC Collins, PL Pickles, RJ AF Zhang, Liqun Button, Brian Gabriel, Sherif E. Burkett, Susan Yan, Yu Skiadopoulos, Mario H. Dang, Yan Li Vogel, Leatrice N. McKay, Tristan Mengos, April Boucher, Richard C. Collins, Peter L. Pickles, Raymond J. TI CFTR Delivery to 25% of Surface Epithelial Cells Restores Normal Rates of Mucus Transport to Human Cystic Fibrosis Airway Epithelium SO PLOS BIOLOGY LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PARAINFLUENZA VIRUS TYPE-3; ENHANCES GENE-TRANSFER; IN-VIVO; LIQUID VOLUME; PERICILIARY LIQUID; LENTIVIRAL VECTOR; NASAL EPITHELIUM; FLUID SECRETION; SODIUM-CHANNELS AB Dysfunction of CFTR in cystic fibrosis (CF) airway epithelium perturbs the normal regulation of ion transport, leading to a reduced volume of airway surface liquid (ASL), mucus dehydration, decreased mucus transport, and mucus plugging of the airways. CFTR is normally expressed in ciliated epithelial cells of the surface and submucosal gland ductal epithelium and submucosal gland acinar cells. Critical questions for the development of gene transfer strategies for CF airway disease are what airway regions require CFTR function and how many epithelial cells require CFTR expression to restore normal ASL volume regulation and mucus transport to CF airway epithelium? An in vitro model of human CF ciliated surface airway epithelium (CF HAE) was used to test whether a human parainfluenza virus (PIV) vector engineered to express CFTR (PIVCFTR) could deliver sufficient CFTR to CF HAE to restore mucus transport, thus correcting the CF phenotype. PIVCFTR delivered CFTR to >60% of airway surface epithelial cells and expressed CFTR protein in CF HAE approximately 100-fold over endogenous levels in non-CF HAE. This efficiency of CFTR delivery fully corrected the basic bioelectric defects of Cl 2 and Na(+) epithelial ion transport and restored ASL volume regulation and mucus transport to levels approaching those of non-CF HAE. To determine the numbers of CF HAE surface epithelial cells required to express CFTR for restoration of mucus transport to normal levels, different amounts of PIVCFTR were used to express CFTR in 3%-65% of the surface epithelial cells of CF HAE and correlated to increasing ASL volumes and mucus transport rates. These data demonstrate for the first time, to our knowledge, that restoration of normal mucus transport rates in CF HAE was achieved after CFTR delivery to 25% of surface epithelial cells. In vivo experimentation in appropriate models will be required to determine what level of mucus transport will afford clinical benefit to CF patients, but we predict that a future goal for corrective gene transfer to the CF human airways in vivo would attempt to target at least 25% of surface epithelial cells to achieve mucus transport rates comparable to those in non-CF airways. C1 [Zhang, Liqun; Button, Brian; Gabriel, Sherif E.; Burkett, Susan; Yan, Yu; Dang, Yan Li; McKay, Tristan; Boucher, Richard C.; Pickles, Raymond J.] Univ N Carolina, CF Pulm Res & Treatment Ctr, Chapel Hill, NC 27515 USA. [Skiadopoulos, Mario H.; Vogel, Leatrice N.; Collins, Peter L.] NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Mengos, April] Mayo Clin, Coll Med, Scottsdale, AZ USA. RP Zhang, LQ (reprint author), Univ N Carolina, CF Pulm Res & Treatment Ctr, Chapel Hill, NC 27515 USA. EM branston@med.unc.edu FU National Institutes of Health (NIH); Cystic Fibrosis Foundation (CFF) [NIH R01 HL77844, NIH P01 HL051818, ZHAN03I0, GABRIE04G1, GABRIE05P0]; NIH Molecular Therapy Core Center [P30 DK065988] FX This work was funded by the National Institutes of Health (NIH) and Cystic Fibrosis Foundation (CFF) grants NIH R01 HL77844 (RP), NIH P01 HL051818 ( RP); NIH Molecular Therapy Core Center P30 DK065988 (RB, SG, RP); CFF ZHAN03I0 (LZ), GABRIE04G1 (SG) and GABRIE05P0 (SG); and the NIAID Intramural Research Program (MS, LV, PC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 57 TC 81 Z9 82 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD JUL PY 2009 VL 7 IS 7 AR e1000155 DI 10.1371/journal.pbio.1000155 PG 17 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 475ZE UT WOS:000268405700008 PM 19621064 ER PT J AU Pan, YP Nussinov, R AF Pan, Yongping Nussinov, Ruth TI Cooperativity Dominates the Genomic Organization of p53-Response Elements: A Mechanistic View SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR P53; DNA-BINDING SITE; MOLECULAR-DYNAMICS; CORE DOMAIN; TRANSCRIPTIONAL CONTROL; P53-RNA INTERACTIONS; PROTEIN COMPLEXES; STRUCTURAL BASIS; FOLDING FUNNELS; ALLOSTERY AB p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0-2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization. C1 [Pan, Yongping; Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Pan, YP (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported ( in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 75 TC 14 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUL PY 2009 VL 5 IS 7 AR e1000448 DI 10.1371/journal.pcbi.1000448 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 486TD UT WOS:000269220100013 PM 19629163 ER PT J AU Adeyemo, A Gerry, N Chen, GJ Herbert, A Doumatey, A Huang, HX Zhou, J Lashley, K Chen, YX Christman, M Rotimi, C AF Adeyemo, Adebowale Gerry, Norman Chen, Guanjie Herbert, Alan Doumatey, Ayo Huang, Hanxia Zhou, Jie Lashley, Kerrie Chen, Yuanxiu Christman, Michael Rotimi, Charles TI A Genome-Wide Association Study of Hypertension and Blood Pressure in African Americans SO PLOS GENETICS LA English DT Article ID GROWTH-FACTOR-I; DIABETES SUSCEPTIBILITY GENES; LEFT-VENTRICULAR HYPERTROPHY; ANTIHYPERTENSIVE THERAPY; DETERMINANTS; ALLELES; CLONING; SEARCH; FAMILY; MEMBER AB The evidence for the existence of genetic susceptibility variants for the common form of hypertension ("essential hypertension") remains weak and inconsistent. We sought genetic variants underlying blood pressure (BP) by conducting a genome-wide association study (GWAS) among African Americans, a population group in the United States that is disproportionately affected by hypertension and associated complications, including stroke and kidney diseases. Using a dense panel of over 800,000 SNPs in a discovery sample of 1,017 African Americans from the Washington, D. C., metropolitan region, we identified multiple SNPs reaching genome-wide significance for systolic BP in or near the genes: PMS1, SLC24A4, YWHA7, IPO7, and CACANA1H. Two of these genes, SLC24A4 (a sodium/potassium/calcium exchanger) and CACNA1H (a voltage-dependent calcium channel), are potential candidate genes for BP regulation and the latter is a drug target for a class of calcium channel blockers. No variant reached genome wide significance for association with diastolic BP (top scoring SNP rs1867226, p = 5.8x10(-7)) or with hypertension as a binary trait (top scoring SNP rs9791170, p = 5.1x10(-7)). We replicated some of the significant SNPs in a sample of West Africans. Pathway analysis revealed that genes harboring top-scoring variants cluster in pathways and networks of biologic relevance to hypertension and BP regulation. This is the first GWAS for hypertension and BP in an African American population. The findings suggests that, in addition to or in lieu of relying solely on replicated variants of moderate-to-large effect reaching genome-wide significance, pathway and network approaches may be useful in identifying and prioritizing candidate genes/loci for further experiments. C1 [Adeyemo, Adebowale; Chen, Guanjie; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Rotimi, Charles] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. [Gerry, Norman; Christman, Michael] Coriell Inst Biomed Res, Camden, NJ USA. [Herbert, Alan] Boston Univ, Dept Genet & Genom, Boston, MA 02215 USA. [Lashley, Kerrie; Chen, Yuanxiu] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. RP Adeyemo, A (reprint author), NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA. EM adeyemoa@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU NIGMS/MBRS/SCORE Program [S06GM008016-320107, S06GM008016-380111]; National Center for Research Resources (NCRR) [2M01RR010284]; Coriell Institute for Biomedical Sciences; National Human Genome Research Institute; National Institutes of Health; Center for Research in Genomics and Global Health [Z01HG200362] FX The study was supported by grants S06GM008016-320107 to CR and S06GM008016-380111 to AA, both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center (GCRC), which is supported by grant number 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Additional support was provided by the Coriell Institute for Biomedical Sciences. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research in Genomics and Global Health (Z01HG200362). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 195 Z9 202 U1 3 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2009 VL 5 IS 7 AR e1000564 DI 10.1371/journal.pgen.1000564 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 486SZ UT WOS:000269219500022 PM 19609347 ER PT J AU Jun, G Guo, H Klein, BEK Klein, R Wang, JJ Mitchell, P Miao, H Lee, KE Joshi, T Buck, M Chugha, P Bardenstein, D Klein, AP Bailey-Wilson, JE Gong, XH Spector, TD Andrew, T Hammond, CJ Elston, RC Iyengar, SK Wang, BC AF Jun, Gyungah Guo, Hong Klein, Barbara E. K. Klein, Ronald Wang, Jie Jin Mitchell, Paul Miao, Hui Lee, Kristine E. Joshi, Tripti Buck, Matthias Chugha, Preeti Bardenstein, David Klein, Alison P. Bailey-Wilson, Joan E. Gong, Xiaohua Spector, Tim D. Andrew, Toby Hammond, Christopher J. Elston, Robert C. Iyengar, Sudha K. Wang, Bingcheng TI EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans SO PLOS GENETICS LA English DT Article ID BEAVER DAM EYE; DISEASE RISK-FACTORS; LENS OPACITIES; CHROMOSOME 1P; CARDIOVASCULAR-DISEASE; POWER-TRANSFORMATIONS; POPULATION; IDENTIFICATION; EXPRESSION; LOCUS AB Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age. C1 [Jun, Gyungah; Joshi, Tripti; Iyengar, Sudha K.] Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Guo, Hong; Miao, Hui; Wang, Bingcheng] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Rammelkamp Ctr Res, Cleveland, OH 44106 USA. [Guo, Hong; Miao, Hui; Wang, Bingcheng] Case Western Reserve Univ, Sch Med, Ireland Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Klein, Barbara E. K.; Klein, Ronald; Lee, Kristine E.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Ctr Vis Res, Westmead Hosp, Westmead Millennium Inst,Dept Ophthalmol, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Wang, Jie Jin] Univ Melbourne, Dept Ophthalmol, Melbourne, Vic, Australia. [Buck, Matthias; Chugha, Preeti] Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. [Bardenstein, David] Case Western Reserve Univ, Sch Med, Dept Ophthalmol & Pathol, Ocular Oncol Serv, Cleveland, OH 44106 USA. [Klein, Alison P.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Gong, Xiaohua] Univ Calif Berkeley, Univ Calif San Francisco, Sch Optometry, Joint Bioengn Grad Program, Berkeley, CA 94720 USA. [Gong, Xiaohua] Univ Calif Berkeley, Univ Calif San Francisco, Vis Sci Program, Joint Bioengn Grad Program, Berkeley, CA 94720 USA. [Spector, Tim D.; Andrew, Toby; Hammond, Christopher J.; Elston, Robert C.] Kings Coll London, St Thomas Hosp Campus, Twin Res & Genet Epidemiol Unit, London WC2R 2LS, England. [Iyengar, Sudha K.] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA. [Iyengar, Sudha K.] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH 44106 USA. RP Jun, G (reprint author), Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. EM ski@case.edu; bxw14@case.edu RI Wang, Jie Jin/P-1499-2014; Mitchell, Paul/P-1498-2014; Buck, Matthias/B-2106-2017; OI Wang, Jie Jin/0000-0001-9491-4898; Buck, Matthias/0000-0002-2958-0403; Andrew, Toby/0000-0001-8838-4384; Jun, Gyungah/0000-0002-3230-8697; Bailey-Wilson, Joan/0000-0002-9153-2920; Klein, Ronald/0000-0002-4428-6237; Hammond, Christopher/0000-0002-3227-2620 FU National Cancer Institute [CA96533, CA92259]; National Institute of Diabetes and Digestive and Kidney Diseases [DK077876]; National Eye Institute [EY11373, U10EY06594, EY015286, EY13438, EY10605, P30EY11373, EY015810]; National Institute of General Medical Sciences [GM28356]; NHMRC [974159, 211069]; National Human Genome Research Institute; Wellcome Trust; Arthritis Research Campaign; Guide dogs for the Blind and Chronic Disease Research Foundation; Center for Inherited Disease Research [N01-HG-65403]; National Center for Research Resources [RR03655] FX This study was supported, in part, by grants CA96533 and CA92259 from the National Cancer Institute; DK077876 from National Institute of Diabetes and Digestive and Kidney Diseases; EY11373, U10EY06594, EY015286, EY13438, EY10605, P30EY11373, and EY015810 from the National Eye Institute; GM28356 from the National Institute of General Medical Sciences; and grants 974159 and 211069 from NHMRC and from the intramural program of the National Human Genome Research Institute. The St Thomas' UK Adult Twin Registry (TwinsUK) received funds from Wellcome Trust, the Arthritis Research Campaign, Guide dogs for the Blind and Chronic Disease Research Foundation. Genotyping services were provided by the Center for Inherited Disease Research (contract number N01-HG-65403). This work was conducted using the software package S. A. G. E., supported by RR03655 from the National Center for Research Resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 68 Z9 70 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2009 VL 5 IS 7 AR e1000584 DI 10.1371/journal.pgen.1000584 PG 19 WC Genetics & Heredity SC Genetics & Heredity GA 486SZ UT WOS:000269219500008 PM 19649315 ER PT J AU Kwon, SY Xiao, H Wu, C Badenhorst, P AF Kwon, So Yeon Xiao, Hua Wu, Carl Badenhorst, Paul TI Alternative Splicing of NURF301 Generates Distinct NURF Chromatin Remodeling Complexes with Altered Modified Histone Binding Specificities SO PLOS GENETICS LA English DT Article ID SPERMATID DIFFERENTIATION; DROSOPHILA-MELANOGASTER; GENE-EXPRESSION; MEIOTIC ARREST; PHD FINGER; ISWI; TRANSCRIPTION; PROTEIN; ORGANIZATION; ACTIVATION AB Drosophila NURF is an ISWI-containing chromatin remodeling complex that catalyzes ATP-dependent nucleosome sliding. By sliding nucleosomes, NURF can alter chromatin structure and regulate transcription. NURF301/BPTF is the only NURF specific subunit of NURF and is instrumental in recruiting the complex to target genes. Here we demonstrate that three NURF301 isoforms are expressed and that these encode functionally distinct NURF chromatin remodeling complexes. Full-length NURF301 contains a C-terminal bromodomain and juxtaposed PHD finger that bind histone H3 trimethylated at Lys4 (H3K4me3) and histone H4 acetylated at Lys16 (H4K16Ac) respectively. However, a NURF301 isoform that lacks these C-terminal domains is also detected. This truncated NURF301 isoform assembles a complex containing ISWI, NURF55, and NURF38, indicating that a second class of NURF remodeling complex, deficient in H3K4me3 and H4K16Ac recognition, exists. By comparing microarray expression profiles and phenotypes of null Nurf301 mutants with mutants that remove the C-terminal PHD fingers and bromodomain, we show that full-length NURF301 is not essential for correct expression of the majority of NURF gene targets in larvae. However, full-length NURF301 is required for spermatogenesis. Mutants that lack full-length NURF exhibit a spermatocyte arrest phenotype and fail to express a subset of spermatid differentiation genes. Our data reveal that variants of the NURF ATP-dependent chromatin remodeling complex that recognize post-translational histone modifications are important regulators of primary spermatocyte differentiation in Drosophila. C1 [Kwon, So Yeon; Badenhorst, Paul] Univ Birmingham, Inst Biomed Res, Edgbaston, England. [Xiao, Hua; Wu, Carl] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kwon, SY (reprint author), Univ Birmingham, Inst Biomed Res, Edgbaston, England. EM p.w.badenhorst@bham.ac.uk RI Kwon, So Yeon/M-5625-2014; OI Kwon, So Yeon/0000-0002-8490-9101; Badenhorst, Paul/0000-0002-2542-0250 FU BBSRC; CRUK FX This work was partly supported by grants from the BBSRC (www.bbsrc.ac.uk) and CRUK (www.cancerresearchuk.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 30 Z9 31 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUL PY 2009 VL 5 IS 7 AR e1000574 DI 10.1371/journal.pgen.1000574 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 486SZ UT WOS:000269219500015 PM 19629165 ER PT J AU Malhotra, I Dent, A Mungai, P Wamachi, A Ouma, JH Narum, DL Muchiri, E Tisch, DJ King, CL AF Malhotra, Indu Dent, Arlene Mungai, Peter Wamachi, Alex Ouma, John H. Narum, David L. Muchiri, Eric Tisch, Daniel J. King, Christopher L. TI Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya SO PLOS MEDICINE LA English DT Article ID MEROZOITE SURFACE PROTEIN-1; PLASMODIUM-FALCIPARUM INFECTION; INVASION-INHIBITORY ANTIBODIES; RECEPTOR-BINDING DOMAIN; TIME QUANTITATIVE PCR; IN-UTERO; T-CELL; MATERNAL MALARIA; HUMAN PLACENTA; RESPONSES AB Background: Malaria in pregnancy can expose the fetus to malaria-infected erythrocytes or their soluble products, thereby stimulating T and B cell immune responses to malaria blood stage antigens. We hypothesized that fetal immune priming, or malaria exposure in the absence of priming (putative tolerance), affects the child's susceptibility to subsequent malaria infections. Methods and Findings: We conducted a prospective birth cohort study of 586 newborns residing in a malaria-holoendemic area of Kenya who were examined biannually to age 3 years for malaria infection, and whose malaria-specific cellular and humoral immune responses were assessed. Newborns were classified as (i) sensitized (and thus exposed), as demonstrated by IFN gamma, IL-2, IL-13, and/or IL-5 production by cord blood mononuclear cells (CBMCs) to malaria blood stage antigens, indicative of in utero priming (n = 246), (ii) exposed not sensitized (mother Plasmodium falciparum [Pf]+ and no CBMC production of IFN gamma, IL-2, IL-13, and/or IL-5, n = 120), or (iii) not exposed (mother Pf-, no CBMC reactivity, n = 220). Exposed not sensitized children had evidence for prenatal immune experience demonstrated by increased IL-10 production and partial reversal of malaria antigen-specific hyporesponsiveness with IL-2+IL-15, indicative of immune tolerance. Relative risk data showed that the putatively tolerant children had a 1.61 (95% confidence interval [CI] 1.10-2.43; p = 0.024) and 1.34 (95% CI 0.95-1.87; p = 0.097) greater risk for malaria infection based on light microscopy (LM) or PCR diagnosis, respectively, compared to the not-exposed group, and a 1.41 (95% CI 0.97-2.07, p = 0.074) and 1.39 (95% CI 0.99-2.07, p = 0.053) greater risk of infection based on LM or PCR diagnosis, respectively, compared to the sensitized group. Putatively tolerant children had an average of 0.5 g/dl lower hemoglobin levels (p = 0.01) compared to the other two groups. Exposed not sensitized children also had 2- to 3-fold lower frequency of malaria antigen-driven IFN gamma and/or IL-2 production (p, 0.001) and higher IL-10 release (p, 0.001) at 6-month follow-ups, when compared to sensitized and not-exposed children. Malaria blood stage-specific IgG antibody levels were similar among the three groups. Conclusions: These results show that a subset of children exposed to malaria in utero acquire a tolerant phenotype to blood-stage antigens that persists into childhood and is associated with an increased susceptibility to malaria infection and anemia. This finding could have important implications for malaria vaccination of children residing in endemic areas. C1 [Malhotra, Indu; Dent, Arlene; Mungai, Peter; Tisch, Daniel J.; King, Christopher L.] Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. [Mungai, Peter; Ouma, John H.; Muchiri, Eric] Div Vector Borne Dis, Nairobi, Kenya. [Wamachi, Alex] Kenya Govt Med Res Ctr, Nairobi, Kenya. [Narum, David L.] NIAID, Malaria Vaccine Dev Unit, Bethesda, MD 20892 USA. [King, Christopher L.] Vet Affairs Med Ctr, Cleveland, OH USA. RP Malhotra, I (reprint author), Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. EM cxk21@case.edu FU United States Public Health Service [AI064687, AI054711, MH080601, AI065717]; Veterans' Affairs Research Service FX The work was supported in part by United States Public Health Service grants AI064687, AI054711, MH080601, AI065717 and Veterans' Affairs Research Service. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. They did contribute to the design of the study. NR 63 TC 71 Z9 71 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD JUL PY 2009 VL 6 IS 7 AR e1000116 DI 10.1371/journal.pmed.1000116 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 476OR UT WOS:000268452400013 PM 19636353 ER PT J AU Babu, S Bhat, SQ Kumar, NP Anuradha, R Kumaran, P Gopi, PG Kolappan, C Kumaraswami, V Nutman, TB AF Babu, Subash Bhat, Sajid Q. Kumar, N. Pavan Anuradha, R. Kumaran, Paul Gopi, P. G. Kolappan, C. Kumaraswami, V. Nutman, Thomas B. TI Attenuation of Toll-Like Receptor Expression and Function in Latent Tuberculosis by Coexistent Filarial Infection with Restoration Following Antifilarial Chemotherapy SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID TUMOR-NECROSIS-FACTOR; MYCOBACTERIUM-TUBERCULOSIS; IMMUNE-RESPONSES; HELMINTH-PARASITES; INTERFERON-GAMMA; TH1 RESPONSES; HOST-DEFENSE; MICE; RESISTANCE; DEFECTS AB Mycobacterium tuberculosis (Mtb) and filarial coinfection is highly prevalent, and the presence of filarial infections may regulate the Toll-like receptor (TLR)-dependent immune response needed to control Mtb infection. By analyzing the baseline and mycobacterial antigen-stimulated expression of TLR1, 2, 4, and 9 (in individuals with latent tuberculosis [TB] with or without filarial infection), we were able to demonstrate that filarial infection, coincident with Mtb, significantly diminishes both baseline and Mtb antigen-specific TLR2 and TLR9 expression. In addition, pro-inflammatory cytokine responses to TLR2 and 9 ligands are significantly diminished in filaria/TB-coinfected individuals. Definitive treatment of lymphatic filariasis significantly restores the pro-inflammatory cytokine responses in individuals with latent TB. Coincident filarial infection exerted a profound inhibitory effect on protective mycobacteria-specific TLR-mediated immune responses in latent tuberculosis and suggests a novel mechanism by which concomitant filarial infections predispose to the development of active tuberculosis in humans. C1 [Babu, Subash; Bhat, Sajid Q.; Kumar, N. Pavan; Anuradha, R.] NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. [Babu, Subash] NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Kumaran, Paul; Gopi, P. G.; Kolappan, C.; Kumaraswami, V.] TB Res Ctr, Madras, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIH, Int Ctr Excellence Res, Madras, Tamil Nadu, India. EM sbabu@mail.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID) FX This work was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 31 Z9 31 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2009 VL 3 IS 7 AR e489 DI 10.1371/journal.pntd.0000489 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 476OP UT WOS:000268452200018 PM 19636364 ER PT J AU Grab, DJ Garcia-Garcia, JC Nikolskaia, OV Kim, YV Brown, A Pardo, CA Zhang, YQ Becker, KG Wilson, BA Lima, APCD Scharfstein, J Dumler, JS AF Grab, Dennis J. Garcia-Garcia, Jose C. Nikolskaia, Olga V. Kim, Yuri V. Brown, Amanda Pardo, Carlos A. Zhang, Yongqing Becker, Kevin G. Wilson, Brenda A. Lima, Ana Paula C. de A. Scharfstein, Julio Dumler, J. Stephen TI Protease Activated Receptor Signaling Is Required for African Trypanosome Traversal of Human Brain Microvascular Endothelial Cells SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID PASTEURELLA-MULTOCIDA TOXIN; GENE SET ENRICHMENT; BLOOD-STREAM FORMS; IN-VITRO; PORPHYROMONAS-GINGIVALIS; CYSTEINE PROTEASE; BORRELIA-BURGDORFERI; THROMBIN RECEPTORS; EPITHELIAL-CELLS; HUMAN PLATELETS AB Background: Using human brain microvascular endothelial cells (HBMECs) as an in vitro model for how African trypanosomes cross the human blood-brain barrier (BBB) we recently reported that the parasites cross the BBB by generating calcium activation signals in HBMECs through the activity of parasite cysteine proteases, particularly cathepsin L (brucipain). In the current study, we examined the possible role of a class of protease stimulated HBMEC G protein coupled receptors (GPCRs) known as protease activated receptors (PARs) that might be implicated in calcium signaling by African trypanosomes. Methodology/Principal Findings: Using RNA interference (RNAi) we found that in vitro PAR-2 gene (F2RL1) expression in HBMEC monolayers could be reduced by over 95%. We also found that the ability of Trypanosoma brucei rhodesiense to cross F2RL1-silenced HBMEC monolayers was reduced (39%-49%) and that HBMECs silenced for F2RL1 maintained control levels of barrier function in the presence of the parasite. Consistent with the role of PAR-2, we found that HBMEC barrier function was also maintained after blockade of G alpha(q) with Pasteurella multocida toxin (PMT). PAR-2 signaling has been shown in other systems to have neuroinflammatory and neuroprotective roles and our data implicate a role for proteases (i.e. brucipain) and PAR-2 in African trypanosome/HBMEC interactions. Using gene-profiling methods to interrogate candidate HBMEC pathways specifically triggered by brucipain, several pathways that potentially link some pathophysiologic processes associated with CNS HAT were identified. Conclusions/Significance: Together, the data support a role, in part, for GPCRs as molecular targets for parasite proteases that lead to the activation of G alpha(q)-mediated calcium signaling. The consequence of these events is predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease. C1 [Grab, Dennis J.; Nikolskaia, Olga V.; Kim, Yuri V.] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Grab, Dennis J.; Garcia-Garcia, Jose C.; Dumler, J. Stephen] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Brown, Amanda; Pardo, Carlos A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Wilson, Brenda A.] Univ Illinois, Dept Microbiol, Urbana, IL 61801 USA. [Lima, Ana Paula C. de A.; Scharfstein, Julio] Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. RP Grab, DJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. EM dgrab1@jhmi.edu RI Lima, Ana Paula/G-4122-2012; Inbeb, Inct/K-2317-2013; OI Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health [RO1AI051464, R01AI038936]; Fogarty International Foundation; American Heart Association [SDG 0435177N]; NIH; National Institute on Aging (KGB) FX lThis research was supported in part by grants from the National Institutes of Health (RO1AI051464) to DJG and (R01AI038936) to BAW, the Fogarty International Foundation (FIRCA) to DJG/JS, the American Heart Association (SDG 0435177N) to YVK, and by the Intramural Research Program of the NIH, National Institute on Aging (KGB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 71 TC 35 Z9 36 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2009 VL 3 IS 7 AR e479 DI 10.1371/journal.pntd.0000479 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 476OP UT WOS:000268452200010 PM 19621073 ER PT J AU Tekola, F Bull, SJ Farsides, B Newport, MJ Adeyemo, A Rotimi, CN Davey, G AF Tekola, Fasil Bull, Susan J. Farsides, Bobbie Newport, Melanie J. Adeyemo, Adebowale Rotimi, Charles N. Davey, Gail TI Tailoring Consent to Context: Designing an Appropriate Consent Process for a Biomedical Study in a Low Income Setting SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID INFORMED-CONSENT; THERAPEUTIC MISCONCEPTION; KENYAN COAST; TRUST; PODOCONIOSIS AB Background: Currently there is increasing recognition of the need for research in developing countries where disease burden is high. Understanding the role of local factors is important for undertaking ethical research in developing countries. We explored factors relating to information and communication during the process of informed consent, and the approach that should be followed for gaining consent. The study was conducted prior to a family-based genetic study among people with podoconiosis (non-filarial elephantiasis) in southern Ethiopia. Methodology/Principal Findings: We adapted a method of rapid assessment validated in The Gambia. The methodology was entirely qualitative, involving focus-group discussions and in-depth interviews. Discussions were conducted with podoconiosis patients and non-patients in the community, fieldworkers, researchers, staff of the local non-governmental organisation (NGO) working on prevention and treatment of podoconiosis, and community leaders. We found that the extent of use of everyday language, the degree to which expectations of potential participants were addressed, and the techniques of presentation of information had considerable impact on comprehension of information provided about research. Approaching podoconiosis patients via locally trusted individuals and preceding individual consent with community sensitization were considered the optimal means of communication. Prevailing poverty among podoconiosis patients, the absence of alternative treatment facilities, and participants' trust in the local NGO were identified as potential barriers for obtaining genuine informed consent. Conclusions: Researchers should evaluate the effectiveness of consent processes in providing appropriate information in a comprehensible manner and in supporting voluntary decision-making on a study-by-study basis. C1 [Tekola, Fasil; Davey, Gail] Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. [Tekola, Fasil; Farsides, Bobbie; Newport, Melanie J.] Brighton & Sussex Med Sch, Falmer, Sussex, England. [Tekola, Fasil; Adeyemo, Adebowale; Rotimi, Charles N.] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD USA. [Bull, Susan J.] Univ Oxford, Ethox Ctr, Div Publ Hlth & Primary Care, Oxford OX1 2JD, England. RP Tekola, F (reprint author), Univ Addis Ababa, Sch Publ Hlth, Addis Ababa, Ethiopia. EM F.Tekola@bsms.ac.uk OI Davey, Gail/0000-0003-2796-7468; Adeyemo, Adebowale/0000-0002-3105-3231; Tekola-Ayele, Fasil/0000-0003-4194-9370 FU Wellcome Trust, UK [079791] FX The study was funded by the Wellcome Trust, UK, project grant 079791. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 39 Z9 39 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD JUL PY 2009 VL 3 IS 7 AR e482 DI 10.1371/journal.pntd.0000482 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 476OP UT WOS:000268452200013 PM 19621067 ER PT J AU Ammann, CG Messer, RJ Peterson, KE Hasenkrug, KJ AF Ammann, Christoph G. Messer, Ronald J. Peterson, Karin E. Hasenkrug, Kim J. TI Lactate Dehydrogenase-Elevating Virus Induces Systemic Lymphocyte Activation via TLR7-Dependent IFN alpha Responses by Plasmacytoid Dendritic Cells SO PLOS ONE LA English DT Article AB Background: Lactate dehydrogenase-elevating virus (LDV) is a natural infectious agent of mice. Like several other viruses, LDV causes widespread and very rapid but transient activation of both B cells and T cells in lymphoid tissues and the blood. The mechanism of this activation has not been fully described and is the focus of the current studies. Principal Findings: A known inducer of early lymphocyte activation is IFN alpha, a cytokine strongly induced by LDV infection. Neutralization of IFN alpha in the plasma from infected mice ablated its ability to activate lymphocytes in vitro. Since the primary source of virus-induced IFN alpha in vivo is often plasmacytoid dendritic cells (pDC's), we depleted these cells prior to LDV infection and tested for lymphocyte activation. Depletion of pDC's in vivo eradicated both the LDV-induced IFN alpha response and lymphocyte activation. A primary receptor in pDC's for single stranded RNA viruses such as LDV is the toll-like receptor 7 (TLR7) pattern recognition receptor. Infection of TLR7-knockout mice revealed that both the IFN alpha response and lymphocyte activation were dependent on TLR7 signaling in vivo. Interestingly, virus levels in both TLR7 knockout mice and pDC-depleted mice were indistinguishable from controls indicating that LDV is largely resistant to the systemic IFN alpha response. Conclusion: Results indicate that LDV-induced activation of lymphocytes is due to recognition of LDV nucleic acid by TLR7 pattern recognition receptors in pDC's that respond with a lymphocyte-inducing IFN alpha response. RP Ammann, CG (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov RI Peterson, Karin/D-1492-2016; OI Peterson, Karin/0000-0003-4177-7249; Ammann, Christoph/0000-0002-6267-1286 FU Intramural NIH HHS NR 33 TC 19 Z9 19 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 1 PY 2009 VL 4 IS 7 AR e6105 DI 10.1371/journal.pone.0006105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465HA UT WOS:000267572200008 PM 19568424 ER PT J AU Journo, C Filipe, J About, F Chevalier, SA Afonso, PV Brady, JN Flynn, D Tangy, F Israel, A Vidalain, PO Mahieux, R Weil, R AF Journo, Chloe Filipe, Josina About, Fredegonde Chevalier, Sebastien A. Afonso, Philippe V. Brady, John N. Flynn, David Tangy, Frederic Israel, Alain Vidalain, Pierre-Olivier Mahieux, Renaud Weil, Robert TI NRP/Optineurin Cooperates with TAX1BP1 to Potentiate the Activation of NF-kappa B by Human T-Lymphotropic Virus Type 1 Tax Protein SO PLOS PATHOGENS LA English DT Article ID EDITING ENZYME A20; HTLV-I; ONCOPROTEIN; IKK; UBIQUITINATION; KINASE; ALPHA; GAMMA; NEMO; SUMOYLATION AB Nuclear factor (NF)-kappa B is a major survival pathway engaged by the Human T-Lymphotropic Virus type 1 (HTLV-1) Tax protein. Tax1 activation of NF-kappa B occurs predominantly in the cytoplasm, where Tax1 binds NF-kB Essential Modulator (NEMO/IKK gamma) and triggers the activation of I kappa B kinases. Several independent studies have shown that Tax1-mediated NF-kappa B activation is dependent on Tax1 ubiquitination. Here, we identify by co-immunoprecipitation assays NEMO-Related Protein (NRP/Optineurin) as a binding partner for Tax1 in HTLV-1 infected and Tax1/NRP co-expressing cells. Immunofluorescence studies reveal that Tax1, NRP and NEMO colocalize in Golgi-associated structures. The interaction between Tax1 and NRP requires the ubiquitin-binding activity of NRP and the ubiquitination sites of Tax1. In addition, we observe that NRP increases the ubiquitination of Tax1 along with Tax1-dependent NF-kappa B signaling. Surprisingly, we find that in addition to Tax1, NRP interacts cooperatively with the Tax1 binding protein TAX1BP1, and that NRP and TAX1BP1 cooperate to modulate Tax1 ubiquitination and NF-kappa B activation. Our data strongly suggest for the first time that NRP is a critical adaptor that regulates the assembly of TAX1BP1 and post-translationally modified forms of Tax1, leading to sustained NF-kappa B activation. C1 [Journo, Chloe; About, Fredegonde; Afonso, Philippe V.; Mahieux, Renaud] Inst Pasteur, CNRS, URA 3015, Unite Epidemiol & Physiopathol Virus Oncogenes, Paris, France. [Journo, Chloe; Mahieux, Renaud] INSERM, U758, F-69008 Lyon, France. [Journo, Chloe; Mahieux, Renaud] Ecole Normale Super, Lyon, France. [Journo, Chloe; Mahieux, Renaud] IFR 128 BioSci Lyon Gerland, Lyon, France. [Filipe, Josina; Israel, Alain; Weil, Robert] Inst Pasteur, CNRS, URA 2582, Unite Signalisat Mol & Activat Cellulaire, Paris, France. [Chevalier, Sebastien A.; Brady, John N.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Flynn, David; Tangy, Frederic; Vidalain, Pierre-Olivier] Inst Pasteur, Lab Genom Virale & Vaccinat, Paris, France. RP Journo, C (reprint author), Inst Pasteur, CNRS, URA 3015, Unite Epidemiol & Physiopathol Virus Oncogenes, Paris, France. EM renaud.mahieux@ens-lyon.fr RI Afonso, Philippe/D-2234-2014 OI Afonso, Philippe/0000-0002-4828-3797 FU Ecole Normale Superieure de Lyon; CNRS; Ministere de la Recherche; Fundacao para a Ciencia e a Tecnologia PhD fellowship; Fulbright Fellowship through the U. S. Department of State Bureau of Educational and Cultural Affairs; Pasteur Institute [PTR214]; Rubicon FP6 European Network of Excellence FX RM was supported by INSERM and is now supported by Ecole Normale Superieure de Lyon. RW is supported by CNRS. CJ, SAL and PVA were supported by the Ministere de la Recherche. JF is a recipient of the Fundacao para a Ciencia e a Tecnologia PhD fellowship. DF was supported by a Fulbright Fellowship through the U. S. Department of State Bureau of Educational and Cultural Affairs. This work was supported by PTR214 from the Pasteur Institute and by the Rubicon FP6 European Network of Excellence to AI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 45 Z9 45 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2009 VL 5 IS 7 AR e1000521 DI 10.1371/journal.ppat.1000521 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 486UJ UT WOS:000269224500022 PM 19609363 ER PT J AU Queck, SY Khan, BA Wang, R Bach, THL Kretschmer, D Chen, L Kreiswirth, BN Peschel, A DeLeo, FR Otto, M AF Queck, Shu Y. Khan, Burhan A. Wang, Rong Bach, Thanh-Huy L. Kretschmer, Dorothee Chen, Liang Kreiswirth, Barry N. Peschel, Andreas DeLeo, Frank R. Otto, Michael TI Mobile Genetic Element-Encoded Cytolysin Connects Virulence to Methicillin Resistance in MRSA SO PLOS PATHOGENS LA English DT Article ID PHENOL-SOLUBLE MODULINS; QUORUM-SENSING SYSTEM; CHROMOSOME MEC TYPE; STAPHYLOCOCCUS-AUREUS; HUMAN-NEUTROPHILS; JOINT PROSTHESES; WHOLE GENOME; EPIDERMIDIS; STRAINS; EVOLUTION AB Bacterial virulence and antibiotic resistance have a significant influence on disease severity and treatment options during bacterial infections. Frequently, the underlying genetic determinants are encoded on mobile genetic elements (MGEs). In the leading human pathogen Staphylococcus aureus, MGEs that contain antibiotic resistance genes commonly do not contain genes for virulence determinants. The phenol-soluble modulins (PSMs) are staphylococcal cytolytic toxins with a crucial role in immune evasion. While all known PSMs are core genome-encoded, we here describe a previously unidentified psm gene, psm-mec, within the staphylococcal methicillin resistance-encoding MGE SCCmec. PSM-mec was strongly expressed in many strains and showed the physico-chemical, pro-inflammatory, and cytolytic characteristics typical of PSMs. Notably, in an S. aureus strain with low production of core genome-encoded PSMs, expression of PSM-mec had a significant impact on immune evasion and disease. In addition to providing high-level resistance to methicillin, acquisition of SCCmec elements encoding PSM-mec by horizontal gene transfer may therefore contribute to staphylococcal virulence by substituting for the lack of expression of core genome-encoded PSMs. Thus, our study reveals a previously unknown role of methicillin resistance clusters in staphylococcal pathogenesis and shows that important virulence and antibiotic resistance determinants may be combined in staphylococcal MGEs. C1 [Queck, Shu Y.; Khan, Burhan A.; Wang, Rong; Bach, Thanh-Huy L.; DeLeo, Frank R.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Queck, Shu Y.; Khan, Burhan A.; Wang, Rong; Bach, Thanh-Huy L.; DeLeo, Frank R.; Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT USA. [Kretschmer, Dorothee; Peschel, Andreas] Univ Tubingen, Med Microbiol & Hyg Dept, Cellular & Mol Microbiol Unit, Tubingen, Germany. [Chen, Liang; Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ 07103 USA. RP Queck, SY (reprint author), Nanyang Polytech, Singapore, Singapore. EM motto@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU NIH; German Research Council; German Ministry of Education and Research FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH ( to M. O. and F. R. D.), the German Research Council ( SFB 685) and the German Ministry of Education and Research ( to A. P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 94 Z9 101 U1 1 U2 15 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD JUL PY 2009 VL 5 IS 7 AR e1000533 DI 10.1371/journal.ppat.1000533 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 486UJ UT WOS:000269224500009 PM 19649313 ER PT J AU Weinstein, AA Drinkard, BM Diao, GQ Furst, G Dale, JK Straus, SE Gerber, LH AF Weinstein, Ali A. Drinkard, Bart M. Diao, Guoqing Furst, Gloria Dale, Janet K. Straus, Stephen E. Gerber, Lynn H. TI Exploratory Analysis of the Relationships between Aerobic Capacity and Self-Reported Fatigue in Patients with Rheumatoid Arthritis, Polymyositis, and Chronic Fatigue Syndrome SO PM&R LA English DT Article AB Objective: To determine if self-reported levels of physical activity and fatigue are related to peak oxygen uptake (VO2peak) and whether these relationships differ among the patient groups (rheumatoid arthritis [RA], polymyositis [PM], and chronic fatigue syndrome [CFS]). Design: Correlational investigation. Setting: Two ambulatory research clinics at the National Institutes of Health, Clinical Center, Bethesda, MD. Participants: There were 9 patients with PM, 10 with RA, and 10 with CFS. All patients met case criteria for their respective diagnoses. Methods/Main Outcome Measurements: VO2peak during bicycle ergometry and self-reported fatigability, fatigue, and physical activity. VO2peak was used as the criterion measurement of physiological fatigue with which the self-reported variables were compared. Results: The Pearson r revealed that self-reported physical activity correlated with VO2peak (r = 61, P = .01). However, fatigability and fatigue did not correlate with VO2peak. Linear regression analysis was performed to assess the effects of diagnosis group, self-reported activity level or fatigue, and their interaction. A trend in the data showed a distinctive relationship between fatigue/fatigability within the 3 groups. In addition, when controlling for group status, self-reported activity predicted aerobic capacity as measured by VO2peak Conclusions: This study confirms that patients with chronic, but stable RA, PM, or CFS are fatigued and have significantly decreased aerobic capacity. Self-reports of physical activity predicted VO2peak, and may be used as an indicator of activity-based aerobic capacity. Self-reports of fatigue, however, did not correlate with VO2peak and hence are assessing something other than an index of aerobic capacity, and provide additional information about patients' perceptions, which will require further investigation. C1 [Weinstein, Ali A.; Gerber, Lynn H.] George Mason Univ, Ctr Study Chron Illness & Disabil, Fairfax, VA 22030 USA. [Drinkard, Bart M.; Furst, Gloria] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Diao, Guoqing] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Dale, Janet K.] NIAID, Clin Res Program, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Straus, Stephen E.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Weinstein, AA (reprint author), George Mason Univ, Ctr Study Chron Illness & Disabil, 4400 Univ Dr,MSN 5B7, Fairfax, VA 22030 USA. EM aweinst2@gmu.edu FU Divisions for Intramural Research, Rehabilitation Medicine Department of the Clinical Center; NIAID, National Institute of Health FX Research supported by the Divisions for Intramural Research, Rehabilitation Medicine Department of the Clinical Center, and NIAID, National Institute of Health. NR 62 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1934-1482 J9 PM&R JI PM&R PD JUL PY 2009 VL 1 IS 7 BP 620 EP 628 DI 10.1016/j.pmrj.2009.04.007 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA V24LK UT WOS:000208411700004 PM 19627955 ER PT J AU Esposito, L Fisher, JO Mennella, JA Hoelscher, DM Huang, TT AF Esposito, Layla Fisher, Jennifer O. Mennella, Julie A. Hoelscher, Deanna M. Huang, Terry T. TI Developmental Perspectives on Nutrition and Obesity From Gestation to Adolescence SO PREVENTING CHRONIC DISEASE LA English DT Article AB Obesity results from a complex combination of factors that act at many stages throughout a person's life. Therefore, examining childhood nutrition and obesity from a developmental perspective is warranted. A developmental perspective recognizes the cumulative effects of factors that contribute to eating behavior and obesity, including biological and socioenvironmental factors that are relevant at different stages of development. A developmental perspective considers family, school, and community context. During gestation, risk factors for obesity include maternal diet, overweight, and smoking. In early childhood, feeding practices, taste acquisition, and eating in the absence of hunger must be considered. As children become more independent during middle childhood and adolescence, school nutrition, food marketing, and social networks become focal points for obesity prevention or intervention. Combining a multilevel approach with a developmental perspective can inform more effective and sustainable strategies for obesity prevention. C1 [Esposito, Layla; Huang, Terry T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Fisher, Jennifer O.] Temple Univ, Philadelphia, PA 19122 USA. [Mennella, Julie A.] Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. [Hoelscher, Deanna M.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. RP Huang, TT (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,4B11, Bethesda, MD 20892 USA. EM huangter@mail.nih.gov NR 99 TC 5 Z9 5 U1 3 U2 10 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2009 VL 6 IS 3 AR A94 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20RX UT WOS:000208158200014 PM 19527595 ER PT J AU Haemer, MA Huang, TT Daniels, SR AF Haemer, Matthew A. Huang, Terry T. Daniels, Stephen R. TI The Effect of Neurohormonal Factors, Epigenetic Factors, and Gut Microbiota on Risk of Obesity SO PREVENTING CHRONIC DISEASE LA English DT Article AB Molecular, cellular, and epidemiologic findings suggest that neurohormonal, epigenetic, and microbiologic mechanisms may influence risk for obesity by interacting with socioenvironmental factors. Homeostatic and nonhomeostatic neural controls of energy predispose people to obesity, and this predisposition may be exaggerated by the influence of media, marketing, and sleep patterns. Epigenetic gene regulation may account for the influence of modifiable early life or maternal exposures on obesity risk. Alterations in gut flora caused by infant feeding practices or later diet may influence the absorption and storage of energy. Further exploration of how these molecular-cellular mechanisms might increase obesity risk in response to modifiable socioeconomic factors requires the partnership of laboratory and public health researchers. C1 [Haemer, Matthew A.] Univ Colorado, Sch Med, Pediat Sect Nutr, Childrens Hosp, Aurora, CO 80045 USA. [Huang, Terry T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Haemer, MA (reprint author), Univ Colorado, Sch Med, Pediat Sect Nutr, Childrens Hosp, 13123 E 16th Ave,B270, Aurora, CO 80045 USA. EM Haemer.matthew@tchden.org FU NIDDK NIH HHS [T32 DK007658] NR 68 TC 6 Z9 7 U1 2 U2 5 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2009 VL 6 IS 3 AR A96 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20RX UT WOS:000208158200016 PM 19527597 ER PT J AU Huang, TT Yaroch, AL AF Huang, Terry T. Yaroch, Amy L. TI A Public-Private Partnership Model for Obesity Prevention SO PREVENTING CHRONIC DISEASE LA English DT Letter C1 [Huang, Terry T.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Yaroch, Amy L.] Ctr Human Nutr, Omaha, NE USA. RP Huang, TT (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. NR 5 TC 9 Z9 9 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2009 VL 6 IS 3 AR A110 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20RX UT WOS:000208158200030 PM 19527582 ER PT J AU Huang, TT Drewnowski, A Kumanyika, SK Glass, TA AF Huang, Terry T. Drewnowski, Adam Kumanyika, Shiriki K. Glass, Thomas A. TI A Systems-Oriented Multilevel Framework for Addressing Obesity in the 21st Century SO PREVENTING CHRONIC DISEASE LA English DT Editorial Material C1 [Drewnowski, Adam] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Kumanyika, Shiriki K.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Glass, Thomas A.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Huang, TT (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, 6100 Execut Blvd,4B11, Bethesda, MD 20892 USA. EM huangter@mail.nih.gov NR 52 TC 129 Z9 131 U1 2 U2 13 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2009 VL 6 IS 3 AR A82 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20RX UT WOS:000208158200002 PM 19527584 ER PT J AU Koehly, LM Loscalzo, A AF Koehly, Laura M. Loscalzo, Aunchalee TI Adolescent Obesity and Social Networks SO PREVENTING CHRONIC DISEASE LA English DT Article ID FOOD PREFERENCES; CHILDREN; OVERWEIGHT; ASSOCIATIONS; HERITABILITY; PREVENTION; CHILDHOOD; MEDICINE; MASS AB The prevalence of overweight among children worldwide is growing at an alarming rate. Social relationships may contribute to the development of obesity through the interaction of biological, behavioral, and environmental factors. Although there is evidence that early environment influences the expression of obesity, very little research elucidates the social context of obesity among children or adolescents. Social network approaches can contribute to research on the role of social environments in overweight and obesity and strengthen interventions to prevent disease and promote health. By capitalizing on the structure of the network system, a targeted intervention that uses social relationships in families, schools, neighborhoods, and communities may be successful in encouraging healthful behaviors among children and their families. C1 [Loscalzo, Aunchalee] NHGRI, Bethesda, MD 20892 USA. RP Koehly, LM (reprint author), NIH, Bldg 31,B1B37D,31 Ctr Dr,MSC 2073, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov FU National Human Genome Research Institute; Robert Wood Johnson Foundation FX The authors were supported in part by funding from the Intramural Research Program of the National Human Genome Research Institute and the Robert Wood Johnson Foundation. We thank Thomas Valente, Donna Stroup, Valerie Johnson, and 4 anonymous reviewers for reviewing an earlier version of the manuscript. NR 28 TC 19 Z9 19 U1 1 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD JUL PY 2009 VL 6 IS 3 AR A99 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V20RX UT WOS:000208158200019 PM 19527601 ER PT J AU Priola, SA McNally, KL AF Priola, Suzette A. McNally, Kristin L. TI The role of the prion protein membrane anchor in prion infection SO PRION LA English DT Article DE prion; GPI anchor; PrP; prion spread; scrapie ID PERIPHERAL NERVOUS-SYSTEM; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; SCRAPIE INFECTION; IN-VITRO; PRP-RES; CELLS; RESISTANT; CONVERSION; EXPRESSION; DISEASE AB Normal cellular and abnormal disease-associated forms of prion protein (PrP) contain a C-terminal glycophosphatidyl-inositol (GPI) membrane anchor. The importance of the GPI membrane anchor in prion diseases is unclear but there are data to suggest that it both is and is not required for abnormal prion protein formation and prion infection. Utilizing an in vitro model of prion infection we have recently demonstrated that, while the GPI anchor is not essential for the formation of abnormal prion protein in a cell, it is necessary for the establishment of persistent prion infection. In combination with previously published data, our results suggest that GPI anchored PrP is important in the amplification and spread of prion infectivity from cell to cell. C1 [Priola, Suzette A.; McNally, Kristin L.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. EM spriola@niaid.nih.gov FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases [1-Z01-AI000752-12] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases ( Project # 1-Z01-AI000752-12). NR 42 TC 17 Z9 17 U1 1 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6896 J9 PRION JI Prion PD JUL-SEP PY 2009 VL 3 IS 3 BP 134 EP 138 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 506UQ UT WOS:000270802300003 PM 19786843 ER PT J AU Malkesman, O Weller, A AF Malkesman, O. Weller, A. TI Two different putative genetic animal models of childhood depression-A review SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Childhood depression; Animal models; FSL; WKY; Rats ID NATIONAL-COMORBIDITY-SURVEY; CHRONIC ANTIDEPRESSANT TREATMENT; WISTAR-KYOTO RATS; ADOLESCENT MAJOR DEPRESSION; CENTRAL-NERVOUS-SYSTEM; SPRAGUE-DAWLEY RATS; PLASMA-LEVEL DESIGN; SENSITIVE LINE RATS; FORCED SWIM TEST; NEUROTROPHIC FACTOR AB Estimated prevalence of childhood and adolescent depression varies from 0.4% to 3% at the 0-12 age range and 3.3% to 12.4% at the 13-18 age range. Despite similarities in the clinical picture of major depression in children, adolescents, and adults, there are notable differences in the neurobiological correlates and treatment response of depressed patients in these different age cohorts. In contrast to adults, most depressed children fail to respond to antidepressants. The main aim of this paper is to review several studies which attempt to develop and examine genetic animal models for childhood depression, in order to enable a search for new, unique treatment approaches for depressed children. Two different "depressive-like" rat strains were studied: Flinders Sensitive Line (FSL) and their controls, Sprague-Dawley (SD) rats; and the Wistar Kyoto (WKY) strain and their controls, Wistar rats. The results suggest that prepubertal FSL and WKY rats exhibit different styles of depressive behavior, one co-morbid with "anxiety-like" behavior (WKY), and one that is not (FSL). These two profiles may model clinical characteristics that resemble two subgroups of depressed children. However, in general the data on the WKY rats would seem most consistent with a classic childhood depressive profile. The FSL profile may possibly be related to chronic stress, and its role as a potential model of childhood depression requires further support. These two different putative genetic animal models of childhood depression can help in the attempts to understand the neurobiological basis and to predict successful treatment strategies for different patterns of childhood psychopathology. Published by Elsevier Ltd. C1 [Malkesman, O.] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Weller, A.] Bar Ilan Univ, Dept Psychol, Ramat Gan, Israel. [Weller, A.] Bar Ilan Univ, Gonda Goldschmied Multidisciplinary Brain Res Ctr, Ramat Gan, Israel. RP Malkesman, O (reprint author), NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. EM malkesmano@mail.nih.gov OI Weller, Aron/0000-0002-0663-4384 FU Bar-Ilan University President's Fellowship; Israel Science Foundation; Institute for the Study of Affective Neuroscience, Haifa University FX The authors thank Dr. D.H. Overstreet for his advice and for providing the initial FSL colony, and all their colleagues who participated in the research projects reviewed in this paper. Drs. Y. Braw and G. Yadid are especially noted for their parts. The research reviewed here was supported by a Bar-Ilan University President's Fellowship awarded to OM and a grant from the Israel Science Foundation (AW). Writing of this manuscript was also supported by a grant from the Institute for the Study of Affective Neuroscience, Haifa University (AW). NR 194 TC 38 Z9 39 U1 5 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUL PY 2009 VL 88 IS 3 BP 153 EP 169 DI 10.1016/j.pneurobio.2009.03.003 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 473MB UT WOS:000268209800001 PM 19545781 ER PT J AU Olfson, M Mojtabai, R Sampson, NA Hwang, I Druss, B Wang, PS Wells, KB Pincus, HA Kessler, RC AF Olfson, Mark Mojtabai, Ramin Sampson, Nancy A. Hwang, Irving Druss, Benjamin Wang, Philip S. Wells, Kenneth B. Pincus, Harold Alan Kessler, Ronald C. TI Dropout From Outpatient Mental Health Care in the United States SO PSYCHIATRIC SERVICES LA English DT Article ID NATIONAL COMORBIDITY SURVEY; SURVEY REPLICATION; PREMATURE TERMINATION; METHADONE TREATMENT; PSYCHOTHERAPY; DEPRESSION; SERVICES; DISORDERS; ABUSE; CONTINUITY AB Objective: Although mental health treatment dropout is common, patterns and predictors of dropout are poorly understood. This study explored patterns and predictors of mental health treatment dropout in a nationally representative sample. Methods: Data were from the National Comorbidity Survey Replication, a nationally representative household survey. Respondents who had received mental health treatment in the 12 months before the interview (N=1,664) were asked about dropout, which was defined as quitting treatment before the provider wanted them to stop. Cross-tabulation and discrete-time survival analyses were used to identify predictors. Results: Approximately one-fifth (22%) of patients quit treatment prematurely. The highest dropout rate was from treatment received in the general medical sector (32%), and the lowest was from treatment received by psychiatrists (15%). Dropout rates were intermediate from treatment in the human services sector (20%) and among patients seen by nonpsychiatrist mental health professionals (19%). Over 70% of all dropout occurred after the first or second visits. Mental health insurance was associated with low odds of dropout (odds ratio=.6, 95% confidence interval=.4-.9). Psychiatric comorbidity was associated with a trend toward dropout. Several patient characteristics differentially predicted dropout across treatment sectors and in early and later phases of treatment. Conclusions: Roughly one-fifth of adults in mental health treatment dropped out before completing the recommended course of treatment. Dropout was most common in the general medical sector and varied by patient characteristics across treatment sectors. Interventions focused on high-risk patients and sectors that have higher dropout rates will likely be required to reduce the large proportion of patients who prematurely terminate treatment. (Psychiatric Services 60:898-907, 2009) C1 [Hwang, Irving; Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Olfson, Mark] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Mojtabai, Ramin] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Druss, Benjamin] Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. [Wang, Philip S.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Wells, Kenneth B.] Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. [Pincus, Harold Alan] Columbia Univ, Irving Inst Clin & Translat Res, New York, NY USA. [Pincus, Harold Alan] New York Presbyterian Hosp, New York, NY USA. [Olfson, Mark] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu FU National Institute of Mental Health (NIMH); National Institute on Drug Abuse; Robert Wood Johnson Foundation [044780]; John W. Alden Trust; NIMH [U01-MH60220, R01-MH070884]; John D. and Catherine T. MacArthur Foundation; Pfizer Foundation; U.S. Public Health Service [R13-MH066849, R01-MH069864, R01-DA016558]; Fogarty International Center [R03-TW006481]; Pan American Health Organization; Eli Lilly and Company; Ortho-McNeil Pharmaceuticals; GlaxoSmithKline; Bristol-Myers Squibb; AstraZeneca; Johnson & Johnson Pharmaceuticals; Sanofi-Aventis FX Dr. Olfson has received research support from Eli Lilly and Company and AstraZeneca, has served as a consultant to Pfizer and AstraZeneca, and has served as a speaker for Janssen. Dr. Kessler has been a consultant for GlaxoSmithKline, Kaiser Permanente, Pfizer, Sanofi-Aventis, Shire Pharmaceuticals, and Wyeth-Ayerst; has served on advisory boards for Eli Lilly and Company and Wyeth-Ayerst; and has received research support for epidemiological studies from Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Pharmaceuticals, Pfizer, and Sanofi-Aventis. The other authors report no competing interests. NR 59 TC 77 Z9 78 U1 3 U2 6 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUL PY 2009 VL 60 IS 7 BP 898 EP 907 PG 10 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 463TU UT WOS:000267455800006 PM 19564219 ER PT J AU DeVido, J Jones, M Geraci, M Hollon, N Blair, RJR Pine, DS Blair, K AF DeVido, J. Jones, M. Geraci, M. Hollon, N. Blair, R. J. R. Pine, D. S. Blair, K. TI Stimulus-reinforcement-based decision making and anxiety: impairment in generalized anxiety disorder (GAD) but not in generalized social phobia (GSP) SO PSYCHOLOGICAL MEDICINE LA English DT Article DE Decision making; generalized anxiety disorder; generalized social phobia ID NEUROBIOLOGICAL MECHANISMS; ANTERIOR CINGULATE; PREFRONTAL CORTEX; BRAIN ACTIVATION; ANGRY FACES; BIAS; ADOLESCENTS; INFORMATION; ATTENTION; SUBTYPES AB Background. Generalized social phobia (GSP) involves the fear/avoidance Of Social Situations whereas generalized anxiety disorder (GAD) involves an intrusive worry about everyday life circumstances. It remains unclear whether these, highly co-morbid, conditions represent distinct disorders or alternative presentations of a single underlying pathology. In this study, we examined stimulus-reinforcement-based decision making in GSP and GAD. Method. Twenty unmedicated patients with GSP, 16 unmedicated patients with GAD and 19 age-, IQ- and gender-matched healthy comparison (HQ individuals completed the Differential Reward/Punishment Learning Task (DRPLT). In this task, the subject chooses between two objects associated with different levels of reward or punishment. Thus, response choice indexes not only reward/punishment sensitivity but also sensitivity to reward/punishment level according to between-object reinforcement distance. Results. We found that patients with GAD committed a significantly greater number of errors than both the patients with GSP and the HC individuals. By contrast, the patients with GSP and the HC individuals did not differ in performance on this task. Conclusions. These results link GAD with anomalous non-affective-based decision making. They also indicate that CSP and GAD are associated with distinct pathophysiologies. C1 [DeVido, J.; Jones, M.; Geraci, M.; Hollon, N.; Blair, R. J. R.; Pine, D. S.; Blair, K.] NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Blair, K (reprint author), NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Mental Health FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. NR 47 TC 7 Z9 7 U1 2 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD JUL PY 2009 VL 39 IS 7 BP 1153 EP 1161 DI 10.1017/S003329170800487X PG 9 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 461TZ UT WOS:000267296100011 PM 19102795 ER PT J AU Schmidt, LA Fox, NA Perez-Edgar, K Hamer, DH AF Schmidt, Louis A. Fox, Nathan A. Perez-Edgar, Koraly Hamer, Dean H. TI Linking Gene, Brain, and Behavior: DRD4, Frontal Asymmetry, and Temperament SO PSYCHOLOGICAL SCIENCE LA English DT Article ID DOPAMINE-D4 RECEPTOR DRD4; NOVELTY SEEKING; DIFFERENTIAL SUSCEPTIBILITY; EXTERNALIZING BEHAVIOR; EEG ASYMMETRY; ATTACHMENT DISORGANIZATION; ENVIRONMENTAL-INFLUENCES; MOLECULAR-GENETICS; SOCIAL-BEHAVIOR; EARLY-CHILDHOOD AB Gene-environment interactions involving exogenous environmental factors are known to shape behavior and personality development. Although gene-environment interactions involving endogenous environmental factors are hypothesized to play an equally important role, this conceptual approach has not been empirically applied in the study of early-developing temperament in humans. Here we report evidence for a gene-endoenvironment (i.e., resting frontal brain electroencephalogram, EEG, asymmetry) interaction in predicting child temperament. The dopamine D4 receptor (DRD4) gene (long allele vs. short allele) moderated the relation between resting frontal EEG asymmetry (left vs. right) at 9 months and temperament at 48 months. Children who exhibited left frontal EEG asymmetry at 9 months and who possessed the DRD4 long allele were significantly more soothable at 48 months than other children. Among children with right frontal EEG asymmetry at 9 months, those with the DRD4 long allele had significantly more difficulties focusing and sustaining attention at 48 months than those with the DRD4 short allele. Resting frontal EEG asymmetry did not influence temperament in the absence of the DRD4 long allele. We discuss how the interaction of genetic and endoenvironmental factors may confer risk and protection for different behavioral styles in children. C1 [Schmidt, Louis A.] McMaster Univ, Dept Psychol Neurosci & Behav, Hamilton, ON L8S 4K1, Canada. [Fox, Nathan A.] Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. [Perez-Edgar, Koraly] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Hamer, Dean H.] NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Schmidt, LA (reprint author), McMaster Univ, Dept Psychol Neurosci & Behav, 1280 Main St W, Hamilton, ON L8S 4K1, Canada. EM schmidtl@mcmaster.ca OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU NICHD NIH HHS [HD 17899, R01 HD017899, R37 HD017899, R37 HD017899-23] NR 40 TC 33 Z9 33 U1 5 U2 20 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD JUL PY 2009 VL 20 IS 7 BP 831 EP 837 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 469GV UT WOS:000267885400007 PM 19493320 ER PT J AU Abbas, AI Hedlund, PB Huang, XP Tran, TB Meltzer, HY Roth, BL AF Abbas, Atheir I. Hedlund, Peter B. Huang, Xi-Ping Tran, Thuy B. Meltzer, Herbert Y. Roth, Bryan L. TI Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo SO PSYCHOPHARMACOLOGY LA English DT Article DE Amisulpride; 5-HT7; 5-HT7 antagonist; Antidepressant; Atypical antipsychotic; DAN 2163 ID RECEPTOR ANTAGONIST; PREFRONTAL CORTEX; SUBSTITUTED BENZAMIDES; MAJOR DEPRESSION; HIPPOCAMPAL NEUROGENESIS; CELL-PROLIFERATION; ANTIPSYCHOTIC-DRUG; LIMBIC SELECTIVITY; RAT HYPOTHALAMUS; MOOD DISORDERS AB Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D-2/D-3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties. The purpose of these studies was to determine if amisulpride's antidepressant actions are mediated by off-target interactions with other receptors. We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knockout mice. We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo. Significantly, and in contrast to their wild-type littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test. These results indicate that 5-HT7a receptor antagonism, and not D-2/D-3 receptor antagonism, likely underlies the antidepressant actions of amisulpride. C1 [Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol & Psychiat, Chapel Hill, NC 27516 USA. [Roth, Bryan L.] Univ N Carolina, Sch Med, Lineberger Canc Ctr, Chapel Hill, NC 27516 USA. [Roth, Bryan L.] Univ N Carolina, Sch Pharm, Dept Med Chem, Chapel Hill, NC 27516 USA. [Abbas, Atheir I.] Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. [Hedlund, Peter B.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Huang, Xi-Ping; Tran, Thuy B.; Roth, Bryan L.] Univ N Carolina, Sch Med, Natl Inst Mental Hlth, Psychoact Drug Screening Program,Dept Pharmacol, Chapel Hill, NC 27516 USA. [Meltzer, Herbert Y.] Vanderbilt Univ, Dept Psychiat, Sch Med, Nashville, TN 37215 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol & Psychiat, Chapel Hill, NC 27516 USA. EM bryan_roth@med.unc.edu RI Roth, Bryan/F-3928-2010; Meltzer, Herbert/E-8131-2013 FU NIMH [MH61887, U19MH82441, MH73923]; NARSAD; NIH [T32 GM007250] FX A. A., X. P. H., T. B. T., and B. L. R. were supported by NIMH61887, U19MH82441, and the NIMH Psychoactive Drug Screening Program; B. L. R. received additional support as a NARSAD Distinguished Investigator. A. A. was also supported by the CWRU MSTP and NIH T32 GM007250. P. B. H. was supported by NIMH MH73923. NR 57 TC 126 Z9 131 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 205 IS 1 BP 119 EP 128 DI 10.1007/s00213-009-1521-8 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 457RO UT WOS:000266950600012 PM 19337725 ER PT J AU Nair, SG Adams-Deutsch, T Pickens, CL Smith, DG Shaham, Y AF Nair, Sunila G. Adams-Deutsch, Tristan Pickens, Charles L. Smith, Daniel G. Shaham, Yavin TI Effects of the MCH1 receptor antagonist SNAP 94847 on high-fat food-reinforced operant responding and reinstatement of food seeking in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Melanin-concentrating hormone; Extinction; Pellet priming; Cues; Reinstatement; Relapse; Self-administration; SNAP 94847; Stress; Yohimbine ID MELANIN-CONCENTRATING-HORMONE; ANXIOGENIC DRUG YOHIMBINE; CUE-INDUCED REINSTATEMENT; PRIMING-INDUCED REINSTATEMENT; PROTEIN-COUPLED RECEPTOR; EXCESSIVE SUGAR INTAKE; COCAINE-SEEKING; PALATABLE FOOD; NUCLEUS-ACCUMBENS; INDUCED RELAPSE AB The melanin-concentrating hormone 1 (MCH1) receptors play an important role in home-cage food consumption in rodents, but their role in operant high-fat food-reinforced responding or reinstatement of food seeking in animal models is unknown. Here, we used the MCH1 receptor antagonist SNAP 94847 to explore these questions. In experiment 1, we trained food-restricted rats (16 g/day of nutritionally balanced rodent diet) to lever press for high-fat (35%) pellets (3-h/day, every other day) for 14 sessions. We then tested the effect of SNAP 94847 (3-30 mg/kg, intraperitoneal (i.p.)) on food-reinforced operant responding. In experiments 2 and 3, we trained rats to lever press for the food pellets (9 to 14 3-h sessions) and subsequently extinguished the food-reinforced lever responding by removing the food (10 to 17 sessions). We then tested the effect of SNAP 94847 on reinstatement of food seeking induced by MCH (20 mu g, intracerebroventricular), noncontingent delivery of three pellets during the first minute of the test session (pellet-priming), contingent tone-light cues previously associated with pellet delivery (cue), or the pharmacological stressor yohimbine (2 mg/kg, i.p.). Systemic injections of SNAP 94847 decreased food-reinforced operant responding and MCH-induced reinstatement of food seeking. SNAP 94847 had no effect on pellet-priming-, cue-, or yohimbine-induced reinstatement. Results indicate that MCH1 receptors are involved in food-reinforced operant responding but not in reinstatement induced by acute exposure to high-fat food, food cues, or the stress-like state induced by yohimbine. These results suggest that different mechanisms mediate food-reinforced operant responding and reinstatement of food seeking. C1 [Nair, Sunila G.; Adams-Deutsch, Tristan; Pickens, Charles L.; Shaham, Yavin] NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. [Smith, Daniel G.] Lundbeck Res USA, Dept Neurosci, Paramus, NJ USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM Yshaham@intra.nida.nih.gov RI Pickens, Charles/E-8984-2010; shaham, yavin/G-1306-2014 FU National Institute on Drug Abuse FX The work was supported by the Intramural Research Program of the National Institute on Drug Abuse. We thank Evan Goldart for technical support. NR 67 TC 27 Z9 27 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 EI 1432-2072 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 205 IS 1 BP 129 EP 140 DI 10.1007/s00213-009-1523-6 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 457RO UT WOS:000266950600013 PM 19340414 ER PT J AU Le Foll, B Gorelick, DA Goldberg, SR AF Le Foll, Bernard Gorelick, David A. Goldberg, Steven R. TI The future of endocannabinoid-oriented clinical research after CB1 antagonists SO PSYCHOPHARMACOLOGY LA English DT Editorial Material DE Rimonabant; CB1 receptor antagonist; Pharmacotherapy; Safety; Drug dependence; Addiction; Obesity ID CARDIOMETABOLIC RISK-FACTORS; RANDOMIZED CONTROLLED-TRIAL; CORONARY-ARTERY-DISEASE; ANANDAMIDE HYDROLYSIS; RECEPTOR ANTAGONIST; OVERWEIGHT PATIENTS; BLOCKER RIMONABANT; RIO-EUROPE; OBESITY; DEPENDENCE AB Great interest has been shown by the medical community and the public in the cannabinoid CB1 receptor antagonists, such as rimonabant, for treatment of obesity, metabolic syndrome, and possibly drug addiction. This novel class of drug has therapeutic potential for other disorders, as the endocannabinoid system is involved in various health conditions. However, rimonabant, the first clinically available member of this class of drugs, has been linked to increased risk of anxiety, depression, and suicidality. Due to those risks, the European Medicines Agency called for its withdrawal from the market in October, 2008. Shortly after this decision, several pharmaceutical companies (Sanofi-aventis, Merck, Pfizer, Solvay) announced that they would stop further clinical research on this class of drug. Here, we provide an overview of those events and make several suggestions for continuing such clinical research, while safeguarding the safety of patients and clinical trial subjects. C1 [Le Foll, Bernard] Univ Toronto, Translat Addict Res Lab, Ctr Addict & Mental Hlth, Toronto, ON M5S 2S1, Canada. [Gorelick, David A.] Natl Inst Drug Abuse, Off Sci Director, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. [Goldberg, Steven R.] Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Le Foll, B (reprint author), Univ Toronto, Translat Addict Res Lab, Ctr Addict & Mental Hlth, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Intramural NIH HHS [Z01 DA000001-23, Z01 DA000003-22] NR 42 TC 87 Z9 89 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 205 IS 1 BP 171 EP 174 DI 10.1007/s00213-009-1506-7 PG 4 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 457RO UT WOS:000266950600018 PM 19300982 ER PT J AU Sigmon, SC Herning, RI Better, W Cadet, JL Griffiths, RR AF Sigmon, Stacey C. Herning, Ronald I. Better, Warren Cadet, Jean L. Griffiths, Roland R. TI Caffeine withdrawal, acute effects, tolerance, and absence of net beneficial effects of chronic administration: cerebral blood flow velocity, quantitative EEG, and subjective effects SO PSYCHOPHARMACOLOGY LA English DT Article DE Cerebral blood flow velocity; EEG; Caffeine; Withdrawal; Physical dependence; Tolerance; Subjective effects; Humans ID DIETARY CAFFEINE; MOOD; PERFORMANCE; CONSUMPTION; REVERSAL; HUMANS; ELECTROENCEPHALOGRAPHY; SYMPTOMS; HEADACHE; SLEEP AB Although the subjective effects of caffeine abstinence, acute and chronic administration, and tolerance are well described, the corresponding neurophysiological effects are not. Caffeine withdrawal, acute caffeine effects, caffeine tolerance, and net beneficial effects of chronic caffeine administration were investigated using cerebral blood flow velocity, quantitative electroencephalography (EEG), and subjective effects. Sixteen regular caffeine users participated in this double-blind, within-subject study during which they received acute caffeine and placebo challenges (1) while maintained on 400 mg caffeine daily for a parts per thousand yen14 days and (2) while maintained on placebo for a parts per thousand yen14 days. Blood flow velocity was determined for the middle (MCA) and anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded from 16 scalp sites. Subjective effects were assessed with questionnaires. Acute caffeine abstinence (evaluated 24 h after placebo substitution) increased mean, systolic, and diastolic velocity in the MCA and ACA and decreased pulsatility index in the MCA. Acute caffeine abstinence increased EEG theta and decreased beta 2 power. Acute caffeine abstinence also increased measures of Tired, Fatigue, Sluggish, and Weary and decreased ratings of Energetic, Friendly, Lively, and Vigor. Acute caffeine effects were demonstrated across a wide range of measures, including cerebral blood flow, EEG, and subjective effects. Tolerance and "complete" tolerance were observed on subjective but not physiological measures. Chronic caffeine effects were demonstrated only on the measure of EEG beta 2 power. Acute caffeine abstinence and administration produced changes in cerebral blood flow velocity, EEG, and subjective effects. Tolerance to subjective but not physiological measures was demonstrated. There was almost no evidence for net effects of chronic caffeine administration on these measures. Overall, these findings provide the most rigorous demonstration to date of physiological effects of caffeine withdrawal. C1 [Griffiths, Roland R.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21224 USA. [Griffiths, Roland R.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. [Sigmon, Stacey C.] Univ Vermont, Dept Psychiat, Coll Med, SATC UHC, Burlington, VT 05401 USA. [Herning, Ronald I.; Better, Warren; Cadet, Jean L.] Natl Inst Drug Abuse, Mol Neuropsychiat Sect, Div Intramural Res, Baltimore, MD USA. RP Griffiths, RR (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, 5510 Nathan Shock Dr, Baltimore, MD 21224 USA. EM stacey.sigmon@uvm.edu; rgriff@jhmi.edu FU National Institute on Drug Abuse [R01 DA-03890, T32-DA07209] FX This research was supported in part by research grant R01 DA-03890 and training grant T32-DA07209 from the National Institute on Drug Abuse. The authors thank John Yingling for computer programming assistance, Allison Chausmer, Tiffany Tomlin, and Krista Powell for their help with data collection, and Paul Nuzzo for assistance with statistical analysis. This study complies with current laws of the United States and the authors report no conflicting interests. NR 36 TC 27 Z9 29 U1 5 U2 56 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 204 IS 4 BP 573 EP 585 DI 10.1007/s00213-009-1489-4 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 451RD UT WOS:000266486700002 PM 19241060 ER PT J AU Mueller, D Olivera-Figueroa, LA Pine, DS Quirk, GJ AF Mueller, Devin Olivera-Figueroa, Lening A. Pine, Daniel S. Quirk, Gregory J. TI The effects of yohimbine and amphetamine on fear expression and extinction in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Fear conditioning; Psychostimulant; Norepinephrine; Fear extinction; Bar-press suppression; Freezing; alpha(2)-Adrenoceptor antagonist; Reuptake blocker; Anxiety disorders ID POSTTRAUMATIC-STRESS-DISORDER; D-CYCLOSERINE; CONDITIONED FEAR; POTENTIATED STARTLE; MEMORY; FACILITATION; RECEPTORS; NORADRENALINE; CONSOLIDATION; PSYCHOTHERAPY AB Psychostimulants, such as yohimbine and amphetamine, can enhance learning and memory. Extinction of conditioned fear involves new learning, so we asked whether psychostimulants could enhance this learning. Previous work suggests that yohimbine facilitates extinction, using freezing as a fear measure. However, psychostimulant-induced alterations in locomotion can confound freezing measurements. Furthermore, the effects of amphetamine on fear extinction have never been examined. We evaluated the effectiveness of yohimbine and amphetamine in enhancing fear extinction. In addition to freezing, we measured bar-press suppression, which is less sensitive to changes in locomotion. We asked: Do psychostimulants reduce fear during extinction training when drug is present? Does learning extinction with psychostimulants result in better extinction retention? Rats received fear conditioning on day 1 followed by partial extinction training on days 2 and 3. Yohimbine (1.0, 2.0, or 5.0 mg/kg, i.p.), amphetamine (1.0 mg/kg, i.p.), or vehicle were injected prior to extinction on day 2. Yohimbine dose-dependently reduced freezing during extinction training on day 2, whereas bar-press suppression was reduced at the highest dose only. When tested drug-free, yohimbine-treated rats showed equivalent levels of freezing and suppression to controls. Amphetamine also decreased freezing during extinction, but did not decrease suppression. During the drug-free test, there was no difference between amphetamine-treated rats and controls in either measure. Although yohimbine and amphetamine are capable of decreasing freezing, neither drug strengthened retention of fear extinction. Based on these rodent findings, psychostimulants may not be suitable adjuncts to extinction-based therapies for the treatment of anxiety disorders. C1 [Mueller, Devin; Quirk, Gregory J.] Univ Puerto Rico, Sch Med, Dept Psychiat & Anat, San Juan, PR 00936 USA. [Mueller, Devin; Quirk, Gregory J.] Univ Puerto Rico, Sch Med, Dept Neurobiol, San Juan, PR 00936 USA. [Olivera-Figueroa, Lening A.] Ponce Sch Med, Clin Psychol Program, Ponce, PR 00732 USA. [Pine, Daniel S.] NIMH, Intramural Res Program, Sect Dev & Affect Neurosci, Bethesda, MD 20817 USA. RP Quirk, GJ (reprint author), Univ Puerto Rico, Sch Med, Dept Psychiat & Anat, POB 365067, San Juan, PR 00936 USA. EM gjquirk@yahoo.com OI Olivera-Figueroa, Lening/0000-0001-6325-9819; Mueller, Devin/0000-0002-7397-9219 FU FQRNT (Quebec, Canada); [R01-MH058883]; [S06-GM008224]; [G12-RR03051] FX This work was supported by R01-MH058883, S06-GM008224, G12-RR03051 (RCMI) and the UPR President's Office to GJQ and a FQRNT (Quebec, Canada) postdoctoral fellowship to DM. NR 50 TC 29 Z9 31 U1 3 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 204 IS 4 BP 599 EP 606 DI 10.1007/s00213-009-1491-x PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 451RD UT WOS:000266486700004 PM 19242678 ER PT J AU Haller, J Barna, I Barsvari, B Pelczer, KG Yasar, S Panlilio, LV Goldberg, S AF Haller, J. Barna, I. Barsvari, B. Pelczer, K. Gyimesi Yasar, S. Panlilio, L. V. Goldberg, S. TI Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE FAAH; URB597; Anxiety; Stress; Aversive; Elevated plus-maze; Rat ID ELEVATED PLUS-MAZE; GLUTAMATERGIC SYNAPTIC-TRANSMISSION; AMIDE HYDROLASE INHIBITION; ANXIETY-LIKE BEHAVIOR; ENDOCANNABINOID SYSTEM; CB1 RECEPTORS; ANANDAMIDE; STRESS; ACTIVATION; MODELS AB Since the discovery of endogenous cannabinoid signaling, the number of studies exploring its role in health and disease has increased exponentially. Fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of the endocannabinoid anandamide, has emerged as a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of URB597 as an anxiolytic. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 (0.1-0.3 mg/kg) did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Close inspection of experimental conditions employed in earlier reports suggests that conflicting findings with URB597 can be explained by different testing conditions, such as those manipulated in the present study. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli. C1 [Haller, J.; Barna, I.; Barsvari, B.; Pelczer, K. Gyimesi] Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. [Yasar, S.] Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. [Yasar, S.] Natl Inst Drug Abuse, Dept Hlth & Human Serv, Mol Neuropsychiat Branch, Intramural Res Program,NIH, Baltimore, MD USA. [Panlilio, L. V.; Goldberg, S.] Natl Inst Drug Abuse, Dept Hlth & Human Serv, Preclin Pharmacol Sect, Intramural Res Program,NIH,Biomed Res Ctr, Baltimore, MD 21224 USA. RP Haller, J (reprint author), Hungarian Acad Sci, Inst Expt Med, POB 67, H-1450 Budapest, Hungary. EM haller@koki.hu OI Haller, Jozsef/0000-0002-1953-3726 FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services, Baltimore, MD, USA; OTKA (Hungarian Scientific Research Fund) [K72621] FX This study was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD, USA and OTKA (Hungarian Scientific Research Fund) grant No. K72621 to J. Haller. The authors thank Sachin Patel for help provided during preparation of the manuscript. Both funding institutions sponsor basic research. No income was obtained from commercial sponsors. The authors have full control of all primary data NR 44 TC 68 Z9 72 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD JUL PY 2009 VL 204 IS 4 BP 607 EP 616 DI 10.1007/s00213-009-1494-7 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 451RD UT WOS:000266486700005 PM 19259645 ER PT J AU Keil, A Heim, S AF Keil, Andreas Heim, Sabine TI Prolonged reduction of electrocortical activity predicts correct performance during rapid serial visual processing SO PSYCHOPHYSIOLOGY LA English DT Article DE Attention; Dense-array EEG; Rapid serial visual presentation; Steady-state potential ID SPATIAL SELECTIVE ATTENTION; TIME-COURSE; CORTICAL FACILITATION; BLINK; TASK; POTENTIALS; PERCEPTION; COMPETITION; SPOTLIGHT; DYNAMICS AB When two targets are shown in a rapid temporal stream of distractors, performance for the second target (T2) is typically reduced when presented between 200 and 500 ms after the first (T1). The present study used the steady-state visual evoked potential (ssVEP), a continuous index of electrocortical facilitation, to compare brain responses in trials with correct versus incorrect T2 responses. We found a reduction of the electrocortical response following T1 in trials with correct T2 identification. By contrast, incorrect T2 trials were characterized by enhanced electrocortical amplitude. Amplitude attenuation predictive of successful T2 report was sustained over time, suggesting a reduction of resources allocated to the distractor stream in correct trials. Across intertarget intervals, T2 performance was a linear function of the ssVEP amplitude reduction in correct trials, weighted by the stimulus onset asynchrony. C1 [Keil, Andreas] Univ Florida, Dept Psychol, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32611 USA. [Heim, Sabine] Univ Konstanz, Dept Psychol, Constance, Germany. RP Keil, A (reprint author), Univ Florida, Dept Psychol, NIMH, Ctr Study Emot & Attent, POB 112766, Gainesville, FL 32611 USA. EM akeil@ufl.edu RI Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 FU Deutsche Forschungsgemeinschaft; National Institute of Mental Health FX Research was supported by grants from the Deutsche Forschungsgemeinschaft and from the National Institute of Mental Health. The authors thank Alexander Dienst and Niklas Ihssen for help in data acquisition and data reduction. NR 37 TC 12 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD JUL PY 2009 VL 46 IS 4 BP 718 EP 725 DI 10.1111/j.1469-8986.2009.00824.x PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 456UF UT WOS:000266876200004 PM 19490512 ER PT J AU Terracciano, A Sutin, AR McCrae, RR Deiana, B Ferrucci, L Schlessinger, D Uda, M Costa, PT AF Terracciano, Antonio Sutin, Angelina R. McCrae, Robert R. Deiana, Barbara Ferrucci, Luigi Schlessinger, David Uda, Manuela Costa, Paul T., Jr. TI Facets of Personality Linked to Underweight and Overweight SO PSYCHOSOMATIC MEDICINE LA English DT Article DE personality; obesity; BMI; central adiposity; waist/hip ratio; Five-Factor Model ID BODY-MASS INDEX; NEO-PI-R; 5-FACTOR MODEL; PHYSICAL-ACTIVITY; EATING-DISORDERS; SEVERE OBESITY; UNITED-STATES; WEIGHT-LOSS; FTO GENE; HIV RISK AB Objective: Personality traits underlie maladaptive behaviors, and cognitive and emotional disturbances that contribute to major preventable causes of global disease burden. This study examines detailed personality profiles of underweight, normal, and overweight individuals to provide insights into the causes and treatments of abnormal weight. Methods: More than half of the population from four towns in Sardinia, Italy (n = 5693; age = 14-94 years; mean +/- standard deviation = 43 +/- 17 years) were assessed on multiple anthropometric measures and 30 facets that comprehensively cover the five major dimensions of personality, using the Revised NEO Personality Inventory. Results: High Neuroticism and low Conscientiousness were associated with being underweight and obese, respectively. High Impulsiveness (specifically eating-behavior items) and low Order were associated with body mass index categories of overweight and obese, and with measures of abdominal adiposity (waist and hip circumference). Those scoring in the top 10% of Impulsiveness were about 4 kg heavier than those in the bottom 10%, an effect independent and larger than the FTO genetic variant. Prospective analyses confirmed that Impulsiveness and Order were significant predictors of general and central measures of adiposity assessed 3 years later. Conclusions: Overweight and obese individuals have difficulty resisting cravings and lack methodical and organized behaviors that might influence diet and weight control. Although individuals' traits have limited impact on the current obesogenic epidemic, personality traits can improve clinical assessment, suggest points of intervention, and help tailor prevention and treatment approaches. C1 [Terracciano, Antonio] NIA, Lab Personal & Cognit, NIH, DHHS, Baltimore, MD 21224 USA. [Deiana, Barbara; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. RP Terracciano, A (reprint author), NIA, Lab Personal & Cognit, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM Terraccianoa@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU National Institutes of Heath; National Institute on Aging FX This research was supported entirely by the Intramural Research Program of the National Institutes of Heath, National Institute on Aging. Robert R. McCrae and Paul T. Costa, Jr, receive royalties from the Revised NEO Personality Inventory. The authors declare that they have no other potential conflict of interest. NR 57 TC 80 Z9 80 U1 9 U2 35 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUL-AUG PY 2009 VL 71 IS 6 BP 682 EP 689 DI 10.1097/PSY.0b013e3181a2925b PG 8 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 471JA UT WOS:000268052100014 PM 19414622 ER PT J AU Kwan, ML Jensen, CD Block, G Hudes, ML Chu, LW Buffler, PA AF Kwan, Marilyn L. Jensen, Christopher D. Block, Gladys Hudes, Mark L. Chu, Lisa W. Buffler, Patricia A. TI Maternal Diet and Risk of Childhood Acute Lymphoblastic Leukemia SO PUBLIC HEALTH REPORTS LA English DT Article ID OXIDATIVE DNA-DAMAGE; UNITED-STATES; CHILDREN; CANCER; VITAMIN; RECORDS; REPAIR; LYMPHOCYTES; CONSUMPTION; NUTRIENTS AB Objective. Intrauterine environmental factors, including maternal diet, may play an etiologic role in acute lymphoblastic leukemia (ALL), a common childhood cancer Expanding on previous findings from phase 1 of the Northern California Childhood Leukemia Study (NCCLS), a population-based case-control study, we sought to further elucidate and replicate the relationships between maternal diet and ALL risk. Methods. We matched 282 case-control sets of children (205 pairs and 77 triplets) from phases 1 and 2 of the NCCLS on sex, date of birth, mother's race, Hispanic racial/ethnic status, and county of residence at birth. We used an interviewer-administered food frequency questionnaire to obtain information on maternal dietary intake in the 12 months prior to pregnancy. Results. Risk of ALL was inversely associated with maternal consumption of vegetable (adjusted odds ratio [AOR] = 0.65, 95% confidence interval [CI] 0.50, 0.84); protein sources (AOR=0.55, 95% Cl 0.32, 0.96); fruit (AOR=0.81, 95% Cl 0.65, 1.00); and legume food groups (AOR=0.75, 95% Cl 0.59, 0.95). The risk reduction was strongest for consumption of the protein sources and vegetable food groups, independent of the child's diet up to age 2 years, and consistent across phases 1 and 2 of data collection for vegetable consumption. Conclusions. These data suggest that it may be prudent for women to consume a diet rich in vegetables and adequate in protein prior to and during pregnancy as a possible means of reducing childhood ALL risk in their offspring. C1 [Kwan, Marilyn L.] Kaiser Permanente, Div Res, Oakland, CA 94612 USA. [Jensen, Christopher D.; Block, Gladys; Buffler, Patricia A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Hudes, Mark L.; Chu, Lisa W.] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA. [Hudes, Mark L.; Chu, Lisa W.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20892 USA. RP Kwan, ML (reprint author), Kaiser Permanente, Div Res, 2000 Broadway, Oakland, CA 94612 USA. EM Marilyn.L.Kwan@kp.org RI Block, Gladys/E-3304-2010 FU U.S. Public Health Service [ROIES09137, P42ES04705]; Paul O'Gonnan Foundation for Children With Leukaeniia FX This research was supported by two U.S. Public Health Service grants, #ROIES09137 (Environmental Exposures and Childhood Leukemia) and #P42ES04705 (Superfund, Molecular Epidemicilogy of Childhood Leukemia), and a grant from the Paul O'Gonnan Foundation for Children With Leukaeniia. NR 37 TC 19 Z9 20 U1 0 U2 4 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1101 15TH ST NW, STE 910, WASHINGTON, DC 20005 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD JUL-AUG PY 2009 VL 124 IS 4 BP 503 EP 514 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 455VO UT WOS:000266795700006 PM 19618787 ER PT J AU Tyburski, JB Patterson, AD Krausz, KW Slavik, J Fornace, AJ Gonzalez, FJ Idle, JR AF Tyburski, John B. Patterson, Andrew D. Krausz, Kristopher W. Slavik, Josef Fornace, Albert J., Jr. Gonzalez, Frank J. Idle, Jeffrey R. TI Radiation Metabolomics. 2. Dose- and Time-Dependent Urinary Excretion of Deaminated Purines and Pyrimidines after Sublethal Gamma-Radiation Exposure in Mice SO RADIATION RESEARCH LA English DT Article ID TANDEM MASS-SPECTROMETRY; OXIDATIVE DNA-DAMAGE; LIPID-PEROXIDATION; DIURNAL-VARIATION; NITRIC-OXIDE; IDENTIFICATION; MOUSE; METABOLISM; BIOMARKERS; IRRADIATION AB Gamma-radiation exposure of humans is a major public health concern as the threat of terrorism and potential hostile use of radiological devices increases worldwide. We report here the effects of sublethal gamma-radiation exposure on the mouse urinary metabolome determined using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry-based metabolomics. Five urinary biomarkers of sublethal radiation exposure that were statistically significantly elevated during the first 24 h after exposure to doses ranging from 1 to 3 Gy were unequivocally identified by tandem mass spectrometry. These are deaminated purine and pyrimidine derivatives, namely, thymidine, 2'-deoxyuridine, 2'-deoxyxanthosine, xanthine and xanthosine. Furthermore, the aminopyrimidine 2'-deoxycytidine appeared to display reduced urinary excretion at 2 and 3 Gy. The elevated biomarkers displayed a time-dependent excretion, peaking in urine at 8-12 h but returning to baseline by 36 h after exposure. It is proposed that 2'-deoxyuridine and 2'-deoxyxanthosine arise as a result of gamma irradiation by nitrosative deamination of 2'-deoxycytidine and 2'-deoxyguanosine, respectively, and that this further leads to increased synthesis of thymidine, xanthine and xanthosine. The urinary excretion of deaminated purines and pyrimidines, at the expense of aminopurines and aminopyrimidines, appears to form the core of the urinary radiation metabolomic signature of mice exposed to sublethal doses of ionizing radiation. (C) 2009 by Radiation Research Society C1 [Slavik, Josef; Idle, Jeffrey R.] Univ Bern, Inst Clin Pharmacol & Visceral Res, CH-3010 Bern, Switzerland. [Tyburski, John B.; Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Fornace, Albert J., Jr.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Idle, JR (reprint author), Univ Bern, Inst Clin Pharmacol & Visceral Res, Murtenstr 35, CH-3010 Bern, Switzerland. EM jidle@ikp.unibe.ch RI Fornace, Albert/A-7407-2008; Patterson, Andrew/G-3852-2012; OI Fornace, Albert/0000-0001-9695-085X; Patterson, Andrew/0000-0003-2073-0070; Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS [Z99 CA999999]; NIAID NIH HHS [U19 AI067773-02, U19 AI067773] NR 42 TC 63 Z9 65 U1 0 U2 10 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUL PY 2009 VL 172 IS 1 BP 42 EP 57 DI 10.1667/RR1703.1 PG 16 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 465WF UT WOS:000267619200005 PM 19580506 ER PT J AU Choyke, PL AF Choyke, Peter L. TI Can Imaging Gene Expression in Human Mesenchymal Stem Cells be Successful in Large Animals? SO RADIOLOGY LA English DT Editorial Material AB Transplantation of human mesenchymal stem cells (MSCs) is an exciting area of medical research, and cell-based tissue regeneration seems only a matter of time before becoming a reality. This development could dramatically alter our perspective about disease. Much hype has accompanied the potential of stem cell therapy to restore organs to their original state; however, we remain a long way from that goal. The development of objective and quantitative imaging approaches for tracking stem cell fate, including stem cell location, survival, engraftment, and differentiation, may lead to better patient stratification and eventual successful translation of cardiac stem cell therapy into the clinic. The contributions of Willmann et al (1) represent an important step toward this goal. C1 NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,Bldg 10,Room B3B69F, Bethesda, MD 20892 USA. EM pchoyke@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2009 VL 252 IS 1 BP 1 EP 3 DI 10.1148/radiol.2521090595 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 475ME UT WOS:000268362900001 PM 19561244 ER PT J AU Guo, MQ Huang, BX Kim, HY AF Guo, Mingquan Huang, Bill X. Kim, Hee-Yong TI Conformational changes in Akt1 activation probed by amide hydrogen/deuterium exchange and nano-electrospray ionization mass spectrometry SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID PROTEIN-KINASE-B; PLECKSTRIN HOMOLOGY DOMAIN; SOLVENT ACCESSIBILITY; CRYSTAL-STRUCTURE; PHOSPHORYLATION; DYNAMICS; PKB/AKT; BINDING AB Amide hydrogen exchange coupled to nano-electrospray ionization mass spectrometry (nano-ESI-MS) has been used to identify and characterize localized conformational changes of Akt upon activation. Active or inactive Akt was incubated in D(2)O buffer, digested with pepsin, and analyzed by nano-ESI-MS to determine the deuterium incorporation. The hydrogen/deuterium (H/D) exchange profiles revealed that Akt undergoes considerable conformational changes in the core structures of all three individual domains after activation. In the PH domain, four beta-strand (beta 1, beta 2 beta 5 and beta 6) regions containing membrane-binding residues displayed higher solvent accessibility in the inactive state, suggesting that the PH domain is readily available for the binding to the plasma membrane for activation. In contrast, these beta-strands became less exposed or more folded in the active form, which is favored for the dissociation of Akt from the membrane. The beginning alpha-helix J region and the C-terminal locus (T450-470P) of the regulatory domain showed less folded structures that probably enable substrate entry. Our data also revealed detailed conformational changes of Akt in the kinase domain due to activation, some of which may be attributed to the interaction of the basic residues with phosphorylation sites. Our H/D exchange results indicating the conformational status of Akt at different activation states provided new insight for the regulation of this critical protein involved in cell survival. Published in 2009 by John Wiley & Sons, Ltd. C1 [Guo, Mingquan; Huang, Bill X.; Kim, Hee-Yong] NIAAA, Mol Signalling Lab, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural NIH HHS [Z01 AA000284-18] NR 21 TC 2 Z9 2 U1 0 U2 5 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0951-4198 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD JUL PY 2009 VL 23 IS 13 BP 1885 EP 1891 DI 10.1002/rcm.4085 PG 7 WC Chemistry, Analytical; Spectroscopy SC Chemistry; Spectroscopy GA 463US UT WOS:000267458300001 PM 19462409 ER PT J AU Zhu, XC Anderson, VE Sayre, LM AF Zhu, Xiaochun Anderson, Vernon E. Sayre, Lawrence M. TI Charge-derivatized amino acids facilitate model studies on protein side-chain modifications by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry SO RAPID COMMUNICATIONS IN MASS SPECTROMETRY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; AGE-DEPENDENT DISEASES; LIPID-PEROXIDATION; LINOLEIC-ACID; COVALENT MODIFICATION; OXIDATIVE STRESS; 4-HYDROXY-TRANS-2-NONENAL HNE; IONIZATION EFFICIENCY; CONTAINING PEPTIDES; MICHAEL ADDUCTS AB The alpha-amino groups of histidine and lysine were derivatized with p-carboxylbenzyltriphenyl-phosphonium to form the pseudo dipeptides, PHis and PLys, which can be sensitively detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) due to the fixed positive charge of the phosphonium group. Detection limits of PHis and PLys by MALDI-TOFMS were both 30 fmol with a signal-to-noise ratio of 5:1. These pseudo dipeptides were excellent surrogates for His- or Lys-containing peptides in model reactions mimicking proteins with reactive electrophiles, prominently those generated by peroxidation of polyunsaturated fatty acids including 4-hydroxy-2(E)-nonenal (HNE), 4-oxo-2(E)-nonenal (ONE), 2(E)-octenal, and 2(E)-heptenal. An air-saturated solution of linoleic acid (d(0):d(5) = 1:1) was incubated in the presence of Fe(II) and ascorbate with these two pseudo dipeptides, and the reaction products were characterized by MALDI-TOFMS and liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS). By using PHis and PLys, the previously reported ONE-derived His-furan adduct was detected along with evidence for a cyclic alpha,beta-unsaturated ketone. A dimer formed from ONE was found to react with PHis through Michael addition. Alkenals were found to form two novel adducts with PLys. 2(E)-Octenoic acid-His Michael adduct and N(epsilon)-pentanoyllysine were identified as potential protein side-chain adducts modified by products of linoleic acid peroxidation. In addition, when PHis or PLys and AcHis or BocLys were exposed to the linoleic acid peroxidation, an epoxy-keto-ocatadecenoic acid mediated His-His cross-link was detected, along with the observation of a His-ONE/9,12-dioxo-10-dodecenoic acid-Lys derived pyrrole cross-link. Copyright (C) 2009 John Wiley & Sons, Ltd. C1 [Zhu, Xiaochun; Sayre, Lawrence M.] Case Western Reserve Univ, Dept Chem, Cleveland, OH 44106 USA. [Anderson, Vernon E.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. RP Anderson, VE (reprint author), Natl Inst Gen Med Sci, 45 Ctr Dr, Bethesda, MD 20892 USA. EM andersonve@mail.nih.gov RI Zhu, Xiaochun/A-5179-2010 FU NIH [HL 53315, AG 15885] FX We thank Dr. Quan Yuan for synthesizing d11-HNE, Jianye Zhang for synthesizing d9-ONE, Dale Ray for the help with 600MHz NMR and James Faulk for acquiring FAB mass spectra for us. This work was supported by NIH grants HL 53315 and AG 15885. NR 54 TC 4 Z9 4 U1 2 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0951-4198 J9 RAPID COMMUN MASS SP JI Rapid Commun. Mass Spectrom. PD JUL PY 2009 VL 23 IS 14 BP 2113 EP 2124 DI 10.1002/rcm.4116 PG 12 WC Chemistry, Analytical; Spectroscopy SC Chemistry; Spectroscopy GA 470TM UT WOS:000268003400001 PM 19517464 ER PT J AU Cocola, C Anastasi, P Astigiano, S Piscitelli, E Pelucchi, P Vilardo, L Bertoli, G Beccaglia, M Veronesi, MC Sanzone, S Barbieri, O Reinbold, RA Luvoni, GC Zucchi, I AF Cocola, C. Anastasi, P. Astigiano, S. Piscitelli, E. Pelucchi, P. Vilardo, L. Bertoli, G. Beccaglia, M. Veronesi, M. C. Sanzone, S. Barbieri, O. Reinbold, R. A. Luvoni, G. C. Zucchi, I. TI Isolation of Canine Mammary Cells With Stem Cell Properties and Tumour-Initiating Potential SO REPRODUCTION IN DOMESTIC ANIMALS LA English DT Article; Proceedings Paper CT 6th International Symposium on Canine and Feline Reproduction CY JUL 09-11, 2008 CL Vienna Univ Vet Sci, Vienna, AUSTRIA HO Vienna Univ Vet Sci ID IN-VITRO PROPAGATION; BREAST-CANCER CELLS; GLAND AB Recent data suggest that mammary carcinogenesis may be driven by cancer stem cells (CSCs) derived from mutated adult stem cells, which have acquired aberrant cell self-renewal or by progenitor cells that have acquired the capacity for cell self-renewal. Spontaneous mammary cancers in cats and dogs are important models for the understanding of human breast cancer and may represent alternative species model systems that can significantly contribute to the study of human oncogenesis. With the goal of identifying markers for isolating human breast CSCs, we have generated a canine model system to isolate and characterize normal and CSCs from dog mammary gland. Insight into the hierarchical organization of canine tumours may contribute to the development of universal concepts in oncogenesis by CSCs. Cells with stem cell properties were isolated from normal and tumoural canine breast tissue and propagated as mammospheres and tumour-spheres in long-term non-adherent culture conditions. We showed that cells obtained from spheres that display self-renewing properties, have multi-lineage differentiation potential, could generate complex branched tubular structures in vitro and form tumours in NOD/SCID mice. We analysed these cells for the expression of human stem and CSC markers and are currently investigating the tumour-initiating properties of these cells and the hierarchical organization of normal and neoplastic canine mammary tissue. C1 [Anastasi, P.; Beccaglia, M.; Veronesi, M. C.; Luvoni, G. C.] Univ Milan, Dept Vet Clin Sci Obstet & Gynaecol, I-20133 Milan, Italy. [Cocola, C.; Piscitelli, E.; Pelucchi, P.; Vilardo, L.; Bertoli, G.; Sanzone, S.; Zucchi, I.] CNR, Inst Biomed Technol, Milan, Italy. [Astigiano, S.; Barbieri, O.] Natl Canc Inst, Genoa, Italy. [Reinbold, R. A.] Max Planck Inst, Munster, Germany. RP Luvoni, GC (reprint author), Univ Milan, Dept Vet Clin Sci Obstet & Gynaecol, Via Celoria 10, I-20133 Milan, Italy. EM cecilia.luvoni@unimi.it RI Barbieri, Ottavia/E-8768-2011; Bertoli, Gloria/J-6559-2016; OI Bertoli, Gloria/0000-0002-5901-4269; Luvoni, Gaia Cecilia/0000-0002-9598-9098 NR 11 TC 21 Z9 21 U1 1 U2 8 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0936-6768 J9 REPROD DOMEST ANIM JI Reprod. Domest. Anim. PD JUL PY 2009 VL 44 BP 214 EP 217 DI 10.1111/j.1439-0531.2009.01413.x PG 4 WC Agriculture, Dairy & Animal Science; Reproductive Biology; Veterinary Sciences SC Agriculture; Reproductive Biology; Veterinary Sciences GA 467QF UT WOS:000267756400045 PM 19754572 ER PT J AU Leon, SR Konda, KA Klausner, JD Jones, FR Caceres, CF Coates, TJ AF Leon, Segundo R. Konda, Kelika A. Klausner, Jeffrey D. Jones, Franca R. Caceres, Carlos F. Coates, Thomas J. CA NIMH Collaborative HIV STD Prevent TI Chlamydia trachomatis infection and associated risk factors in a low-income marginalized urban population in coastal Peru SO REVISTA PANAMERICANA DE SALUD PUBLICA-PAN AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article DE Chlamydia; sexually transmitted diseases; vulnerable populations; women; Peru ID SEXUALLY-TRANSMITTED INFECTIONS; REPRODUCTIVE-TRACT INFECTIONS; PELVIC-INFLAMMATORY-DISEASE; ECTOPIC PREGNANCY; HIGH PREVALENCE; WOMEN; BEHAVIORS; GONORRHEA AB Objectives. To estimate Chlamydia trachomatis (CT) infection prevalence and associated risk factors among a low-income marginalized urban population in Peru. Methods. Between April 2003 and April 2005, men and women at high-risk for sexually transmitted infections (STIs) were recruited from low-income urban areas in three coastal cities in Peru (Chiclayo, Lima, and Trujillo). Consenting participants were studied using a sero-epidemiologic survey. Urine and vaginal swabs collected from men and women were evaluated using polymerase chain reaction (PCR) (COBAS (R) AMPLICOR (CT/NG) Test, Roche Molecular Diagnostics, Branchburg, NJ, USA) for CT. Results. Among the 2 440 participants recruited for the study (2145 men and 295 women), overall prevalence of CT infection was 6.6% (95% CI, 5.6-7.6%): 5.5% (95% CI, 4.5-6.5%) in men and 14.9% ( 95% CI, 11.7-27.1%) in women. Chlamydial infection was inversely associated with age and positively associated with HIV infection and dysuria in men. Among women, chlamydial infection was inversely associated with age and positively associated with number of sex partners. Conclusions. CT infection was common among high-risk men and women in urban coastal Peru. Because chlamydial infection is associated with complications related to female reproduction, including infertility and ectopic pregnancy, interventions to prevent and treat infection and studies to determine the feasibility of population-based screening for CT should be conducted among the high-risk female population. C1 [Leon, Segundo R.] Univ Peruana Cayetano Heredia, Fac Salud Publ, Lima 18, Peru. [Konda, Kelika A.; Coates, Thomas J.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Klausner, Jeffrey D.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [Jones, Franca R.] US Naval Med Res Ctr, Bethesda, MD USA. [NIMH Collaborative HIV STD Prevent] NIMH Multisite Int Grp, Bethesda, MD USA. RP Leon, SR (reprint author), Univ Peruana Cayetano Heredia, Fac Salud Publ, Av Armendariz 445, Lima 18, Peru. EM Segundo.Leon@upch.pe OI Caceres, Carlos/0000-0002-8101-0790 FU NIMH NIH HHS [U10 MH061536, U10 MH061536-08, U10 MH61536]; PHS HHS [NM-04-171787] NR 35 TC 7 Z9 9 U1 1 U2 4 PU PAN AMER HEALTH ORGANIZATION PI WASHINGTON PA 525 23RD ST NW, WASHINGTON, DC 20037 USA SN 1020-4989 J9 REV PANAM SALUD PUBL JI Rev. Panam. Salud Publica PD JUL PY 2009 VL 26 IS 1 BP 39 EP 45 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 489XW UT WOS:000269461000006 PM 19814880 ER PT J AU Andersen, JB Mazan-Mamczarz, K Zhan, M Gorospe, M Hassel, BA AF Andersen, Jesper B. Mazan-Mamczarz, Krystyna Zhan, Ming Gorospe, Myriam Hassel, Bret A. TI Ribosomal protein mRNAs are primary targets of regulation in RNase-L-induced senescence SO RNA BIOLOGY LA English DT Article DE RNase-L; ribosomal protein; senescence; mRNA stability; 2 '-5 '-oligoadenylate ID INTERFERON-TREATED CELLS; 2-5A-DEPENDENT RNASE; 2-5A SYSTEM; CELLULAR SENESCENCE; L INHIBITOR; ACTIVATION; CLEAVAGE; APOPTOSIS; CLONING; PATHWAY AB The endoribonuclease RNase-L requires 2',5'-linked oligoadenylates for activation, and mediates antiviral and antiproliferative activities. We previously determined that RNase-L activation induces senescence; to determine potential mechanisms underlying this activity, we used microarrays to identify RNase-L-regulated mRNAs. RNase-L activation affected affected a finite number of transcripts, and thus does not lead to a global change in mRNA turnover. The largest classes of downregulated transcripts, that represent candidate RNase-L substrates, function in protein biosynthesis, metabolism and proliferation. Among these, mRNAs encoding ribosomal proteins (RPs) were particularly enriched. The reduced levels of four RP mRNAs corresponded with a decrease in their half lives and a physical association with an RNase-L-ribonucleoprotein (RNP) complex in cells, suggesting that they represent authentic RNase-L substrates. Sequence and structural analysis of the downregulated mRNAs identified a putative RNase-L target motif that was used for the in silico identification of a novel RNase-L-RNP-interacting transcript. The downregulation of RP mRNAs corresponded with a marked reduction in protein translation, consistent with the roles of RP proteins in ribosome function. Our data support a model in which the RNase-L-mediated degradation of RP mRNAs inhibits translation, and may contribute to its antiproliferative, senescence inducing and tumor suppressor activities. C1 [Andersen, Jesper B.; Hassel, Bret A.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Sch Med, Baltimore, MD 21201 USA. [Hassel, Bret A.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. [Hassel, Bret A.] Univ Maryland, Grad Program Mol Med, Sch Med, Baltimore, MD 21201 USA. [Mazan-Mamczarz, Krystyna; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Zhan, Ming] NIA, Bioinformat Unit, RRB, NIH, Baltimore, MD 21224 USA. RP Hassel, BA (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Sch Med, 655 W Redwood St,9th Floor BRB, Baltimore, MD 21201 USA. EM bhassel@som.umaryland.edu FU National Institute on Aging [AG20355]; NIH; Veteran's Administration; NIA Intramural Research Program FX We thank Drs. Robert Silverman and Beihua Dong, The Cleveland Clinic Foundation, for the generous gift of RNase-L antibody and Aimin Zhou, Cleveland State University, for kindly providing us with 2-5A. This work was supported by grant AG20355 from the National Institute on Aging, NIH, and a merit Review Award from the Veteran's Administration to B.A.H. K.M.M., M.Z. and M.G. were supported by the NIA Intramural Research Program, NIH. NR 54 TC 22 Z9 22 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1547-6286 J9 RNA BIOL JI RNA Biol. PD JUL-AUG PY 2009 VL 6 IS 3 BP 305 EP 315 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 545FA UT WOS:000273716700015 PM 19411840 ER PT J AU Park, MK Fontana, JR Babaali, H Gilbert-McClain, LI Stylianou, M Joo, J Moss, J Manganiello, VC AF Park, M. K. Fontana, J. R. Babaali, H. Gilbert-McClain, L. I. Stylianou, M. Joo, J. Moss, J. Manganiello, V. C. TI STEROID-SPARING EFFECTS OF PENTOXIFYLLINE IN PULMONARY SARCOIDOSIS SO SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES LA English DT Article DE pentoxifylline; phosphodiesterase; sarcoidosis; steroid-sparing; pulmonary function ID TUMOR-NECROSIS-FACTOR; ALVEOLAR MACROPHAGES; TNF-ALPHA; CYTOKINE RELEASE; CLINICAL-TRIALS; LUNG-DISEASE; DOUBLE-BLIND; T-CELLS; INHIBITION; EXPRESSION AB Background: Agents that target pro-inflammatory cytokines may be useful in pulmonary sarcoidosis. Objective: To determine effectiveness of a non-selective cyclic nucleotide phosphodiesterase (PDE) inhibitor, pentoxifylline (POF). Design: Randomized, double-blind, placebo-controlled trial, Setting: Clinical Research Center, National Institutes of Health. Patients: 27 patients with biopsy-confirmed pulmonary sarcoidosis receiving prednisone. Intervention: Placebo or POF (1200-2000 mg/day) for 10 months, as prednisone was tapered. Measurements: Primary endpoints: sustained improvement in two or more pulmonary function parameters, or a combination of one pulmonary function parameter and dyspnea. Results: Except for one patient, primary endpoints were not reached in POF-treated patients. Therefore, a post hoc analysis was performed. The observed relative risk reduction for flares associated with POF treatment was 54.9% (95% CI 0.21, 0.89) and the absolute risk reduction was 50.6% (95% CI 0.22, 0.80). Compared to placebo treatment, in the POF group, the mean prednisone dose was lower at 8 and 10 months (p = 0.007 and 0.01 respectively), and there was a trend towards less prednisone usage over the entire study period (p = 0.053), as determined by cumulative change analysis. Conclusions: Although our exploratory post hoc analysis suggested that POF reduced flares and had steroid-sparing effects, given the study limitations, definitive conclusions cannot be drawn regarding the efficacy of POF in pulmonary sarcoidosis. In addition, gastrointestinal side-effects, at the doses used, would seem to limit the use of POF in treating pulmonary sarcoidosis. Overall, however, this trial may provide a basis for using more specific, better-tolerated, PDE inhibitors in future clinical trials. (Sarcoidosis Vasc Diffuse Lung Dis 2009; 26: 121-131) C1 [Park, M. K.; Babaali, H.; Gilbert-McClain, L. I.; Moss, J.; Manganiello, V. C.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Fontana, J. R.] NHLBI, Pulm Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Stylianou, M.; Joo, J.] NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Manganiello, VC (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,Rm 5N307,9000 Rockville Pike, Bethesda, MD 20892 USA. EM manganiv@nhlbi.nih.gov FU Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute FX Research support: Division of Intramural Research, National Institutes of Health, National Heart, Lung, and Blood Institute NR 43 TC 35 Z9 36 U1 0 U2 2 PU FONDAZIONE PNEUMOLOGIA U I P ONLUS PI MILANO PA VIA FRUA 15, MILANO, ITALY SN 1124-0490 J9 SARCOIDOSIS VASC DIF JI Sarcoidosis Vasc. Diffus. Lung Dis. PD JUL PY 2009 VL 26 IS 2 BP 121 EP 131 PG 11 WC Respiratory System SC Respiratory System GA 571VJ UT WOS:000275783700006 PM 20560292 ER PT J AU Leyva, FJ Pershouse, MA AF Leyva, Francisco J. Pershouse, Mark A. TI Quantitative and Qualitative Methods Using Fluorescence Microscopy for the Study of Modified Low Density Lipoproteins Uptake SO SCANNING LA English DT Article DE lipids; low-density lipoproteins; scavenger receptors; macrophage; endocytosis ID MACROPHAGE SCAVENGER RECEPTORS; ATHEROSCLEROTIC LESIONS; TRANSGENIC MICE; SR-A; EXPRESSION; RECOGNITION; DOMAIN; LEADS AB Atherosclerosis and heart disease are the main cause of death in United States. The development of atherosclerosis includes lipid deposition and foam cell formation in the artery wall. Scavenger Receptors A-I and II (SRA-I/II) have an important role of in foam cell formation and atherogenesis. Most of the SRA-I/II studies had been performed using Iodine-125-radiolabeled modified low-density lipoprotein. This report attempts to validate the use of fluorescence microscopy techniques as an alternative to obtain qualitative and quantitative information of the uptake of fluorescence-labeled acetylated low-density lipoprotein (AcLDL) in adherent CHO cells expressing SRA-I/II. After verifying the protein expression of SRA-I and II, uptake was quantified using a Laser Scan Cytometer, and images of cells containing fluorescent AcLDL were obtained. A significant increase in fluorescence was found in the cells transfected with SRA-I/II vs. those with empty vector. When SRA-I/II competitive ligands were used, the uptake of AcLDL was significantly decreased. In conclusion, the use of fluorescence microscopy techniques in obtaining qualitative and quantitative information of the uptake of fluorescence-labeled AcLDL by adherent cells, such as CHO cells, is an alternative to the traditional use of radiolabeled iodine. SCANNING 31: 167-173, 2009. (c) 2009 Wiley Periodicals, Inc. C1 [Leyva, Francisco J.] NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. [Pershouse, Mark A.] Univ Montana, Environm Hlth Sci Ctr, Missoula, MT 59812 USA. RP Leyva, FJ (reprint author), Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, 600 N Wolfe St,Osler 527, Baltimore, MD 21287 USA. EM leyvaf@mail.nih.gov FU National Center for Research Resources [P20-RR-017670] FX Contract grant sponsor: National Center for Research Resources; Contract grant number: P20-RR-017670. NR 19 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0161-0457 J9 SCANNING JI Scanning PD JUL-AUG PY 2009 VL 31 IS 4 BP 167 EP 173 DI 10.1002/sca.20155 PG 7 WC Instruments & Instrumentation; Microscopy SC Instruments & Instrumentation; Microscopy GA 513RK UT WOS:000271340700004 PM 19768737 ER PT J AU Shapiro, DI Marenco, S Spoor, EH Egan, MF Weinberger, DR Gold, JM AF Shapiro, D. I. Marenco, S. Spoor, E. H. Egan, M. F. Weinberger, D. R. Gold, J. M. TI The Premorbid Adjustment Scale as a measure of developmental compromise in patients with schizophrenia and their healthy siblings SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Premorbid Adjustment Scale; Premorbid; Siblings ID ONSET SCHIZOPHRENIA; ATTENTION DEFICITS; BIRTH COHORT; FOLLOW-UP; HIGH-RISK; ADOLESCENTS; SCHIZOTYPY; CHILDHOOD; PREDICTOR; PSYCHOSES AB Schizophrenia is associated with subtle developmental compromise, but the degree to which this is also associated with heritability and genetic risk is uncertain. The goal of the current study was to investigate the childhood, adolescent, and early adulthood social and academic function of patients with schizophrenia, their healthy siblings, and normal controls, using the Premorbid Adjustment Scale (PAS). Generalized Estimating Equations were conducted to account for nesting of subjects within families. Patients (N = 286) scored significantly worse than their healthy siblings (N = 315) at every age period; siblings scored significantly worse than controls (N = 261) at every age period. In probands, PAS scores got worse after early adolescence while control and proband scores improved after late adolescence. Furthermore, patient PAS scores significantly predicted the scores of their own discordant siblings in childhood and late adolescence. This effect approached significance in early adolescence and in the general scale. Thus, the most premorbidly impaired patients tended to have non-ill siblings with worse premorbid adjustment scores than the siblings of less impaired probands. The results suggest that both patients and many of their siblings share poor adjustment in childhood and adolescence, possibly due to shared genetic or environmental risk factors. Published by Elsevier B.V. C1 [Shapiro, D. I.; Marenco, S.; Spoor, E. H.; Egan, M. F.; Weinberger, D. R.; Gold, J. M.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, 10 Ctr Dr,Room 4S235, Bethesda, MD 20892 USA. EM daniel.shapiro@emory.edu; marencos@mail.nih.gov; Michael_egan@merck.com; weinberd@mail.nih.gov; jgold@mprc.umaryland.edu RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 FU Intramural NIH HHS [Z01 MH002904-01, Z01 MH002908-01] NR 26 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD JUL PY 2009 VL 112 IS 1-3 BP 136 EP 142 DI 10.1016/j.schres.2009.04.007 PG 7 WC Psychiatry SC Psychiatry GA 472TA UT WOS:000268153900019 PM 19410430 ER PT J AU Walsh, TJ AF Walsh, Thomas J. TI Advances and Challenges in Infectious Diseases Supportive Care of Patients With Hematologic Malignancies, Hematopoietic Stem Cell Transplantation, and Severe Aplastic Anemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID IN-SITU HYBRIDIZATION; CLINICAL-PRACTICE GUIDELINES; ACUTE MYELOID-LEUKEMIA; HIGH-RISK; RAPID IDENTIFICATION; ASPERGILLUS-TERREUS; PEDIATRIC-PATIENTS; CONTROLLED-TRIAL; BETA-LACTAMASES; DOUBLE-BLIND AB Infectious diseases are important causes of morbidity and mortality in immunocompromised patients with hematological malignancies, severe aplastic anemia (SAA), and myelodysplasia. Major advances in infectious diseases supportive care have been critical to improving the outcome of patients Suffering from these life-threatening diseases. Advances in diagnosis, treatment, and prevention of life-threatening infections have reduced morbidity and mortality, improved quality of life, and enabled the use of potentially curative chemotherapy, radiation, hematopoietic stem cell transplantation (HSCI), and immunosuppressive therapy to patients battling these devastating diseases. Despite these advances, the continued development of antimicrobial resistance, emergence of new pathogens, and the evolution Of host factors present evolving challenges to the successful management of infectious complications in this expanding patient population. Semin Hematol 46:191-197. (C) 2009 Published by Elsevier Inc. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, POB ICHS,CRC 1-5750,MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. NR 67 TC 5 Z9 8 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2009 VL 46 IS 3 BP 191 EP 197 DI 10.1053/j.seminhematol.2009.05.001 PG 7 WC Hematology SC Hematology GA 463RF UT WOS:000267448800001 PM 19549573 ER PT J AU Jancel, T Penzak, SR AF Jancel, Timothy Penzak, Scott R. TI Antiviral Therapy in Patients With Hematologic Malignancies, Transplantation, and Aplastic Anemia SO SEMINARS IN HEMATOLOGY LA English DT Review ID HERPES-SIMPLEX-VIRUS; STEM-CELL TRANSPLANTATION; HUMAN-IMMUNODEFICIENCY-VIRUS; VARICELLA-ZOSTER-VIRUS; DOUBLE-BLIND TRIAL; GANCICLOVIR-RESISTANT CYTOMEGALOVIRUS; HELICASE-PRIMASE INHIBITORS; BONE-MARROW-TRANSPLANTATION; SIALIDASE FUSION PROTEIN; BENZIMIDAZOLE L-RIBOSIDE AB Advances in supportive care over the past two decades have decreased the morbidity and mortality attributed to opportunistic infections in immunocompromised patients, including those with hematologic malignancies, hematopoietic stem cell transplantation (HSCT), and aplastic anemia. Despite advances in antiviral therapy, opportunistic viral infections such as influenza, herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) still cause significant morbidity and mortality in patients with compromised host defenses. Antiviral agents are key antimicrobials used for treatment and prophylaxis of viral infections in immunocompromised hosts. Currently, there are more than 40 antiviral agents approved for clinical use, but the majority of these agents are for the treatment of human immunodeficiency virus (HIV) or viral hepatitis. This review will focus on antiviral agents used for the treatment of herpesviruses (HSV, VZV, CNM, community-acquired respiratory viruses (influenza), and adenoviruses. Antiviral agents used for the treatment of HIV and viral hepatitis will not be addressed in this review. Semin Hematol 46:230-247. Published by Elsevier Inc. C1 [Jancel, Timothy] NCI, Ctr Clin, Dept Pharm, NIH, Bethesda, MD 20892 USA. RP Jancel, T (reprint author), NCI, Ctr Clin, Dept Pharm, NIH, Bldg 10,Room 1N257,10 Ctr Dr, Bethesda, MD 20892 USA. EM jancelt@cc.nih.gov NR 191 TC 10 Z9 10 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2009 VL 46 IS 3 BP 230 EP 247 DI 10.1053/j.seminhematol.2009.03.004 PG 18 WC Hematology SC Hematology GA 463RF UT WOS:000267448800004 PM 19549576 ER PT J AU Valdez, JM Scheinberg, P Young, NS Walsh, TJ AF Valdez, Jessica M. Scheinberg, Phillip Young, Neal S. Walsh, Thomas J. TI Infections in Patients With Aplastic Anemia SO SEMINARS IN HEMATOLOGY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; ANTI-THYMOCYTE GLOBULIN; PSEUDOMONAS-AERUGINOSA; ANTITHYMOCYTE GLOBULIN; BACILLUS-CEREUS; COST-EFFECTIVENESS; RISK FACTOR; CYCLOSPORINE; FUSARIUM; EPIDEMIOLOGY AB Infection is a major cause of death in patients with aplastic anemia (AA). There are differences between the immunocompromised state of a patient with AA and the patient who is neutropenic due to chemotherapy and this leads to a difference in the infections that they incur. Prolonged neutropenia is one of the largest risk factors for the development of infections with the invasive mycoses and bacteria. Recovery from neutropenia is directly related to survival, and supportive care plays a large role in protection while the patient is in a neutropenic state. The most common invasive mycoses include the Aspergillus species, Zygomycetes, Candida spp., and Fusarium spp. Bacterial infections that are seen in patients with AA include gram-positive coagulase-negative Staphylococcus species, Enterococcus, Staphylococus aureus, Clostridium spp., Micrococcus, alpha-hemolytic streptococci, Listeria monocytogenes, and Bacillus cereus. Gram-negative infections including gram-negative bacilli, Escherichia coli, Salmonella, Bacteroides freigilis, Klebsiella, oxytoca, Klebsiella pneumonia, Aeromonas hydrophilia, Pseudomonas aeruginosa, and Vibrio vulnificus. Viral infections are much less common but include those that belong to the Herpes-viridae family, community-acquired respiratory viral infection, and the viral hepatitides A, 13, and C. Evidence of the parasite Strongyloides stercoralis has also been documented. This review discusses the major invasive fungal infections, bacterial pathogens, parasites, and viral infections that are found in patients with AA who are treated with immunosuppressive therapy. The specific immune impairment and current treatment parameters for each of these classes of infection will also be discussed. Semin Hernatol 46:269-276. (C) 2009 Published by Elsevier Inc. C1 [Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Valdez, Jessica M.] Howard Hughes Med Inst, Natl Inst Hlth, Res Scholars Program, Bethesda, MD 20817 USA. [Scheinberg, Phillip; Young, Neal S.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov OI Scheinberg, Phillip/0000-0002-9047-4538 FU Howard Hughes Medical Institute NR 69 TC 28 Z9 31 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JUL PY 2009 VL 46 IS 3 BP 269 EP 276 DI 10.1053/j.seminhematol.2009.03.008 PG 8 WC Hematology SC Hematology GA 463RF UT WOS:000267448800007 PM 19549579 ER PT J AU Kreisl, TN AF Kreisl, Teri N. TI Chemotherapy for Malignant Gliomas SO SEMINARS IN RADIATION ONCOLOGY LA English DT Article ID PHASE-II TRIAL; BRAIN-TUMOR CONSORTIUM; RECURRENT GLIOBLASTOMA-MULTIFORME; INTRAVENOUS CARBOPLATIN; ANAPLASTIC ASTROCYTOMA; BARRIER DISRUPTION; IMATINIB MESYLATE; BREAST-CANCER; TEMOZOLOMIDE; ETOPOSIDE AB Malignant gliomas are rare but lethal tumors in which the mainstays of therapy remain surgery and radiation therapy. Chemotherapy currently plays a primarily adjuvant role in the management of these patients with, unfortunately, little success in the recurrent disease setting. Barriers to efficacy of standard cytotoxic agents are related to drug-delivery challenges and inherent chemoresistance. Newer agents designed as directed antiglioma therapy are being explored with exciting preliminary results. Bevacizumab and other antiangiogenic drugs are likely to play a key role in the treatment of malignant glioma, as are combinations of molecularly targeted compounds. A greater understanding of cancer biology has afforded an increasing number and variety of oncogenic targets for therapeutic development, providing hope for brain tumor patients with historically poor outcomes. Semin Radiat Oncol 19:150-154 Published by Elsevier Inc. C1 NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. RP Kreisl, TN (reprint author), NCI, Neurooncol Branch, NIH, 9030 Old Georgetown Rd,Bldg 82, Bethesda, MD 20892 USA. EM kreislt@mail.nih.gov NR 57 TC 14 Z9 14 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD JUL PY 2009 VL 19 IS 3 BP 150 EP 154 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 454JF UT WOS:000266677500003 PM 19464629 ER PT J AU Kim, MS Merke, DP AF Kim, Mimi S. Merke, Deborah P. TI Cardiovascular Disease Risk in Adult Women with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency SO SEMINARS IN REPRODUCTIVE MEDICINE LA English DT Article DE Cardiovascular risk; congenital adrenal hyperplasia; metabolic syndrome; hyperandrogenism ID POLYCYSTIC-OVARY-SYNDROME; INSULIN-RESISTANCE; BLOOD-PRESSURE; METABOLIC SYNDROME; EPINEPHRINE RESERVE; BODY-COMPOSITION; ADIPOSE-TISSUE; YOUNG-WOMEN; CHILDREN; OBESITY AB Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by impaired cortisol biosynthesis, with or without aldosterone deficiency, and androgen excess. Patients with the classic (severe) form also have epinephrine deficiency. Patients with CAH have an increased prevalence of risk factors for cardiovascular disease including obesity, hypertension, and insulin resistance. Androgen excess in women appears to be an additional risk factor for cardiovascular disease. Carotid intima-media thickness, a measure of subclinical atherosclerosis, also has been found to be increased in adults with CAR The multiple hormonal imbalances present in the adult woman with CAH, in combination with chronic glucocorticoid therapy, contribute to cardiovascular disease risk. Further investigation of the predisposition to cardiovascular disease in women with CAH is warranted. Longitudinal studies are needed, and interventions targeting obesity, insulin resistance, hypertension, and hyperandrogenism may offer improved outcome. C1 [Kim, Mimi S.; Merke, Deborah P.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Kim, Mimi S.; Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1-2740,MSC 1932, Bethesda, MD 20892 USA. EM dmerke@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 50 TC 16 Z9 16 U1 2 U2 2 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1526-8004 EI 1526-4564 J9 SEMIN REPROD MED JI Semin. Reprod. Med. PD JUL PY 2009 VL 27 IS 4 BP 316 EP 321 DI 10.1055/s-0029-1225259 PG 6 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 462TG UT WOS:000267378900005 PM 19530065 ER PT J AU Jennings, JM Ellen, JM Deeds, BG Harris, DR Muenz, LR Barnes, W Lee, SS Auerswald, CL AF Jennings, Jacky M. Ellen, Jonathan M. Deeds, Bethany Griffin Harris, D. Robert Muenz, Larry R. Barnes, William Lee, Sonia S. Auerswald, Colette L. CA Adolescent Trials Network HIV AIDS TI Youth Living With HIV and Partner-Specific Risk for the Secondary Transmission of HIV SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; BISEXUAL MEN; SEROPOSITIVE GAY; SAN-FRANCISCO; UNITED-STATES; SUBSTANCE USE; DRUG-USE; SEX; ADOLESCENTS; PREVALENCE AB Background: Secondary transmission remains I significant concern among HIV-infected youth. Little is known, however, about how partner-specific sexual risk behaviors for the secondary transmission of HIV may differ between the 2 largest subgroups of HIV-positive youth, women-who-have-sex-with-men (WSM) and men-who-have-sex-wtih-men (MSM) Methods: During 2003-2004, a convenience sample of HIV-infected Youth, 13 to 24 years of age. were recruited from 15 Adolescent Medicine Trials Network clinical sites. Approximately 10 to 15 Youth were recruited at each site. Participants completed an ACASI survey including questions about sex partners in the past year. Cross-sectional data analyses. including bivariate and multivariable regressions. using generalized estimating equations, were conducted during 2008 to compare recent partner-specific sexual risk behaviors between WSM and MSM. Results: Of 409 participants, 91% (371) were included in this analysis. including 176 WSM and 195 MSM. Ninety-two percent (163 WSM, 177 MSM) provided information on characteristics of their sexual partners. There were significant differences between the 2 groups in recent partner-specific sexual risk behaviors including: lower rates of condom use at last sex among WSM (61% WSM vs. 78% MSM; P = 0.0011) a larger proportion of the sex partners of MSM reported as concurrent (56% MSM vs. 36% WSM P = 0.0001): and greater use of hard drugs at last sex by MSM and/or their partner (18% MSM vs. 4% WSK P = 0.0008). When measuring risk as a composite measure of sexual risk behaviors known to be associated with HIV transmission, both groups had high rates of risky behaviors, 74.7% among young MSM compared to 68.1% of WSM. Conclusions: These data suggest that recent partner-specific sexual risk behaviors for HIV transmission are high among young infected MSM and WSM. These findings suggest the need to offer interventions to reduce the secondary transmission of HIV to all HIV-positive youth in care. However, differences in risk behaviors between young MSM and WSM supports population-specific interventions. C1 [Jennings, Jacky M.; Ellen, Jonathan M.] Johns Hopkins Univ, Dept Pediat, Sch Med, Div Gen Pediat & Adolescent Med, Baltimore, MD 21224 USA. [Jennings, Jacky M.; Ellen, Jonathan M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Deeds, Bethany Griffin] NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. [Harris, D. Robert; Muenz, Larry R.] WESTAT Corp, Rockville, MD 20850 USA. [Barnes, William] George Washington Univ, Childrens Natl Med Ctr, Div Adolescent & Young Adult Med, Washington, DC USA. [Lee, Sonia S.] NICHHD, Ctr Res Mothers & Children, Eunice Shriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD 20892 USA. [Auerswald, Colette L.] Univ Calif San Francisco, Sch Med, Dept Pediat, Div Adolescent Med, San Francisco, CA 94143 USA. [Auerswald, Colette L.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley UCSF Joint Med Program, UC, Berkeley, CA 94720 USA. RP Jennings, JM (reprint author), Johns Hopkins Univ, Dept Pediat, Sch Med, Div Gen Pediat & Adolescent Med, 5200 Eastern Ave,Mason F Lord Bldg Ctr Towers,Rm, Baltimore, MD 21224 USA. EM jjennin1@jhmi.edu FU NICHD NIH HHS [U01 HD040474, U01 HD040506, U01 HD040506-01, U01 HD040533, U01 HD040533-01]; NIDA NIH HHS [K01 DA022298]; PHS HHS [H25/CCH222333-01] NR 34 TC 7 Z9 7 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JUL PY 2009 VL 36 IS 7 BP 439 EP 444 DI 10.1097/OLQ.0b013e3181ad516c PG 6 WC Infectious Diseases SC Infectious Diseases GA 463QJ UT WOS:000267446400009 PM 19525889 ER PT J AU Arumugam, TV Okun, E Tang, SC Thundyil, J Taylor, SM Woodruff, TM AF Arumugam, Thiruma V. Okun, Eitan Tang, Sung-Chun Thundyil, John Taylor, Stephen M. Woodruff, Trent M. TI TOLL-LIKE RECEPTORS IN ISCHEMIA-REPERFUSION INJURY SO SHOCK LA English DT Review DE Toll-like receptors; ischemia-reperfusion injury; myocardial infarction; neuron; stroke; apoptosis ID NF-KAPPA-B; HEPATIC ISCHEMIA/REPERFUSION INJURY; FOCAL CEREBRAL-ISCHEMIA; ACUTE MYOCARDIAL-INFARCTION; CENTRAL-NERVOUS-SYSTEM; NECROSIS-FACTOR-ALPHA; IN-VIVO EXPRESSION; OXIDATIVE STRESS; INFLAMMATORY RESPONSE; DENDRITIC CELLS AB Ischemia-reperfusion (I/R) injuries are implicated in a large array of pathological conditions such as myocardial infarction, cerebral stroke, and hepatic, renal, and intestinal ischemia, as well as following cardiovascular and transplant surgeries. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands such as low-molecular hyaluronic acid, fibronectin, heat shock protein 70, and heparin sulfate were all found to be cleaved in the inflamed tissue and to activate TLR2 and TLR4, initiating an inflammatory response even in the absence of pathogens and infiltrating immune cells. In this review, we discuss the contribution of TLR activation in hepatic, renal, cerebral, intestinal, and myocardial I/R injuries. A greater understanding of the role of TLRs in I/R injuries may aid in the development of specific TLR-targeted therapeutics to treat these conditions. C1 [Arumugam, Thiruma V.; Thundyil, John] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Sch Pharm, Amarillo, TX 79106 USA. [Okun, Eitan] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Tang, Sung-Chun] Natl Taiwan Univ Hosp, Dept Neurol, Yunlin, Taiwan. [Taylor, Stephen M.; Woodruff, Trent M.] Univ Queensland, Sch Biomed Sci, Brisbane, Qld, Australia. RP Arumugam, TV (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Sch Pharm, 1300 Coulter Dr, Amarillo, TX 79106 USA. EM thiruma.arumugam@ttuhsc.edu; t.woodruff@uq.edu.au RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Woodruff, Trent/B-4861-2009; okun, eitan/K-1314-2016; OI Woodruff, Trent/0000-0003-1382-911X; okun, eitan/0000-0001-8474-1487; Tang, Sung-Chun/0000-0003-3731-5973 NR 158 TC 157 Z9 176 U1 0 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1073-2322 EI 1540-0514 J9 SHOCK JI Shock PD JUL PY 2009 VL 32 IS 1 BP 4 EP 16 DI 10.1097/SHK.0b013e318193e333 PG 13 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 459DU UT WOS:000267081400002 PM 19008778 ER PT J AU Furuya, F Lu, CX Guigon, CJ Cheng, SY AF Furuya, Fumihiko Lu, Changxue Guigon, Celine J. Cheng, Sheue-Yann TI Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors SO STEROIDS LA English DT Article; Proceedings Paper CT FASEB Summer Research Meeting on Extra-Nuclear Steroid Receptors - Integration with Multiple Signaling Pathways CY JUL 27-AUG 01, 2008 CL Carefree, AZ SP FASEB, Endocrine Soc, Ordway Inst, Wyeth, Novartis, Cell Press, NIH DE Thyroid hormone receptors; Phosphatidylinositol 3-kinase; Nongenomic actions; Mouse model; Thyroid cancer; Nuclear receptor corepressor ID PANCREATIC BETA-CELLS; NUCLEAR RECEPTOR; PLASMA-MEMBRANE; MOUSE MODEL; ESTROGEN-RECEPTOR; TUMOR PROGRESSION; LIGAND-BINDING; MICE; RESISTANCE; KINASE AB Thyroid hormone (T3) is critical in growth, development, differentiation, and maintenance of metabolic homeostasis. Recent studies suggest that thyroid hormone receptors (TRs) not only mediate the biological activities of T3 via nucleus-initiated transcription, but also could act via nongenomic pathways. The striking phenotype of thyroid cancer exhibited by a knockin mutant mouse that harbors a dominant negative TR beta mutant (TR beta(PV/PV) mouse) allows the elucidation of novel oncogenic activity of a TR beta mutant (PV) via extra-nuclear actions. PV physically interacts with the regulatory p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K) to activate the downstream AKT-mammalian target of rapamycin (mTOR) and p70(S6K) and PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathways. The PV-mediated PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Remarkably, a nuclear receptor corepressor (NCoR) was found to regulate the PV-activated PI3K signaling by competing with PV for binding to the C-terminal SH2 domain of p85 alpha. Over-expression of NCoR in thyroid tumor cells of TR beta(PV/PV) mice reduces AKT-mTOR-p70(S6K) signaling. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells leads to over-activated PI3K-AKT signaling to increase cell proliferation and motility. Furthermore, NCoR protein levels are significantly lower in thyroid tumor cells than in wild type thyrocytes, allowing more effective binding of PV to p85 alpha to activate PI3K signaling, thereby contributing to tumor progression. Thus, PV, an apo-TR beta, could act via direct protein-protein interaction to mediate critical oncogenic actions. These studies also uncovered a novel extranuclear role of NCoR in modulating the nongenomic actions of a mutated TR beta in controlling thyroid carcinogenesis. Published by Elsevier Inc. C1 [Furuya, Fumihiko; Lu, Changxue; Guigon, Celine J.; Cheng, Sheue-Yann] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural NIH HHS [ZIA BC011191-03] NR 39 TC 29 Z9 37 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD JUL PY 2009 VL 74 IS 7 BP 628 EP 634 DI 10.1016/j.steroids.2008.10.009 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 443ES UT WOS:000265893600013 PM 19014961 ER PT J AU Lyden, P Raman, R Liu, L Emr, M Warren, M Marler, J AF Lyden, Patrick Raman, Rema Liu, Lin Emr, Marian Warren, Margo Marler, John TI National Institutes of Health Stroke Scale Certification Is Reliable Across Multiple Venues SO STROKE LA English DT Article DE clinimetrics; reliability; scales; stroke ID RELIABILITY; RECOMMENDATIONS; TRIAL AB Background and Purpose-National Institutes of Health Stroke Scale certification is required for participation in modern stroke clinical trials and as part of good clinical care in stroke centers. A new training and demonstration DVD was produced to replace existing training and certification videotapes. Previously, this DVD, with 18 patients representing all possible scores on 15 scale items, was shown to be reliable among expert users. The DVD is now the standard for National Institutes of Health Stroke Scale training, but the videos have not been validated among general (ie, nonexpert) users. Methods-We sought to measure interrater reliability of the certification DVD among general users using methodology previously published for the DVD. All raters who used the DVD certification through the American Heart Association web site were included in this study. Each rater evaluated one of 3 certification groups. Results-Responses were received from 8214 raters overall, 7419 raters using the Internet and 795 raters using other venues. Among raters from other venues, 33% of all responses came from registered nurses, 23% from emergency department MD/other emergency department/other physicians, and 44% from neurologists. Half (51%) of raters were previously National Institutes of Health Stroke Scale-certified and 93% were from the United States/Canada. Item responses were tabulated, scoring performed as previously published, and agreement measured with unweighted kappa coefficients for individual items and an intraclass correlation coefficient for the overall score. In addition, agreement in this study was compared with the agreement obtained in the original DVD validation study to determine if there were differences between novice and experienced users. Kappas ranged from 0.15 (ataxia) to 0.81 (Item 1c, Level of Consciousness-commands [LOCC] questions). Of 15 items, 2 showed poor, 11 moderate, and 2 excellent agreement based on kappa scores. Agreement was slightly lower to that obtained from expert users for LOCC, best gaze, visual fields, facial weakness, motor left arm, motor right arm, and sensory loss. The intraclass correlation coefficient for total score was 0.85 (95% CI, 0.72 to 0.90). Reliability scores were similar among specialists and there were no major differences between nurses and physicians, although scores tended to be lower for neurologists and trended higher among raters not previously certified. Scores were similar across various certification settings. Conclusions-The data suggest that certification using the National Institute of Neurological Disorders and Stroke DVDs is robust and surprisingly reliable for National Institutes of Health Stroke Scale certification across multiple venues. (Stroke. 2009; 40: 2507-2511.) C1 [Lyden, Patrick] Univ Calif San Diego, Dept Neurosci, Sch Med, Stroke Ctr, San Diego, CA 92103 USA. [Raman, Rema; Liu, Lin] Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, San Diego, CA 92103 USA. [Lyden, Patrick] Vet Adm Med Ctr, Dept Neurol, San Diego, CA 92161 USA. [Emr, Marian; Warren, Margo; Marler, John] NINDS, Bethesda, MD 20892 USA. RP Lyden, P (reprint author), Univ Calif San Diego, Dept Neurosci, Sch Med, Stroke Ctr, OPC 3rd Floor,Suite 3,200 W Arbor Dr, San Diego, CA 92103 USA. EM plyden@ucsd.edu FU National Institute of Neurological Disorders and Stroke [P50 NS044148]; Veterans Affairs Medical Research Service FX This work was supported by National Institute of Neurological Disorders and Stroke P50 NS044148 and the Veterans Affairs Medical Research Service. NR 12 TC 32 Z9 32 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2009 VL 40 IS 7 BP 2507 EP 2511 DI 10.1161/STROKEAHA.108.532069 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 463XR UT WOS:000267467900036 PM 19520998 ER PT J AU Milhorat, TH Bolognese, PA Nishikawa, M Francomano, CA McDonnell, NB Roonprapunt, C Kula, RW AF Milhorat, Thomas H. Bolognese, Paolo A. Nishikawa, Misao Francomano, Clair A. McDonnell, Nazli B. Roonprapunt, Chan Kula, Roger W. TI Association of Chiari malformation type I and tethered cord syndrome: preliminary results of sectioning filum terminale SO SURGICAL NEUROLOGY LA English DT Article DE Chiari malformation; Tethered cord; Filum terminale; Brain stem ID POSTERIOR CRANIAL FOSSA; OCCULT SPINAL DYSRAPHISM; CONUS MEDULLARIS; NORMAL POSITION; ADULTS; LIPOMYELOMENINGOCELE; SYRINGOMYELIA; SCOLIOSIS; CHILDREN; BIFIDA AB Objective: The pathogenesis of CM-I is incompletely understood. We describe an association of CM-I and TCS that occurs in a subset of patients with normal size of the PCF. Methods: The prevalence of TCS was determined in a consecutively accrued cohort of 2987 patients with CM-I and 289 patients with low-lying cerebellar tonsils (LLCT). Findings in 74 children and 244 adults undergoing SFT were reviewed retrospectively. Posterior cranial fossa size and volume were measured using reconstructed 2D computed tomographic scans and MR images. Results were compared to those in 155 age- and sex-matched healthy control individuals and 280 patients with generic CM-I. The relationships of neural and osseus structures at the CCJ and TLJ were investigated morphometrically on MR images. Intraoperative CDU was used to measure anatomical structures and CSF flow in the lumbar theca. Results: Tethered cord syndrome was present in 408 patients with CM-I (14%) and 182 patients with LLCT (63%). In 318 patients undergoing SFT, there were no significant differences in the size or volume of the PCF as compared to healthy control individuals. Morphometric measurements demonstrated elongation of the brain stem (mean, 8.3 mm; P < .001), downward displacement of the medulla (mean, 4.6 mm; P < .001), and normal position of the CMD except in very young patients. Compared to patients with generic CM-I, the FM was significantly enlarged (P < .001). The FT was typically thin and taut (mean transverse diameter, 0.8 mm). After SFT, the cut ends of the FT distracted widely (mean, 41.7 mm) and CSF flow in the lumbar theca increased from a mean of 0.7 cm/s to a mean of 3.7 cm/s (P < .001). Symptoms were improved or resolved in 69 children (93%) and 203 adults (83%) and unchanged in 5 children (7%) and 39 adults (16%) and, worse, in 2 adults (1%) over a follow-up period of 6 to 27 months (mean, 16.1 months +/- 4.6 SD). Magnetic resonance imaging I to 18 months after surgery (mean, 5.7 months +/- 3.8 SD) revealed upward migration of the CMD (mean, 5.1 mm, P < .001), ascent of the cerebellar tonsils (mean, 3.8 mm, P < .001), reduction of brain stem length (mean, 3.9 mm, P < .001), and improvement of scoliosis or syringomyclia in some cases. Conclusions: Chiari malformation type I/TCS appears to be a unique clinical entity that occurs as a continuum with LLCT/TCS and is distinguished from generic CM-I by enlargement of the FM and the absence of a small PCF. Distinctive features include elongation and downward displacement of the hindbrain, normal position of the CMD, tight FT, and reduced CSF flow ill the lumbar theca. There is preliminary evidence that SFT can reverse moderate degrees of tonsillar ectopia and is appropriate treatment for cerebellar ptosis after Chiari surgery in this cohort. (C) 2009 Elsevier Inc. All rights reserved. C1 [Milhorat, Thomas H.; Bolognese, Paolo A.; Nishikawa, Misao; Roonprapunt, Chan; Kula, Roger W.] N Shore Long Isl Jewish Hlth Syst, Harvey Cushing Inst Neurosci, Chiari Inst, Dept Neurosurg, Manhasset, NY 11030 USA. [Francomano, Clair A.] Greater Baltimore Med Ctr, Harvey Inst Med Genet, Baltimore, MD 21204 USA. [McDonnell, Nazli B.] NIA, NIH, Baltimore, MD 21224 USA. RP Milhorat, TH (reprint author), N Shore Long Isl Jewish Hlth Syst, Harvey Cushing Inst Neurosci, Chiari Inst, Dept Neurosurg, Manhasset, NY 11030 USA. EM milhorat@nshs.edu NR 82 TC 26 Z9 26 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-3019 J9 SURG NEUROL JI Surg. Neurol. PD JUL PY 2009 VL 72 IS 1 BP 20 EP 35 DI 10.1016/j.surneu.2009.03.008 PG 16 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 467XG UT WOS:000267775800004 PM 19559924 ER PT J AU Skinbjerg, M Ariano, MA Thorsell, A Heilig, M Halldin, C Innis, RB Sibley, DR AF Skinbjerg, Mette Ariano, Marjorie A. Thorsell, Annika Heilig, Markus Halldin, Christer Innis, Robert B. Sibley, David R. TI Arrestin3 Mediates D-2 Dopamine Receptor Internalization SO SYNAPSE LA English DT Article DE D-2 receptor; arrestin; internalization ID PROTEIN-COUPLED RECEPTORS; DESENSITIZATION; BETA-ARRESTIN-2; ENDOCYTOSIS; STRIATUM; KINASES; MICE C1 [Skinbjerg, Mette; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Skinbjerg, Mette; Innis, Robert B.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Skinbjerg, Mette; Halldin, Christer] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, Stockholm, Sweden. [Ariano, Marjorie A.] Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Neurosci, N Chicago, IL 60064 USA. [Thorsell, Annika; Heilig, Markus] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, 5625 Fishers Lane,Room 4S-04,MSC-9405, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov OI Thorsell, Annika/0000-0003-3535-3845 FU Intramural NIH HHS [Z01 NS002263-31] NR 19 TC 17 Z9 17 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JUL PY 2009 VL 63 IS 7 BP 621 EP 624 DI 10.1002/syn.20636 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 448ZI UT WOS:000266300100010 PM 19309759 ER PT J AU Perez, MA Cohen, LG AF Perez, Monica A. Cohen, Leonardo G. TI The Corticospinal System and Transcranial Magnetic Stimulation in Stroke SO TOPICS IN STROKE REHABILITATION LA English DT Review DE motor control; neuroplasticity; primate models; primary motor cortex; rehabilitation ID HUMAN MOTOR CORTEX; INDIVIDUATED FINGER MOVEMENTS; INTRACORTICAL INHIBITORY CIRCUITS; NONINVASIVE BRAIN-STIMULATION; LOWER-LIMB MOTONEURONS; INTERHEMISPHERIC INHIBITION; SUBCORTICAL STROKE; FOLLOW-UP; POSTSTROKE REORGANIZATION; TRANSCALLOSAL INHIBITION AB During the last decades, transcranial magnetic stimulation (TMS) has been used as a noninvasive method to investigate motor cortical reorganization and neuroplasticity in humans after stroke. An increasing number of studies in the field of motor control have used TMS to gain an understanding of the different aspects of stroke cortical physiology and motor recovery. This review addresses the effects of corticospinal tract (CST) lesions in humans and nonhuman primates on the functional organization of the motor system. We review information on the physiological mechanisms by which the CST contributes to normal motor control and to central nervous system reorganization following stroke when the CST is injured as measured using TMS. Insight into these physiological mechanisms has led to the development of scientifically sound interventional proposals in the field of neurorehabilitation. C1 [Perez, Monica A.] Univ Pittsburgh, Dept Phys Med & Rehabil, Ctr Neural Basis Cognit, Pittsburgh, PA 15260 USA. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabil Sect, NIH, Bethesda, MD 20892 USA. RP Perez, MA (reprint author), Univ Pittsburgh, Dept Phys Med & Rehabil, Ctr Neural Basis Cognit, Pittsburgh, PA 15260 USA. FU Intramural NIH HHS [Z01 NS002978-09] NR 117 TC 23 Z9 24 U1 2 U2 9 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1074-9357 J9 TOP STROKE REHABIL JI Top. Stroke Rehabil. PD JUL-AUG PY 2009 VL 16 IS 4 BP 254 EP 269 DI 10.1310/tsr1604-254 PG 16 WC Rehabilitation SC Rehabilitation GA 498ZH UT WOS:000270185200004 PM 19740731 ER PT J AU Foreman, JE Chang, SC Ehresman, DJ Butenhoff, JL Anderson, CR Palkar, PS Kang, BH Gonzalez, FJ Peters, JM AF Foreman, Jennifer E. Chang, Shu-Ching Ehresman, David J. Butenhoff, John L. Anderson, Cherie R. Palkar, Prajakta S. Kang, Boo-Hyon Gonzalez, Frank J. Peters, Jeffrey M. TI Differential Hepatic Effects of Perfluorobutyrate Mediated by Mouse and Human PPAR-alpha SO TOXICOLOGICAL SCIENCES LA English DT Article DE PPAR alpha; liver; PFBA; receptor ID ACTIVATED RECEPTOR-ALPHA; PEROXISOME PROLIFERATION; ATMOSPHERIC CHEMISTRY; PERFLUOROALKYL ACIDS; DRINKING-WATER; FATTY-ACIDS; RAT-LIVER; MICE; HEPATOCARCINOGENESIS; MECHANISM AB Perfluorobutryate (PFBA) is a short chain perfluoroalkyl carboxylate that is structurally similar to perfluorooctanoate. Administration of PFBA can cause peroxisome proliferation, induction of peroxisomal fatty acid oxidation and hepatomegaly, suggesting that PFBA activates the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). In this study, the role of PPAR-alpha in mediating the effects of PFBA was examined using PPAR-alpha null mice and a mouse line expressing the human PPAR-alpha in the absence of mouse PPAR-alpha (PPAR-alpha humanized mice). PFBA caused upregulation of known PPAR-alpha target genes that modulate lipid metabolism in wild-type and PPAR-alpha humanized mice, and this effect was not found in PPAR-alpha null mice. Increased liver weight and hepatocyte hypertrophy were also found in wild-type and humanized PPAR-alpha mice treated with PFBA, but not in PPAR-alpha null mice. Interestingly, hepatocyte focal necrosis with inflammatory cell infiltrate was only found in wild-type mice administered PFBA; this effect was markedly diminished in both PPAR-alpha null and PPAR-alpha humanized mice. Results from these studies demonstrate that PFBA can modulate gene expression and cause mild hepatomegaly and hepatocyte hypertrophy through a mechanism that requires PPAR-alpha and that these effects do not exhibit a species difference. In contrast, the PPAR-alpha-dependent increase in PFBA-induced hepatocyte focal necrosis with inflammatory cell infiltrate was mediated by the mouse PPAR-alpha but not the human PPAR-alpha. Collectively, these findings demonstrate that PFBA can activate both the mouse and human PPAR-alpha, but there is a species difference in the hepatotoxic response to this chemical. C1 [Foreman, Jennifer E.; Anderson, Cherie R.; Palkar, Prajakta S.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Foreman, Jennifer E.; Anderson, Cherie R.; Palkar, Prajakta S.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Chang, Shu-Ching; Ehresman, David J.; Butenhoff, John L.] 3M Co, Dept Med, St Paul, MN 55144 USA. [Kang, Boo-Hyon] Nonclin Pathol Res Ctr, Seoul 153801, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU 3M Company FX 3M Company. NR 29 TC 16 Z9 18 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JUL PY 2009 VL 110 IS 1 BP 204 EP 211 DI 10.1093/toxsci/kfp077 PG 8 WC Toxicology SC Toxicology GA 460YB UT WOS:000267227800018 PM 19359353 ER PT J AU Zhang, D Hu, XM Qian, L Wilson, B Lee, C Flood, P Langenbach, R Hong, JS AF Zhang, Dan Hu, Xiaoming Qian, Li Wilson, Belinda Lee, Christopher Flood, Patrick Langenbach, Robert Hong, Jau-Shyong TI Prostaglandin E2 released from activated microglia enhances astrocyte proliferation in vitro SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Cyclooxygenase-2; Prostaglandin E2; Microglia; Astrocyte; LPS ID FIBRILLARY ACIDIC PROTEIN; NECROSIS-FACTOR-ALPHA; GLIAL-CELL ACTIVATION; BRAIN-TUMORS; INDUCIBLE CYCLOOXYGENASE; REACTIVE ASTROGLIOSIS; DOWN-REGULATION; MESSENGER-RNA; INHIBITION; RAT AB Microglial activation has been implicated in many astrogliosis-related pathological conditions including astroglioma; however, the detailed mechanism is not clear. in this study, we used primary enriched microglia and astrocyte cultures to determine the role of microglial prostaglandin E(2) (PGE(2)) in the proliferation of astrocytes. The proliferation of astrocytes was measured by BrdU incorporation. The level of PGE(2) was measured by ELISA method. Pharmacological inhibition or genetic ablation of COX-2 in microglia were also applied in this study. We found that proliferation of astrocytes increased following lipopolysaccharide (LPS) treatment in the presence of microglia. Furthermore, increased proliferation of astrocytes was observed in the presence of conditioned media from LPS-treated microglia. The potential involvement of microglial PGE(2) in enhanced astrocyte proliferation was suggested by the findings that PGE(2) production and COX-2 expression in microglia were increased by LPS treatment. In addition, activated microglia-induced increases in astrocyte proliferation were blocked by the PGE2 antagonist AH6809, COX-2 selective inhibitor DuP-697 or by genetic knockout of microglial COX-2. These findings were further supported by the finding that addition of PGE(2) to the media significantly induced astrocyte proliferation. These results indicate that microglial PGE(2) plays an important role in astrocyte proliferation, identifying PGE(2) as a key neuroinflammatory molecule that triggers the pathological response related to uncontrollable astrocyte proliferation. These findings are important in elucidating the role of activated microglia and PGE(2) in astrocyte proliferation and in suggesting a potential avenue in the use of anti-inflammatory agents for the therapy of astroglioma. Published by Elsevier Inc. C1 [Zhang, Dan; Hu, Xiaoming; Qian, Li; Wilson, Belinda; Hong, Jau-Shyong] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. [Qian, Li; Flood, Patrick] Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. [Lee, Christopher; Langenbach, Robert] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, MD F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov FU National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences. NR 55 TC 17 Z9 18 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD JUL 1 PY 2009 VL 238 IS 1 BP 64 EP 70 DI 10.1016/j.taap.2009.04.015 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 458IF UT WOS:000267009800008 PM 19397918 ER PT J AU Bryant, BJ Leitman, SF Klein, HG AF Bryant, Barbara J. Leitman, Susan F. Klein, Harvey G. TI Therapeutic plasma exchange reveals a color-coordinated response to cyclosporine-induced microangiopathic hemolytic anemia and rifampin after stem cell transplant SO TRANSFUSION LA English DT Editorial Material C1 [Bryant, Barbara J.; Leitman, Susan F.; Klein, Harvey G.] NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Bryant, BJ (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM bryantb2@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2009 VL 49 IS 7 BP 1291 EP 1292 DI 10.1111/j.1537-2995.2009.02155.x PG 2 WC Hematology SC Hematology GA 467CX UT WOS:000267715300005 PM 19602210 ER PT J AU Kannan, M Mohan, KVK Kulkarni, S Atreya, C AF Kannan, Meganathan Mohan, Ketha V. Krishna Kulkarni, Sandhya Atreya, Chintamani TI Membrane array-based differential profiling of platelets during storage for 52 miRNAs associated with apoptosis SO TRANSFUSION LA English DT Article ID MICRORNAS; ACTIVATION; CANCER; CELL; TRANSFUSION; EXPRESSION; MECHANISM; SEQUENCE; MARKERS; STRESS AB BACKGROUND: Enucleated platelets (PLTs) utilize posttranscriptional gene (mRNA) regulation (PTGR) for their normal morphologic and physiologic functions, which are altered in their ex vivo storage, also collectively referred to as storage lesions. While cellular micro-RNAs (miRNAs) play a significant role in posttranscriptional gene (mRNA) regulation by binding to their target mRNAs, comprehensive analysis of apoptosis-associated miRNAs and global changes in their profiles during PLT storage have not been evaluated to date. STUDY DESIGN AND METHODS: In this report room temperature-stored PLTs of Days 0, 2, and 9 were analyzed by differential profiling for 52 apoptosis-associated human miRNAs. After total RNA extraction from the samples, a membrane array-based miRNA analysis was carried out. Prediction of target genes was performed by bioinformatics-based approaches. RESULTS: Our analysis revealed that during storage, Let-7a, -7c, -7e, -7f, -7g, and -7i miRNA profiles of the PLTs were barely detectable, while levels of miR-150, -151, -152, -184, -188, -196a, -197, and -202 remained at high levels in PLTs. The rest of the miRNA levels were in between. However, two miRNAs, Let-7b and miR-16, distinctly demonstrated an increasing trend while miR-7 and miR-145 showed a decreasing profile during PLT storage. For these four miRNAs, we also identified their potential target mRNAs. CONCLUSIONS: Overall, these results confirm the fact that miRNAs do exist in PLTs, and among 52 apoptosis-specific miRNAs studied, only a few selected miRNAs did perturb during PLT storage. Future experimental evaluation of these miRNA-target mRNA interactions will provide new insights into the molecular mechanisms of PLT storage-associated lesions. C1 [Kannan, Meganathan; Mohan, Ketha V. Krishna; Kulkarni, Sandhya; Atreya, Chintamani] US FDA, Sect Cell Biol, Lab Cellular Hematol, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Atreya, C (reprint author), Bldg 29A,Room 2C-11,NIH Campus,8800 Rockville Pik, Bethesda, MD 20892 USA. EM chintamani.atreya@fda.hhs.gov FU FDA; CBER Critical Path Research Initiative; Oak Ridge Institute for Science and Engineering fellowship FX This work in part was supported by the FDA, CBER Critical Path Research Initiative funds to CDA. MK is a recipient of Oak Ridge Institute for Science and Engineering fellowship. NR 30 TC 29 Z9 31 U1 0 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2009 VL 49 IS 7 BP 1443 EP 1450 DI 10.1111/j.1537-2995.2009.02140.x PG 8 WC Hematology SC Hematology GA 467CX UT WOS:000267715300025 PM 19389023 ER PT J AU Singh, KA Kampen, RL Hoffmann, SC Eldaif, SM Kirk, AD AF Singh, Kimberly A. Kampen, Robert L. Hoffmann, Steven C. Eldaif, Shady M. Kirk, Allan D. TI Renal epithelial cell-derived monocyte colony stimulating factor as a local informant of renal injury and means of monocyte activation SO TRANSPLANT INTERNATIONAL LA English DT Article DE kidney transplantation; monocyte; monocyte colony stimulating factor ID ALLOGRAFT-REJECTION; MACROPHAGE PROLIFERATION; M-CSF; ACCUMULATION; EXPRESSION; TOLERANCE; INFLAMMATION; CAMPATH-1H; RECIPIENTS; INDUCTION AB Monocyte accumulation in renal allografts is associated with allograft dysfunction. As monocyte influx occurs acutely following reperfusion, we investigated the effect of ischemia-reperfusion injury (IRI) on monocyte colony stimulating factor (m-CSF), a key cytokine in monocyte recruitment. We hypothesized that renal tubule epithelial cells (RTECs) could produce m-CSF in response to IRI, which could in turn promote monocyte activation. Real time PCR was used to measure levels of intragraft m-CSF transcripts in patients during IRI and clinical rejection. Also, m-CSF production by RTECs following IRI simulation in vitro was measured using ELISA. Monocyte expression of CD40 and CD80 was then analyzed using flow cytometry following co-culture with supernatants of RTECs after IRI. Monocyte expression of CD40, CD80 and HLA-DR was then examined following treatment with rh-m-CSF (10, 36, and 100 ng/ml), as was monocyte size and granularity. We found that intragraft m-CSF transcription was significantly increased postreperfusion (P = 0.002) and during clinical rejection (P = 0.002). We also found that RTECs produced m-CSF in response to IRI in vitro (P = 0.036). Monocytes co-cultured with the supernatants of postischemic RTECs became activated as evidenced by increased expression of CD40 and CD80. Also, monocytes treated with recombinant m-CSF assumed an activated phenotype exhibiting increased size, granularity and expression of CD40, CD80, CD86, and HLA-DR, and demonstrating enhanced phagocytic activity. Taken together, we suggest that renal tubular cell derived m-CSF is a stimulus for monocyte activation and may be an important target for control of IRI-associated immune activation. C1 [Singh, Kimberly A.; Kampen, Robert L.; Eldaif, Shady M.; Kirk, Allan D.] Emory Univ, Sch Med, Emory Transplant Ctr, Dept Surg, Atlanta, GA 30322 USA. [Singh, Kimberly A.; Kampen, Robert L.; Hoffmann, Steven C.; Kirk, Allan D.] NIDDKD, Transplantat Branch, NIH, Bethesda, MD 20892 USA. RP Kirk, AD (reprint author), Emory Univ, Sch Med, Emory Transplant Ctr, Dept Surg, 101 Woodruff Circle,5105 WMB, Atlanta, GA 30322 USA. EM adkirk@emory.edu RI Kirk, Allan/B-6905-2012 FU Division of Intramural Research; National Institutes of Health; National Institute of Diabetes, Digestive and Kidney Diseases; Georgia Research Alliance; McKelvey Foundation; Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, Maryland, USA FX This work was supported in part by the Division of Intramural Research, National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases. ADK is supported by the Georgia Research Alliance and by the McKelvey Foundation. KAS is supported by the Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, Maryland, USA. NR 25 TC 3 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0934-0874 J9 TRANSPL INT JI Transpl. Int. PD JUL PY 2009 VL 22 IS 7 BP 730 EP 737 DI 10.1111/j.1432-2277.2009.00840.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 454JI UT WOS:000266677800008 PM 19196448 ER PT J AU DiCarlo, AL Fuldner, R Kaminski, J Hodes, R AF DiCarlo, Andrea L. Fuldner, Rebecca Kaminski, Joseph Hodes, Richard TI Aging in the context of immunological architecture, function and disease outcomes SO TRENDS IN IMMUNOLOGY LA English DT Editorial Material C1 [DiCarlo, Andrea L.; Kaminski, Joseph] NIAID, NIH, Bethesda, MD 20892 USA. [Fuldner, Rebecca; Hodes, Richard] NIA, NIH, Bethesda, MD 20892 USA. RP DiCarlo, AL (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. EM cohena@niaid.nih.gov NR 3 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2009 VL 30 IS 7 BP 293 EP 294 DI 10.1016/j.it.2009.05.003 PG 2 WC Immunology SC Immunology GA 477FT UT WOS:000268504800001 PM 19541534 ER PT J AU Weng, NP Akbar, AN Goronzy, J AF Weng, Nan-ping Akbar, Arne N. Goronzy, Jorg TI CD28(-) T cells: their role in the age-associated decline of immune function SO TRENDS IN IMMUNOLOGY LA English DT Review ID ACUTE CORONARY SYNDROMES; RHEUMATOID-ARTHRITIS; DNA METHYLATION; TELOMERASE ACTIVITY; GENE-EXPRESSION; REPLICATIVE SENESCENCE; HUMAN-LYMPHOCYTES; DOWN-REGULATION; REGULATED EXPRESSION; CHRONIC INFLAMMATION AB The accumulation of CD28(-) T cells, particularly within the CD8 subset, is one of the most prominent changes during T-cell homeostasis and function associated with aging in humans. CD28, a major co-stimulatory receptor, is responsible for the optimal anti g en-mediated T-cell activation, proliferation and survival of T cells. CD28(-) T cells exhibit reduced antigen receptor diversity, defective antigen-induced proliferation and a shorter replicative lifespan while showing enhanced cytotoxicity and regulatory functions. Gene expression analyses reveal profound changes of CD28(-) T cells in comparison to their CD28(+) counterparts and corroborate their functional differences. Here we review recent advances in our understanding of CD28(-) T cells and their role in the age-associated decline of immune function. C1 [Weng, Nan-ping] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. [Akbar, Arne N.] UCL, Dept Immunol, London W1T 4JF, England. [Goronzy, Jorg] Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. RP Weng, NP (reprint author), NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. EM Wengn@mail.nih.gov; a.akbar@ucl.ac.uk; jgoronz@emory.edu FU British Biotechnological and Biological Sciences Research Council; [R01-AR41974]; [R01-AG15043]; [U19-AI57266] FX N-P.W. was supported by the Intramural Research Programs of the National Institute on Aging, National Institutes of Health (NIH). A.N.A. is supported by the British Biotechnological and Biological Sciences Research Council. J.G. is supported by R01-AR41974, R01-AG15043 and U19-AI57266. NR 86 TC 175 Z9 184 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2009 VL 30 IS 7 BP 306 EP 312 DI 10.1016/j.it.2009.03.013 PG 7 WC Immunology SC Immunology GA 477FT UT WOS:000268504800004 PM 19540809 ER PT J AU Holmes, EC Tio, PH Perera, D Muhi, J Cardosa, J AF Holmes, Edward C. Tio, Phaik-Hooi Perera, David Muhi, Jamail Cardosa, Jane TI Importation and co-circulation of multiple serotypes of dengue virus in Sarawak, Malaysia SO VIRUS RESEARCH LA English DT Article DE Dengue; Sarawak; Evolution; Epidemiology; Phylogeny; South-East Asia ID EPIDEMIOLOGY; EMERGENCE; EVOLUTION; BANGKOK AB Although dengue is a common disease in South-East Asia, there is a marked absence of virological data from the Malaysian state of Sarawak located on the island of Borneo. From 1997 to 2002 we noted the co-circulation of DENV-2, DENV-3 and DENV-4 in Sarawak. To determine the origins of these Sarawak viruses we obtained the complete E gene sequences of 21 isolates. A phylogenetic analysis revealed multiple entries of DENV-2 and DENV-4 into Sarawak, such that multiple lineages co-circulate, yet with little exportation from Sarawak. Notably, all viral isolates were most closely related to those circulating in different localities in South-East Asia. In sum, our analysis reveals a frequent traffic of DENV in South-East Asia, with Sarawak representing a local sink population. (C) 2009 Elsevier B.V. All rights reserved. C1 [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Tio, Phaik-Hooi; Perera, David; Cardosa, Jane] Univ Malaysia Sarawak, Inst Hlth & Community Med, Kota Samarahan 94300, Sarawak, Malaysia. [Muhi, Jamail] Minist Hlth, Sarawak Hlth Dept, Kuching, Sarawak, Malaysia. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 18 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JUL PY 2009 VL 143 IS 1 BP 1 EP 5 DI 10.1016/j.virusres.2009.02.020 PG 5 WC Virology SC Virology GA 457QW UT WOS:000266948200001 PM 19463715 ER PT J AU Nelson, RF Singla, N AF Nelson, Ralph F. Singla, Nirmish TI A spectral model for signal elements isolated from zebrafish photopic electroretinogram SO VISUAL NEUROSCIENCE LA English DT Article DE Zebrafish; Spectral sensitivity; b-wave; PIII; ON cone bipolar cells ID DARK-ADAPTED ELECTRORETINOGRAM; SCOTOPIC THRESHOLD RESPONSE; RETINAL HORIZONTAL CELLS; ISOLATED FROG RETINA; BIPOLAR CELLS; B-WAVE; CONE CONTRIBUTIONS; INPUT MECHANISMS; GANGLION-CELLS; AMACRINE CELLS AB The zebrafish photopic electroretinogram (ERG) Sums isolatable elements. In each element, red-, blue-, green-, and UV- (r, g, b, and u) cone signals combine in a way that reflects retinal organization. ERG responses to monochromatic stimuli of different wavelengths and irradiances were recorded on a white rod suppressing background using superfused eyecups. Onset elements were isolated with glutamatergic blockers and response subtractions. CNQX-blocked ionotropic (AMPA/kainate) glutamate receptors; L-AP4 or CPPG-blocked metabotropic (mGluR6) glutamate receptors; TBOA-blocked glutamate transporters; and L-aspartate inactivated all glutamatergic mechanisms. Seven elements emerged: photopic PIII, the L-aspartate-isolated cone response; b1, a CNQX-sensitive early b-wave element of inner retinal origin; PII, a photopic, CNQX-insensitive composite b-wave element front ON bipolar cells; PIIm, an L-AP4/CPPG-sensitive, CNQX-insensitive, metabotropic subelement of PII, PIInm, all L-AP4/CPPG/CNQX-insensitive nonmetabotropic subelement of PII; a1nm, a TBOA-sensitive, CNQX/L-AP4/CPPG-insensitive, nonmetabotropic, postphotoreceptor a-wave element: and a2, a CNQX-sensitive a-wave element linked to OFF bipolar cells. The first five elements were fit with a spectral model that demonstrates independence of cone-color pathways. From this, V(max) and half-saturation values (k) for the contributing r-, g-, b-, and u-cone signals were calculated. Two signal patterns emerged. For PIII or PIInm, the V(max) order was V(r) > V(g) >> V(b) approximate to V(u). For b1, PII, and PIInm, the V(max) order was V(r) approximate to V(b) > V(g) > V(u). In either pattern, u-cone amplitude (V(u)) was smallest, but u-cone sensitivity (k(u362)) was greatest, some 10-30 times greater than r cone (k(r570)). The spectra of b1/PII/PIIm elements peaked near b- and u-cone absorbance maxima regardless of criteria, but the spectra of PIII/PIInm elements shifted from b- toward r-cone absorbance maxima as criterion levels increased. The greatest gains in V(max) relative to PIII occurred for the b- and u-cone signals in the b1/PII/PIIm b-wave elements. This suggests a high-gain prolific metabotropic circuitry for b- and u-cone bipolar cells. C1 [Nelson, Ralph F.; Singla, Nirmish] NINDS, Basic Neurosci Program, NIH, Rockville, MD 20892 USA. RP Nelson, RF (reprint author), NINDS, Basic Neurosci Program, NIH, 5625 Fishers Lane,Room TS-09, Rockville, MD 20892 USA. EM nelsonr@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, NIH FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. We express admiration for,and take inspiration from, the pioneering research of the late Joe Bilotta and his students and colleagues. We thank Anna Wesolowska, Risa Gordon, and Victoria Connaughton for critical contributions to the development of evoked potential recording,.; in zebrafish eyecup. NR 47 TC 11 Z9 11 U1 0 U2 5 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD JUL-AUG PY 2009 VL 26 IS 4 BP 349 EP 363 DI 10.1017/S0952523809990113 PG 15 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 508GE UT WOS:000270916800001 PM 19723365 ER PT J AU Meier-Schellersheim, M Fraser, IDC Klauschen, F AF Meier-Schellersheim, Martin Fraser, Iain D. C. Klauschen, Frederick TI Multiscale modeling for biologists SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Article ID SYSTEMS BIOLOGY; CELLULAR-AUTOMATA; IMMUNE-SYSTEM; SIMULATION; SOFTWARE; DYNAMICS; CELLS; HEART; TIME; MECHANISMS AB Biomedical research frequently involves performing experiments and developing hypotheses that link different scales of biological systems such as, for instance, the scales of intracellular molecular interactions to the scale of cellular behavior and beyond to the behavior of cell populations. Computational modeling efforts that aim at exploring such multiscale systems quantitatively with the help of simulations have to incorporate several different simulation techniques because of the different time and space scales involved. Here, we provide a nontechnical overview of how different scales of experimental research can be combined with the appropriate computational modeling techniques. We also show that current modeling software permits building and simulating multiscale models without having to become involved with the underlying technical details of computational modeling. (C) 2009 John Wiley & Sons, Inc. WIREs Syst Biol Med 2009 1 4-14 C1 [Meier-Schellersheim, Martin; Fraser, Iain D. C.; Klauschen, Frederick] NIAID, Program Syst Immunol & Infect Dis Modeling PSIIM, NIH, Bethesda, MD 20892 USA. RP Meier-Schellersheim, M (reprint author), NIAID, Program Syst Immunol & Infect Dis Modeling PSIIM, NIH, Bethesda, MD 20892 USA. EM mms@niaid.nih.gov RI Klauschen, Frederick/C-5637-2015 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. We thank the reviewers for their comments and for suggesting to cover some additional aspects of multiscale modeling we had previously omitted. Figure 1 contains an image created by Thomas Splettstoesser, published at: (http://commons.wikimedia.org/wiki/Image:Arp23_complex.png). NR 59 TC 49 Z9 50 U1 1 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD JUL-AUG PY 2009 VL 1 IS 1 BP 4 EP 14 DI 10.1002/wsbm.33 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674BP UT WOS:000283708800002 PM 20448808 ER PT J AU Goldberger, NE Hunter, KW AF Goldberger, Natalie E. Hunter, Kent W. TI A systems biology approach to defining metastatic biomarkers and signaling pathways SO WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE LA English DT Article ID BREAST-CANCER METASTASIS; AUTOMATED QUANTITATIVE-ANALYSIS; GENE-EXPRESSION SIGNATURE; DNA COPY NUMBER; PROSTATE-CANCER; IMPORTANT DETERMINANT; PROTEASE INHIBITORS; PARALLEL EVOLUTION; TISSUE MICROARRAYS; TUMOR PROGRESSION AB Metastasis is the final stage of cancer and the primary cause of mortality for most solid malignancies. This terminal phase of cancer progression has been investigated using a variety of high-throughput technologies (i.e., gene expression arrays, array comparative genomic hybridization (aCGH), and proteomics) to identify prognostic expression profiles and better characterize the metastatic process. For decades, the predominant model for the metastatic process has been the 'progression model', yet recent microarray results tend to support an inherent metastatic capability within primary tumors. Moreover, studies using a highly metastatic transgenic mammary tumor model suggest that germline polymorphisms are significant determinants of metastatic efficiency. Likewise, a strong concordance of survival has been observed between family members with cancer, further supporting the link between genetic inheritance and survival. In addition, chromosomal aberrations and signaling pathways related to metastatic capacity have been identified by array comparative genomic hybridization (aCGH) and proteomic studies, respectively. Lastly, carcinoma enzyme activity profiles using activity-based proteomics (ABPP), may be more clinically useful than expression-based proteomics for certain cancers. Most importantly, the application of these high-throughput techniques should expedite the search for additional biomarkers, germline polymorphisms, and expression signatures with greater prognostic value. (C) 2009 John Wiley & Sons, Inc. WIREs Syst Biol Med 2009 1 89-96 C1 [Goldberger, Natalie E.; Hunter, Kent W.] NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural NIH HHS [Z01 CP010146-09, Z01 CP010146-08, ZIA BC011255-01, ZIA CP010146-08, Z99 CA999999] NR 83 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1939-5094 J9 WIRES SYST BIOL MED JI Wiley Interdiscip. Rev.-Syst. Biol PD JUL-AUG PY 2009 VL 1 IS 1 BP 89 EP 96 DI 10.1002/wsbm.006 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 674BP UT WOS:000283708800008 PM 20835983 ER PT J AU Islam, TM Fox, CS Mann, D Muntner, P AF Islam, Tareq M. Fox, Caroline S. Mann, Devin Muntner, Paul TI Age-related associations of hypertension and diabetes mellitus with chronic kidney disease SO BMC NEPHROLOGY LA English DT Article ID STAGE RENAL-DISEASE; NUTRITION EXAMINATION SURVEYS; GLOMERULAR-FILTRATION-RATE; SERUM CREATININE; NATIONAL-HEALTH; INCREASED RISK; UNITED-STATES; POPULATION; OUTCOMES; PREVALENCE AB Background: Studies suggest end-stage renal disease incidence and all-cause mortality rates among patients with chronic kidney disease (CKD) differ by age. The association of diabetes mellitus and hypertension with CKD across the adult lifespan is not well established. Methods: Data from NHANES 1999-2004 were used to determine the association of risk factors for stage 3 or 4 CKD (n = 12,518) and albuminuria (n = 12,778) by age grouping (20 to 49, 50 to 69, and >= 70 years). Stage 3 or 4 CKD was defined as an estimated glomerular filtration rate of 15 to 59 ml/min/1.73 m(2) and albuminuria as an albumin to creatinine ratio >= 30 mg/g. Results: For adults 20 to 49, 50 to 69 and = 70 years of age, the prevalence ratios (95% confidence interval) of stage 3 or 4 CKD associated with hypertension were 1.94 (0.86 - 4.35), 1.51 (1.09 - 2.07), 1.31 (1.15 - 1.49), respectively (p-trend = 0.038). The analogous prevalence ratios (95% confidence interval) were 3.01 (1.35 - 6.74), 1.61 (1.15 - 2.25), 1.40 (1.15 - 1.69), respectively, for diagnosed diabetes mellitus (p-trend = 0.067); and 2.67 (0.53 - 13.4), 1.35 (0.69 - 2.63), 1.08 (0.78 - 1.51), respectively, for undiagnosed diabetes mellitus (p-trend = 0.369). The prevalence ratios of albuminuria associated with hypertension and diagnosed and undiagnosed diabetes mellitus were lower at older age (each p < 0.05). Conclusion: Among US adults, diabetes mellitus and hypertension are associated with CKD and albuminuria regardless of age. However, the associations were stronger at younger ages. C1 [Muntner, Paul] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Islam, Tareq M.] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA USA. [Mann, Devin] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Muntner, P (reprint author), Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. EM tislam@tulane.edu; foxca@nhlbi.nih.gov; devin.mann@mssm.edu; paul.muntner@mssm.edu OI Mann, Devin/0000-0002-2099-0852 NR 28 TC 19 Z9 20 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2369 J9 BMC NEPHROL JI BMC Nephrol. PD JUN 30 PY 2009 VL 10 AR 17 DI 10.1186/1471-2369-10-17 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 665FZ UT WOS:000283022000001 PM 19563681 ER PT J AU Ricciardi, E Pietrini, P Schapiro, MB Rapoport, SI Furey, ML AF Ricciardi, Emiliano Pietrini, Pietro Schapiro, Mark B. Rapoport, Stanley I. Furey, Maura L. TI Cholinergic modulation of visual working memory during aging: A parametric PET study SO BRAIN RESEARCH BULLETIN LA English DT Article DE Cholinergic modulation; Working memory; Aging; PET; Physostigmine; Visual cortex ID CEREBRAL-BLOOD-FLOW; POSITRON-EMISSION-TOMOGRAPHY; PREFRONTAL CORTICAL ACTIVITY; AGE-RELATED-CHANGES; EVENT-RELATED FMRI; ALZHEIMERS-DISEASE; TASK-DIFFICULTY; NEURAL ACTIVITY; ACETYLTRANSFERASE ACTIVITY; PERFORMANCE AB Age-related differences in the regional recruitment of prefrontal cortex (PFC) during cognitive tasks suggests that aging is associated with functional reorganization. Cholinergic enhancement with physostigmine reduces activity in the PFC regions selectively recruited during working memory (WM) and increases activity in visual processing areas, suggesting that augmenting cholinergic function reduces task effort by improving the visual representation of WM stimuli. Here, we investigated how cholinergic enhancement influenced PFC and visual cortical activity in young and older subjects as WM difficulty was altered. Regional cerebral blood flow (rCBF) was measured using H(2)(15)O-PET in 10 young and 10 older volunteers during a parametrically varied face WM task, following an i.v. infusion of saline and physostigmine. Reaction time decreased during physostigmine relative to placebo in both groups. Prefrontal brain regions selectively recruited in each age group that responded differentially to task demands during placebo, had no significant activity during physostigmine. Medial visual processing areas showed task-selective increases in activity during drug in both groups, while lateral regions showed decreased activity in young and increased activity in older participants at longer task delays. These results are consistent with our previous findings, showing that the modulatory role of the cholinergic system persists during aging, and that the effects of cholinergic enhancement are functionally specific rather than anatomically specific. Moreover, the use of the parametric design allowed us to uncover group specific effects in lateral visual processing areas where increasing cholinergic function produced opposite effects on neural activity in the two age groups. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ricciardi, Emiliano; Pietrini, Pietro] Univ Pisa, Lab Clin Biochem & Mol Biol, I-561267 Pisa, Italy. [Ricciardi, Emiliano] Univ Studies & Doctoral Res, St Anna Sch, Pisa, Italy. [Schapiro, Mark B.] Childrens Hosp, Med Ctr, Div Child Neurol, Cincinnati, OH 45229 USA. [Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Furey, Maura L.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Ricciardi, E (reprint author), Univ Pisa, Lab Clin Biochem & Mol Biol, Via San Zeno 61, I-561267 Pisa, Italy. EM emiliano.ricciardi@bioclinica.unipi.it RI Furey, Maura/H-5273-2013; Ricciardi, Emiliano/E-6929-2011 OI Ricciardi, Emiliano/0000-0002-7178-9534 FU National Institute on Aging intramural program; I.R.I.S. Foundation (Livorno, Italy) FX The authors thank P. Herscovitch and the technologists of the NIH positron emission tomography program, and Joanna Szczepanik and Richard Desmond for technical support. NR 55 TC 16 Z9 16 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUN 30 PY 2009 VL 79 IS 5 BP 322 EP 332 DI 10.1016/j.brainresbull.2009.01.013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 464BB UT WOS:000267478300012 PM 19480991 ER PT J AU Ferrucci, LM Cross, AJ Graubard, BI Brinton, LA McCarty, CA Ziegler, RG Ma, X Mayne, ST Sinha, R AF Ferrucci, L. M. Cross, A. J. Graubard, B. I. Brinton, L. A. McCarty, C. A. Ziegler, R. G. Ma, X. Mayne, S. T. Sinha, R. TI Intake of meat, meat mutagens, and iron and the risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; meat; iron; epidemiology ID HETEROCYCLIC AMINES; POSTMENOPAUSAL WOMEN; DIETARY-INTAKE; MAMMARY CARCINOGENESIS; GENETIC-POLYMORPHISM; PREMENOPAUSAL WOMEN; COOKED MEAT; CONSUMPTION; COHORT; MICRONUTRIENTS AB BACKGROUND: Epidemiological evidence on meat intake and breast cancer is inconsistent, with little research on potentially carcinogenic meat-related exposures. We investigated meat subtypes, cooking practices, meat mutagens, iron, and subsequent breast cancer risk. METHODS: Among 52 158 women (aged 55-74 years) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, who completed a food frequency questionnaire, 1205 invasive breast cancer cases were identified. We estimated meat mutagen and haem iron intake with databases accounting for cooking practices. Using Cox proportional hazards regression, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of intake. RESULTS: Comparing the fifth to the first quintile, red meat (HR = 1.23; 95% CI = 1.00-1.51, P trend = 0.22), the heterocyclic amine (HCA), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), (HR = 1.26; 95% CI = 1.03-1.55; P trend = 0.12), and dietary iron (HR = 1.25; 95% CI = 1.02-1.52; P trend = 0.03) were positively associated with breast cancer. We observed elevated, though not statistically significant, risks with processed meat, the HCA 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), mutagenic activity, iron from meat, and haem iron from meat. CONCLUSION: In this prospective study, red meat, MeIQx, and dietary iron elevated the risk of invasive breast cancer, but there was no linear trend in the association except for dietary iron. British Journal of Cancer (2009) 101, 178-184. doi: 10.1038/sj.bjc.6605118 www.bjcancer.com Published online 9 June 2009 (C) 2009 Cancer Research UK C1 [Ferrucci, L. M.; Cross, A. J.; Graubard, B. I.; Brinton, L. A.; Ziegler, R. G.; Sinha, R.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Ferrucci, L. M.; Ma, X.; Mayne, S. T.] Yale Univ, Sch Publ Hlth, New Haven, CT 06520 USA. [McCarty, C. A.] Marshfield Clin Res Fdn, Marshfield, WI 54449 USA. RP Ferrucci, LM (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd, Rockville, MD 20852 USA. EM ferruccil@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; Brinton, Louise/G-7486-2015 OI Sinha, Rashmi/0000-0002-2466-7462; Brinton, Louise/0000-0003-3853-8562 FU National Institutes of Health; National Cancer Institute [TU2 CA105666]; Division of Cancer Prevention FX This research was supported ( in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, by grant TU2 CA105666 from the National Cancer Institute, and by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health. The authors thank Drs Christine Berg and Philip Prorok, the Screening Centre investigators and staff of the PLCO Cancer Screening Trial and, Information Management Services, Inc. NR 46 TC 43 Z9 48 U1 3 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUN 30 PY 2009 VL 101 IS 1 BP 178 EP 184 DI 10.1038/sj.bjc.6605118 PG 7 WC Oncology SC Oncology GA 468KT UT WOS:000267817800025 PM 19513076 ER PT J AU Hsich, E Gorodeski, EZ Starling, RC Blackstone, EH Ishwaran, H Lauer, MS AF Hsich, Eileen Gorodeski, Eiran Z. Starling, Randall C. Blackstone, Eugene H. Ishwaran, Hemant Lauer, Michael S. TI Importance of Treadmill Exercise Time as an Initial Prognostic Screening Tool in Patients With Systolic Left Ventricular Dysfunction SO CIRCULATION LA English DT Article DE heart failure; exercise; sex; prognosis ID PEAK OXYGEN-CONSUMPTION; CHRONIC HEART-FAILURE; ALL-CAUSE MORTALITY; LONG-TERM SURVIVAL; RISK STRATIFICATION; AMBULATORY PATIENTS; CARDIAC TRANSPLANTATION; PREDICT SURVIVAL; CLINICAL INDEX; SUDDEN-DEATH AB Background-We sought to determine whether treadmill exercise time may be of value as an initial prognostic screening tool in ambulatory patients with impaired systolic function who are referred for cardiopulmonary exercise testing. Methods and Results-We studied 2231 adult systolic heart failure patients (27% of whom were women) who underwent cardiopulmonary stress testing using a modified Naughton protocol. We assessed the value of treadmill exercise time for prediction of all-cause death and a composite of death or United Network for Organ Sharing status 1 heart transplantation. During a mean follow-up of 5 years, 742 patients (33%) died. There were 249 United Network for Organ Sharing status 1 heart transplants (11%). Treadmill exercise time was predictive of death and the composite outcome in both women and men, even after accounting for peak oxygen consumption and other clinical covariates (adjusted hazard ratio of lowest versus high sex-specific quartile for prediction of death 1.70, 95% confidence interval 1.05 to 2.75, P=0.03; for prediction of the composite outcome, 1.75, 95% confidence interval 1.15 to 2.66, P=0.009). For a 1-minute change in exercise time, there was a 7% increased hazard of death (eg, comparing 480 to 540 seconds, hazard ratio =1.07, 95% confidence interval 1.02 to 1.12, P=0.004). Conclusions-Because cardiopulmonary stress testing is not available in every hospital, treadmill exercise time with a modified Naughton protocol may be of value as an initial prognostic screening tool. (Circulation. 2009; 119: 3189-3197.) C1 [Hsich, Eileen; Gorodeski, Eiran Z.; Starling, Randall C.] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44106 USA. [Ishwaran, Hemant] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44106 USA. [Blackstone, Eugene H.] Cleveland Clin, Dept Cardiothorac Surg, Cleveland, OH 44106 USA. [Hsich, Eileen; Starling, Randall C.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Prevent & Populat Sci, NIH, Rockledge Ctr 2,6701 Rockledge Dr,Room 10122, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Gorodeski, Eiran/D-5384-2009; Lauer, Michael/L-9656-2013; OI Lauer, Michael/0000-0002-9217-8177; Gorodeski, Eiran/0000-0003-3756-8831 FU Intramural NIH HHS [Z99 HL999999]; NCRR NIH HHS [UL1 RR024989] NR 36 TC 29 Z9 30 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 30 PY 2009 VL 119 IS 25 BP 3189 EP U59 DI 10.1161/CIRCULATIONAHA.109.848382 PG 17 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 463UD UT WOS:000267456700007 PM 19528334 ER PT J AU Klapper, JA Thomasian, AA Smith, DM Gorgas, GC Wunderlich, JR Smith, FO Hampson, BS Rosenberg, SA Dudley, ME AF Klapper, Jacob A. Thomasian, Armen A. Smith, Douglas M. Gorgas, Gayle C. Wunderlich, John R. Smith, Franz O. Hampson, Brian S. Rosenberg, Steven A. Dudley, Mark E. TI Single-pass, closed-system rapid expansion of lymphocyte cultures for adoptive cell therapy SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Adoptive cell therapy; Tumor infiltrating lymphocyte; Rapid expansion; Closed-system bioreactor; rhIL-2 ID TUMOR-INFILTRATING LYMPHOCYTES; T-CELLS; IMMUNOTHERAPY; CANCER; VIVO AB Adoptive cell therapy (ACT) for metastatic melanoma involves the ex vivo expansion and reinfusion of tumor infiltrating lymphocytes (TIL) obtained from resected specimens. With an overall objective response rate of 56%, this T-cell immunotherapy provides an appealing alternative to other therapies, including conventional therapies with lower response rates. However, there are significant regulatory and logistical concerns associated with the ex vivo activation and large-scale expansion of these cells. The best current practice uses a rapid expansion protocol (REP) consisting of an ex vivo process that occurs in tissue culture flasks (T-flasks) and gas-permeable bags. utilizes OKT3 (anti-CD3 monoclonal antibody), recombinant human interleukin-2, and irradiated peripheral blood mononuclear cells to initiate rapid lymphocyte growth. A major limitation to the widespread delivery of therapy to large numbers of melanoma patients is the open system in which a REP is initiated. To address this problem, we have investigated the initiation, expansion and harvest at clinical scale of TIL in a closed-system continuous perfusion bioreactor. Each cell product met all safety criteria for patient treatment and by head-to-head comparison had a similar potency and phenotype as cells grown in control T-flasks and gas-permeable bags. However, the currently available bioreactor cassettes were limited in the total cell numbers that could be generated. This bioreactor may simplify the process of the rapid expansion of TIL under stringent regulatory conditions thereby enabling other institutions to pursue this form of ACT. Published by Elsevier B.V. C1 [Klapper, Jacob A.; Thomasian, Armen A.; Wunderlich, John R.; Smith, Franz O.; Rosenberg, Steven A.; Dudley, Mark E.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Smith, Douglas M.; Gorgas, Gayle C.; Hampson, Brian S.] Aastrom Biosci Inc, Dominos Farms, Ann Arbor, MI 48105 USA. RP Dudley, ME (reprint author), NCI, Surg Branch, CRC 3-5752 10 Ctr Dr, Bethesda, MD 20892 USA. EM dudleym@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999, Z01 SC003811-33] NR 16 TC 23 Z9 27 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD JUN 30 PY 2009 VL 345 IS 1-2 BP 90 EP 99 DI 10.1016/j.jim.2009.04.009 PG 10 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 460FA UT WOS:000267172400009 PM 19389403 ER PT J AU Mendez, PS Cachau, RE Seoane, G Ventura, ON AF Mendez, Patricia Saenz Cachau, Raul E. Seoane, Gustavo Ventura, Oscar N. TI Regioselective epoxide ring-opening using boron trifluoride diethyl etherate: DFT study of an alternative mechanism to explain the formation of syn-fluorohydrins SO JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM LA English DT Article DE Fluorohydrins; Epoxide ring-opening; Reaction mechanisms; DFT ID HALOGENATED STEROID HORMONES; BF3-CATALYZED REARRANGEMENT; CATALYZED REARRANGEMENT; GLYCOSIDASE INHIBITORS; RATIONAL DESIGN; AZA SUGARS; BIOCATALYSIS; MANNOJIRIMYCIN; ORBITALS; DENSITY AB Ring-opening of epoxides with boron trifluoride yielding syn-fluorohydrins was investigated using density functional methods (PBE) and two different basis sets (6-31G(d) and 6-311++G(2df,2pd), both in gas phase and simulating the bulk solvent using the PCM method. The only mechanism previously suggested for the formation of fluorohydrins from epoxides is an S(N) 1-like one. We propose in this work a new mechanism, in which bond breaking in the epoxide is Coupled to fluorine transfer, yielding the fluorohydrine with retention of configuration through a single transition state. (c) 2009 Elsevier B.V. All rights reserved. C1 [Mendez, Patricia Saenz; Seoane, Gustavo] UdelaR, Fac Chem, Dept Organ Chem, Phys Organ Chem & Bioproc Grp, Montevideo 11800, Uruguay. [Mendez, Patricia Saenz; Cachau, Raul E.; Ventura, Oscar N.] UdelaR, Fac Chem, DETEMA, Computat Chem & Biol Group, Montevideo 11800, Uruguay. [Cachau, Raul E.] SAIC Frederick Inc, Natl Canc Inst Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Mendez, PS (reprint author), UdelaR, Fac Chem, Dept Organ Chem, Phys Organ Chem & Bioproc Grp, CC1157,Avda Gral Flores 2124, Montevideo 11800, Uruguay. EM psaenz@fq.edu.uy RI Saenz-Mendez, Patricia/G-3678-2011 OI Saenz-Mendez, Patricia/0000-0002-6711-4972 FU PEDECIBA - Uruguay FX This work was partially funded by PEDECIBA - Uruguay. The contents of this publication do not necessarily reflect the views or policies of the DHHS, nor does mention of trade names, corm-nercial products, or organizations imply endorsement by the U.S. Government. NR 43 TC 7 Z9 7 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-1280 J9 J MOL STRUC-THEOCHEM JI Theochem-J. Mol. Struct. PD JUN 30 PY 2009 VL 904 IS 1-3 BP 21 EP 27 DI 10.1016/j.theochem.2009.02.023 PG 7 WC Chemistry, Physical SC Chemistry GA 452AS UT WOS:000266512600004 ER PT J AU Sibley, CT Bluemke, DA AF Sibley, Christopher T. Bluemke, David A. TI Will 3.0-T Make Coronary Magnetic Resonance Angiography Competitive With Computed Tomography Angiography? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE coronary disease; magnetic resonance imaging; contrast media; 3 Tesla ID ARTERY-DISEASE; DIAGNOSTIC PERFORMANCE; 1.5 T; STENOSIS C1 [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Sibley, Christopher T.] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 10 Ctr Dr,Room 10-1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov RI Sibley, Christopher/C-9900-2013; OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [Z99 CL999999] NR 17 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUN 30 PY 2009 VL 54 IS 1 BP 77 EP 78 DI 10.1016/j.jacc.2009.04.022 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 465AJ UT WOS:000267552000011 PM 19555844 ER PT J AU Xi, ZX Kleitz, HK Deng, X Ladenheim, B Peng, XQ Li, X Gardner, EL Stein, EA Cadet, JL AF Xi, Z. -X. Kleitz, H. K. Deng, X. Ladenheim, B. Peng, X. -Q. Li, X. Gardner, E. L. Stein, E. A. Cadet, J. L. TI A SINGLE HIGH DOSE OF METHAMPHETAMINE INCREASES COCAINE SELF-ADMINISTRATION BY DEPLETION OF STRIATAL DOPAMINE IN RATS SO NEUROSCIENCE LA English DT Article DE methamphetamine; cocaine; dopamine; self-administration; drug-taking; drug reward ID CONDITIONED PLACE PREFERENCE; PROGRESSIVE-RATIO; INDUCED NEUROTOXICITY; NUCLEUS-ACCUMBENS; ATTENUATES COCAINE; MOUSE-BRAIN; TRANSPORTER; REWARD; AMPHETAMINE; SCHEDULES AB Psychostimulant addicts often take high doses of drugs, and high doses of psychostimulants such as methamphetamine (METH) are neurotoxic to striatal dopamine (DA) terminals. Yet, the effects of high doses of METH on drug-seeking and drug-taking behavior have not been examined. In the present study, we found that single high doses of METH in rats (10-20 mg/kg) dose-dependently increased cocaine self-administration under fixed-ratio 2 (FR2) reinforcement conditions, while higher doses (40 mg/kgx1 or 10 mg/kg/2 hx4) caused high mortality among rats maintained on daily cocaine self-administration. The increased cocaine self-administration appeared to be a compensatory response to reduced cocaine reward after METH, because the same doses of METH caused a dose-dependent reduction both in "breakpoint" levels for cocaine self-administration under progressive-ratio reinforcement and in nucleus accumbens DA response to acute cocaine. Further, METH (10-20 mg/kg) produced large DA release (4000%-6000% over baseline), followed by a significant reduction in striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) contents, but without significant changes in striatal DA transporter levels. These findings suggest that the present high doses of METH caused striatal DA depletion or hypofunction without severe damage in DA terminals, which may contribute to the increased cocaine-taking behavior observed in the present study. Provided that the present doses of METH may mimic METH overdose incidents in humans, the present findings suggest that METH-induced DA depletion or neurotoxicity may lead to an increase in subsequent drug-taking and drug-seeking behavior. Published by Elsevier Ltd on behalf of IBRO. C1 [Xi, Z. -X.; Peng, X. -Q.; Li, X.; Gardner, E. L.] Natl Inst Drug Abuse, Chem Biol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Kleitz, H. K.; Stein, E. A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Deng, X.; Ladenheim, B.; Cadet, J. L.] Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Chem Biol Res Branch, Intramural Res Program, 251 Bayview Blvd,BRC Room 05A705, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU Intramural Research Program of the National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH). NR 52 TC 17 Z9 17 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 30 PY 2009 VL 161 IS 2 BP 392 EP 402 DI 10.1016/j.neuroscience.2009.03.060 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 455VC UT WOS:000266794100007 PM 19336247 ER PT J AU Lu, CB Fu, W Xu, X Mattson, MP AF Lu, C. B. Fu, W. Xu, X. Mattson, M. P. TI Numb-MEDIATED NEURITE OUTGROWTH IS ISOFORM-DEPENDENT, AND REQUIRES ACTIVATION OF VOLTAGE-DEPENDENT CALCIUM CHANNELS SO NEUROSCIENCE LA English DT Article DE Numb; neurite; differentiation; VGCC; NGF; PC12 ID NERVE GROWTH-FACTOR; PHEOCHROMOCYTOMA PC12 CELLS; INTRACELLULAR CALCIUM; PROTEIN-KINASE; CA2+ CHANNELS; NEURONAL DIFFERENTIATION; FUNCTIONAL EXPRESSION; FACTOR WITHDRAWAL; SKELETAL-MUSCLE; INFLUX AB Numb is an evolutionarily conserved protein that controls the differentiation of neuronal progenitor cells by unknown mechanisms. Here we report that the neural cells expressing Numb isoforms with short phosphotyrosine-binding (SPTB) domain undergo extensive neurite outgrowth, an effect that can be blocked by voltage-gated Ca(2+) channel (VGCC) inhibitor or by Ca(2+) chelator. In contrast, tyrosine kinase inhibitor, genistein, and selective receptor tyrosine kinase (TrkA) inhibitor, K252 alpha did not affect SPTB Numb-mediated neurite outgrowth. MAP kinase inhibitor, PD98059 partially reduced SPTB Numb-mediated neurite outgrowth. Cells expressing SPTB Numbs exhibit increased whole-cell Ca(2+) current densities (ICa) which can be prevented by preincubation of either nifedipine or PD98095. Cells expressing LPTB Numbs expressed little ICa (density) and were not able to grow neurites. Our results indicate that Ca(2+) influx through VGCC may be required for SPTB Numb-mediated neurite outgrowth, suggesting that Numb promotes neuronal differentiation by a mechanism involving PTB domain-specific regulation of Ca(2+) influx and MAP kinase activation. (c) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Lu, C. B.] Univ Leeds, IMSB, Leeds LS2 9JT, W Yorkshire, England. [Lu, C. B.; Fu, W.; Xu, X.; Mattson, M. P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Lu, CB (reprint author), Univ Leeds, IMSB, Room 5-55M, Leeds LS2 9JT, W Yorkshire, England. EM c.b.lu@leeds.ac.uk RI Mattson, Mark/F-6038-2012 FU National Institute on Aging FX The work was supported by the Intramural Research Program of the National Institute on Aging. The authors disclose that there is no interest conflict related to this study. NR 47 TC 11 Z9 12 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 30 PY 2009 VL 161 IS 2 BP 403 EP 412 DI 10.1016/j.neuroscience.2009.03.063 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 455VC UT WOS:000266794100008 PM 19344753 ER PT J AU Muller, KM Wilke, M Leopold, DA AF Mueller, K. -M. Wilke, M. Leopold, D. A. TI VISUAL ADAPTATION TO CONVEXITY IN MACAQUE AREA V4 SO NEUROSCIENCE LA English DT Article DE visual perception; visual cortex; area V4; electrophysiology; adaptation; visual aftereffects ID UNDERLYING CONTRAST ADAPTATION; INFERIOR TEMPORAL CORTEX; RETINAL GANGLION-CELLS; SHAPE REPRESENTATION; NEURONAL ADAPTATION; INDUCED PLASTICITY; CEREBRAL-CORTEX; TILTED LINES; MECHANISMS; ORIENTATION AB Aftereffects are perceptual illusions caused by visual adaptation to one or more stimulus attribute, such as orientation, motion, or shape. Neurophysiological studies seeking to understand the basis of visual adaptation have observed firing rate reduction and changes in tuning of stimulus-selective neurons following periods of prolonged visual stimulation. In the domain of shape, recent psychophysical work has shown that adaptation to a convex pattern induces a subsequently seen rectangle to appear slightly concave. In the present study, we investigate the possible contribution of V4 neurons of rhesus monkeys, which are thought to be involved in the coding of convexity, to shape-specific adaptation. Visually responsive neurons were monitored during the brief presentation of simple shapes varying in their convexity level. Each test presentation was preceded by either a blank period or several seconds of adaptation to a convex or concave stimulus, presented in two different sizes. Adaptation consistently shifted the tuning of neurons away from the convex or concave adapter, including shifting response to the neutral rectangle in the direction of the opposite convexity. This repulsive shift resembled the known perceptual distortion associated with adaptation to such stimuli. In addition, adaptation caused a nonspecific response decrease, as well as a specific decrease for repeated stimuli. The latter effects were observed whether or not the adapting and test stimuli matched closely in their size. Taken together, these results provide evidence for shape-specific adaptation of neurons in area V4, which may contribute to the perception of the convexity aftereffect. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Mueller, K. -M.; Wilke, M.; Leopold, D. A.] NIMH, Unit Cognit Neurophysiol & Imaging, Neuropsychol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Mueller, K. -M.] Univ Tubingen, Int Max Planck Res Sch, D-72074 Tubingen, Germany. [Wilke, M.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Leopold, D. A.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Leopold, D. A.] NEI, NIH, Bethesda, MD USA. RP Leopold, DA (reprint author), NIMH, Unit Cognit Neurophysiol & Imaging, Neuropsychol Lab, Natl Inst Hlth, Bldg 49,Room B2J-45 MSC 4400,49 Convent Dr, Bethesda, MD 20892 USA. EM leopoldd@mail.nih.gov OI Leopold, David/0000-0002-1345-6360 FU NIMH; NINDS; NEI at the National Institutes of Health FX We thank our collaborators: N. Phipps and K. Smith for assistance with animal training and experimentation; C. Zhu and Dr. F. Ye for help with MRI scans; Dr. D. Sheinberg for providing some of the stimulation software; Dr. A. Maier and Dr. D. McMahon for insightful suggestions concerning date acquisition, analysis, and previous versions of this manuscript. This work was supported by the Intramural Research Programs of NIMH, NINDS and NEI at the National Institutes of Health. NR 51 TC 14 Z9 14 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JUN 30 PY 2009 VL 161 IS 2 BP 655 EP 662 DI 10.1016/j.neuroscience.2009.03.070 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 455VC UT WOS:000266794100030 PM 19345725 ER PT J AU Jayanthi, S Mccoy, MT Beauvais, G Ladenheim, B Gilmore, K Wood, W Becker, K Cadet, JL AF Jayanthi, Subramaniam McCoy, Michael T. Beauvais, Genevieve Ladenheim, Bruce Gilmore, Kristi Wood, William, III Becker, Kevin Cadet, Jean Lud TI Methamphetamine Induces Dopamine D1 Receptor-Dependent Endoplasmic Reticulum Stress-Related Molecular Events in the Rat Striatum SO PLOS ONE LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; ENDOTHELIAL GROWTH-FACTOR; ACTIVATING TRANSCRIPTION FACTOR-3; FOCAL CEREBRAL-ISCHEMIA; APOPTOTIC CELL-DEATH; HEAT-SHOCK PROTEINS; ER STRESS; HEME OXYGENASE-1; OXIDATIVE STRESS; GENE-EXPRESSION AB Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain. RP Jayanthi, S (reprint author), Natl Inst Drug Abuse, Mol Neuropsychiat Res Branch, NIH, DHHS,Intramural Res Program, Baltimore, MD USA. EM jcadet@intra.nida.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU Intramural NIH HHS NR 114 TC 37 Z9 37 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2009 VL 4 IS 6 AR e6092 DI 10.1371/journal.pone.0006092 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464OU UT WOS:000267515700011 PM 19564919 ER PT J AU Tomasi, D Volkow, ND Wang, RL Telang, F Wang, GJ Chang, L Ernst, T Fowler, JS AF Tomasi, Dardo Volkow, Nora D. Wang, Ruiliang Telang, Frank Wang, Gene-Jack Chang, Linda Ernst, Thomas Fowler, Joanna S. TI Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention SO PLOS ONE LA English DT Article AB Background: Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. Methodology/Principal Findings: For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11)C] cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. Conclusions/Significance: These findings provide evidence that dopamine transporters modulate neural activity in the DMN and anterior cingulate gyrus during visuospatial attention. Our findings suggest that dopamine modulates attention in part by regulating neuronal activity in posterior parietal cortex including precuneus (region involved in alertness) and cingulate gyrus (region deactivated in proportion to emotional interference). These findings suggest that the beneficial effects of stimulant medications (increase dopamine by blocking DAT) in inattention reflect in part their ability to facilitate the deactivation of the DMN. RP Tomasi, D (reprint author), NIAAA, Bethesda, MD USA. EM tomasi@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU NCRR NIH HHS [5-M01-RR-10710, M01 RR010710]; NIAAA NIH HHS [2 R01 AA09481, R01 AA009481] NR 75 TC 74 Z9 74 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 30 PY 2009 VL 4 IS 6 AR e6102 DI 10.1371/journal.pone.0006102 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 464OU UT WOS:000267515700016 PM 19564918 ER PT J AU Camberg, JL Hoskins, JR Wickner, S AF Camberg, Jodi L. Hoskins, Joel R. Wickner, Sue TI ClpXP protease degrades the cytoskeletal protein, FtsZ, and modulates FtsZ polymer dynamics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AAA plus ATPase; cell division; ClpP; proteolysis; septum ID BACTERIAL-CELL-DIVISION; ESCHERICHIA-COLI FTSZ; ASSEMBLY DYNAMICS; TUBULIN; CYCLE; RECOGNITION; SPASTIN; BINDING; DEGRADATION; PROTEOLYSIS AB FtsZ is the major cytoskeletal protein in bacteria and a tubulin homologue. It polymerizes and forms a ring where constriction occurs to divide the cell. We found that FtsZ is degraded by E. coli ClpXP, an ATP-dependent protease. In vitro, ClpXP degrades both FtsZ protomers and polymers; however, polymerized FtsZ is degraded more rapidly than the monomer. Deletion analysis shows that the N-terminal domain of ClpX is important for polymer recognition and that the FtsZ C terminus contains a ClpX recognition signal. In vivo, FtsZ is turned over slower in a clpX deletion mutant compared with a WT strain. Overexpression of ClpXP results in increased FtsZ degradation and filamentation of cells. These results suggest that ClpXP may participate in cell division by modulating the equilibrium between free and polymeric FtsZ via degradation of FtsZ filaments and protomers. C1 [Camberg, Jodi L.; Hoskins, Joel R.; Wickner, Sue] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov FU National Institutes of Health National Cancer Institute Center for Cancer Research FX We thank Susan Gottesman for providing strains and Michael Maurizi for providing the ClpXP expression plasmid. We also thank S. Doyle, D. Johnston, M. Miot, and O. Genest for critical reading of the manuscript and helpful discussions. This research was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute Center for Cancer Research. NR 42 TC 59 Z9 59 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2009 VL 106 IS 26 BP 10614 EP 10619 DI 10.1073/pnas.0904886106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300042 PM 19541655 ER PT J AU Mitarai, N Benjamin, JAM Krishna, S Semsey, S Csiszovszki, Z Masse, E Sneppen, K AF Mitarai, Namiko Benjamin, Julie-Anna M. Krishna, Sandeep Semsey, Szabolcs Csiszovszki, Zsolt Masse, Eric Sneppen, Kim TI Dynamic features of gene expression control by small regulatory RNAs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene regulation; mRNA silencing; RyhB; small RNA; Spot42 ID RYHB SMALL RNA; ESCHERICHIA-COLI; IRON HOMEOSTASIS; GLMS EXPRESSION; NONCODING RNAS; ANTISENSE RNA; CYCLIC-AMP; PROTEIN; TRANSLATION; HFQ AB Small regulatory RNAs (sRNAs) in eukaryotes and bacteria play an important role in the regulation of gene expression either by binding to regulatory proteins or directly to target mRNAs. Two of the best-characterized bacterial sRNAs, Spot42 and RyhB, form a complementary pair with the ribosome binding region of their target mRNAs, thereby inhibiting translation or promoting mRNA degradation. To investigate the steady-state and dynamic potential of such sRNAs, we examine the 2 key parameters characterizing sRNA regulation: the capacity to overexpress the sRNA relative to its target mRNA and the speed at which the target mRNA is irreversibly inactivated. We demonstrate different methods to determine these 2 key parameters, for Spot42 and RyhB, which combine biochemical and genetic experiments with computational analysis. We have developed a mathematical model that describes the functional properties of sRNAs with various characteristic parameters. We observed that Spot42 and RyhB function in distinctive parameter regimes, which result in divergent mechanisms. C1 [Mitarai, Namiko] Kyushu Univ 33, Dept Phys, Fukuoka 8128581, Japan. [Mitarai, Namiko; Krishna, Sandeep; Sneppen, Kim] Niels Bohr Inst, DK-2100 Copenhagen, Denmark. [Semsey, Szabolcs] Eotvos Lorand Univ, Dept Genet, H-1117 Budapest, Hungary. [Csiszovszki, Zsolt] NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Benjamin, Julie-Anna M.; Masse, Eric] Univ Sherbrooke, Dept Biochim, RNA Grp, Sherbrooke, PQ J1H 5N4, Canada. RP Mitarai, N (reprint author), Kyushu Univ 33, Dept Phys, Fukuoka 8128581, Japan. EM mitarai@nbi.dk; eric.masse@usherbrooke.ca RI Semsey, Szabolcs/L-6329-2013; Mitarai, Namiko/M-4575-2014; U-ID, Kyushu/C-5291-2016 OI Semsey, Szabolcs/0000-0002-4522-5495; Sneppen, Kim/0000-0001-9820-3567; Mitarai, Namiko/0000-0003-0116-7606; FU Canadian Institute for Health Research [MOP69005]; Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research; Danish National Research Foundation; Hungarian Scientific Research Fund [PD75496]; Canadian Institute for Health Research New Investigator Scholar; Hungarian Academy of Sciences FX We thank Karine Prevost and Takacsne Botond Judit for excellent technical assistance. This work was supported by Canadian Institute for Health Research Grant MOP69005, the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, the Danish National Research Foundation, and Hungarian Scientific Research Fund Grant PD75496. E. M. is a Canadian Institute for Health Research New Investigator Scholar. S. S. is supported by a Janos Bolyai fellowship from the Hungarian Academy of Sciences. NR 40 TC 43 Z9 43 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2009 VL 106 IS 26 BP 10655 EP 10659 DI 10.1073/pnas.0901466106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300049 PM 19541626 ER PT J AU Gao, GJ Bi, XL Chen, J Srikanta, D Rong, YKS AF Gao, Guanjun Bi, Xiaolin Chen, Jie Srikanta, Deepa Rong, Yikang S. TI Mre11-Rad50-Nbs complex is required to cap telomeres during Drosophila embryogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE maternal lethality; telomere capping; targeted mutagenesis; ALTD ID DOUBLE-STRAND BREAK; DNA-REPAIR; MRE11/RAD50/NBS1 COMPLEX; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; MRE11 COMPLEX; MAINTENANCE; CHECKPOINT; PROTEIN; ATM AB Using Drosophila as a model system, we identified here a stringent requirement for Mre11-Rad50-Nbs (MRN) function in telomere protection during early embryonic development. Animals homozygous for hypomorphic mutations in either mre11 or nbs develop normally with minimal telomere dysfunction. However, they produce inviable embryos that succumb to failure of mitosis caused by covalent fusion of telomeric DNA. Interestingly, the molecular defect is not the absence of MRN interaction or of Mre11 nuclease activities, but the depletion of the maternal pool of Nbs protein in these embryos. Because of Nbs depletion, Mre11 and Rad50 (MR) are excluded from chromatin. This maternal effect lethality in Drosophila is similar to that seen in mice carrying hypomorphic mrn mutations found in human patients, suggesting a common defect in telomere maintenance because of the loss of MRN integrity. C1 [Gao, Guanjun; Bi, Xiaolin; Chen, Jie; Srikanta, Deepa; Rong, Yikang S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rong, YKS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI Bi, Xiaolin/E-7469-2010; rong, yikang/G-6179-2011; Bi, Xiaolin/C-7038-2014 OI Bi, Xiaolin/0000-0002-7172-7851; Bi, Xiaolin/0000-0003-2837-9457 FU NCI Intramural Program FX We thank Dr. Paul Goldsmith's group at National Cancer Institute (NCI) for purifying anti-Rad50 antibodies; Drs. Kami Ahmad (Harvard University, Cambridge, MA) and Maurizio Gatti (University of Rome, Rome, Italy) for reagents; members of the Rong lab for comments on the manuscript; and Drs. Maxine Singer, Michael Lichten, and Dhruba Chattoraj at NCI for their efforts in improving this manuscript. This work was supported by the NCI Intramural Program. NR 46 TC 18 Z9 18 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2009 VL 106 IS 26 BP 10728 EP 10733 DI 10.1073/pnas.0902707106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300062 PM 19520832 ER PT J AU Li, YF Poole, S Nishio, K Jang, K Rasulova, F McVeigh, A Savarino, SJ Xia, D Bullitt, E AF Li, Yong-Fu Poole, Steven Nishio, Kazuya Jang, Ken Rasulova, Fatima McVeigh, Annette Savarino, Stephen J. Xia, Di Bullitt, Esther TI Structure of CFA/I fimbriae from enterotoxigenic Escherichia coli SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystal structure; pili; diarrheal disease; adhesion; proline isomerization ID FACTOR ANTIGEN-I; COLONIZATION FACTOR ANTIGENS; CS1 PILI; PROTEINS; BIOGENESIS; ADHESIN; ARCHITECTURE; RESIDUES; SUBUNIT; TOOLS AB Adhesion pili (fimbriae) play a critical role in initiating the events that lead to intestinal colonization and diarrheal disease by enterotoxigenic Escherichia coli (ETEC), an E. coli pathotype that inflicts an enormous global disease burden. We elucidate atomic structures of an ETEC major pilin subunit, CfaB, from colonization factor antigen I (CFA/I) fimbriae. These data are used to construct models for 2 morphological forms of CFA/I fimbriae that are both observed in vivo: the helical filament into which it is typically assembled, and an extended, unwound conformation. Modeling and corroborative mutational data indicate that proline isomerization is involved in the conversion between these helical and extended forms. Our findings affirm the strong structural similarities seen between class 5 fimbriae (from bacteria primarily causing gastrointestinal disease) and class 1 pili (from bacteria that cause urinary, respiratory, and other infections) in the absence of significant primary sequence similarity. They also suggest that morphological and biochemical differences between fimbrial types, regardless of class, provide structural specialization that facilitates survival of each bacterial pathotype in its preferred host microenvironment. Last, we present structural evidence for bacterial use of antigenic variation to evade host immune responses, in that residues occupying the predicted surface-exposed face of CfaB and related class 5 pilins show much higher genetic sequence variability than the remainder of the pilin protein. C1 [Poole, Steven; Rasulova, Fatima; McVeigh, Annette; Savarino, Stephen J.] USN, Enter Dis Dept, Infect Dis Directorate, Med Res Ctr, Silver Spring, MD 20910 USA. [Li, Yong-Fu; Nishio, Kazuya; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jang, Ken; Bullitt, Esther] Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA. [Savarino, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Savarino, SJ (reprint author), USN, Enter Dis Dept, Infect Dis Directorate, Med Res Ctr, Silver Spring, MD 20910 USA. EM stephen.savarino@med.navy.mil; dixia@helix.nih.gov; bullitt@bu.edu RI Savarino, Stephen/A-8030-2011 FU National Cancer Institute Intramural Research Program; Trans National Institutes of Health/Food and Drug Administration Intramural Biodefense Program; U. S. Army Military Infectious Disease Research Program Work Unit [A0307]; Henry M. Jackson Foundation; National Institutes of Health [GM055722] FX We thank the staff at Southeast Regional Collaborative Access Team for assistance in data collection; L. Esser for discussions; N. Pattabiraman for programming; and P. Guerry, A. Fasano, and D. Isaac for critical reading of the manuscript. This research was supported by the National Cancer Institute Intramural Research Program (D. X.), the Trans National Institutes of Health/Food and Drug Administration Intramural Biodefense Program (D. X.), the U. S. Army Military Infectious Disease Research Program Work Unit A0307 (S. J. S.), the Henry M. Jackson Foundation (S. J. S.), and National Institutes of Health Grant GM055722 (to E. B.). NR 34 TC 45 Z9 47 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 30 PY 2009 VL 106 IS 26 BP 10793 EP 10798 DI 10.1073/pnas.0812843106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 465EI UT WOS:000267564300073 PM 19515814 ER PT J AU Yi, M Mudunuri, U Che, A Stephens, RM AF Yi, Ming Mudunuri, Uma Che, Anney Stephens, Robert M. TI Seeking unique and common biological themes in multiple gene lists or datasets: pathway pattern extraction pipeline for pathway-level comparative analysis SO BMC BIOINFORMATICS LA English DT Article ID PROSTATE-CANCER; EXPRESSION PROFILES; BREAST-CANCER; HUMAN-DISEASE; MICROARRAYS; MICRORNAS; SELECTION; CARCINOGENESIS; NETWORKS; ANOVA AB Background: One of the challenges in the analysis of microarray data is to integrate and compare the selected ( e. g., differential) gene lists from multiple experiments for common or unique underlying biological themes. A common way to approach this problem is to extract common genes from these gene lists and then subject these genes to enrichment analysis to reveal the underlying biology. However, the capacity of this approach is largely restricted by the limited number of common genes shared by datasets from multiple experiments, which could be caused by the complexity of the biological system itself. Results: We now introduce a new Pathway Pattern Extraction Pipeline (PPEP), which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of the pathway-level enrichment patterns across multiple gene lists. As an exploratory tool, this analysis pipeline may help reveal the underlying biological themes at both the pathway and gene levels. The analysis scheme provided by PPEP begins with multiple gene lists, which may be derived from different studies in terms of the biological contexts, applied technologies, or methodologies. These lists are then subjected to pathway-level comparative analysis for extraction of pathway-level patterns. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways or biological processes from different but relevant biological systems using a combination of statistical enrichment measurements, pathway-level pattern extraction, and graphical display of the relationships of genes and their associated pathways as Gene-Term Association Networks (GTANs) within the WPS platform. As a proof of concept, we have used the new method to analyze many datasets from our collaborators as well as some public microarray datasets. Conclusion: This tool provides a new pathway-level analysis scheme for integrative and comparative analysis of data derived from different but relevant systems. The tool is freely available as a Pathway Pattern Extraction Pipeline implemented in our existing software package WPS, which can be obtained at http://www.abcc.ncifcrf.gov/wps/wps_ index.php C1 [Yi, Ming; Mudunuri, Uma; Che, Anney; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Yi, M (reprint author), NCI, Adv Biomed Comp Ctr, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM myi@ncifcrf.gov; mudunuri@ncifcrf.gov; chea@ncifcrf.gov; bobs@ncifcrf.gov FU National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX We thank David Liu, Jigui Shan for technical assistance. We also thank Dr. Richard Lempicki's group from NIAID for providing comprehensively curated protein-protein interaction database. We thank Dr. Tim Harris for critical reading of this manuscript. We would like to thank the Editor and two referees for helpful comments that led to improvements in this paper. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 54 TC 12 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUN 29 PY 2009 VL 10 AR 200 DI 10.1186/1471-2105-10-200 PG 17 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 476NX UT WOS:000268450400001 PM 19563622 ER PT J AU Avril, M Hathaway, MJ Cartwright, MM Gose, SO Narum, DL Smith, JD AF Avril, Marion Hathaway, Marianne J. Cartwright, Megan M. Gose, Severin O. Narum, David L. Smith, Joseph D. TI Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris SO MALARIA JOURNAL LA English DT Article ID CHONDROITIN-SULFATE-A; RECEPTOR-BINDING DOMAIN; PLASMODIUM-FALCIPARUM; PLACENTAL MALARIA; HETEROLOGOUS EXPRESSION; INFECTED ERYTHROCYTES; INHIBITORY ANTIBODIES; IMMUNOGLOBULIN-G; STRUCTURAL BASIS; PROTEIN VAR2CSA AB Background: VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. Methods: VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. Results: From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. Conclusion: These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development. C1 [Avril, Marion; Hathaway, Marianne J.; Cartwright, Megan M.; Gose, Severin O.; Smith, Joseph D.] Seattle Biomed Res Inst, Seattle, WA 98109 USA. [Narum, David L.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Smith, JD (reprint author), Seattle Biomed Res Inst, 307 Westlake Ave N,Suite 500, Seattle, WA 98109 USA. EM marion.avril@sbri.org; marianne.hathaway@sbri.org; megan.cartwright@sbri.org; severin.gose@sbri.org; dnarum@niaid.nih.gov; joe.smith@sbri.org OI Gose, Severin/0000-0002-8044-9347 FU Intramural Research Program of the NIH, Malaria Vaccine Development Branch, National Institute for Allergy and Infectious Diseases FX We are grateful to Yuko Ogata (SBRI Proteomic Core) and Karen Callahan (SBRI) and Karine Reiter (MVDB) for her excellent lab assistance. This work was supported by a grant from the Bill and Melinda gates Foundation (JDS). This research was supported in part by the Intramural Research Program of the NIH, Malaria Vaccine Development Branch, National Institute for Allergy and Infectious Diseases. NR 35 TC 12 Z9 12 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 29 PY 2009 VL 8 AR 143 DI 10.1186/1475-2875-8-143 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 474YK UT WOS:000268320900001 PM 19563628 ER PT J AU Adib, AB AF Adib, Artur B. TI Comment on "On the Crooks fluctuation theorem and the Jarzynski equality" [J. Chem. Phys. 129, 091101 (2008)] SO JOURNAL OF CHEMICAL PHYSICS LA English DT Letter DE Brownian motion; fluctuations ID FREE-ENERGY DIFFERENCES AB It has recently been argued that a self-consistency condition involving the Jarzynski equality (JE) and the Crooks fluctuation theorem (CFT) is violated for a simple Brownian process [L. Y. Chen, J. Chem. Phys.129, 091101 (2008)]. This note adopts the definitions in the original formulation of the JE and CFT and demonstrates the contrary. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Adib, AB (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM adiba@mail.nih.gov FU Intramural NIH HHS NR 6 TC 5 Z9 5 U1 0 U2 4 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 28 PY 2009 VL 130 IS 24 AR 247101 DI 10.1063/1.3158474 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 465PX UT WOS:000267600400052 PM 19566186 ER PT J AU Berezhkovskii, AM Barzykin, AV Zitserman, VY AF Berezhkovskii, Alexander M. Barzykin, Alexander V. Zitserman, Vladimir Yu. TI Escape from cavity through narrow tunnel SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biotransport; cellular biophysics; diffusion; Laplace transforms; neurophysiology; probability ID DENDRITIC SPINES; CALCIUM DYNAMICS; DIFFUSION; CHANNEL AB The paper deals with a diffusing particle that escapes from a cavity to the outer world through a narrow cylindrical tunnel. We derive expressions for the Laplace transforms of the particle survival probability, its lifetime probability density, and the mean lifetime. These results show how the quantities of interest depend on the geometric parameters (the cavity volume and the tunnel length and radius) and the particle diffusion coefficients in the cavity and in the tunnel. Earlier suggested expressions for the mean lifetime, which correspond to different escape scenarios, are contained in our result as special cases. In contrast to these expressions, our formula predicts correct asymptotic behavior of the mean lifetime in the absence of the cavity or tunnel. To test the accuracy of our approximate theory we compare the mean lifetime, the lifetime probability density, and the survival probability (the latter two are obtained by inverting their Laplace transforms numerically) with corresponding quantities found by solving numerically the three-dimensional diffusion equation, assuming that the cavity is a sphere and that the particle has the same diffusion coefficient in the cavity and in the tunnel. Comparison shows excellent agreement between the analytical and numerical results over a broad range of the geometric parameters of the problem. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Barzykin, Alexander V.] Royal Bank Scotland, London EC2M 4AA, England. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@helix.nih.gov FU Intramural Research Program of the NIH; Center for Information Technology FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology. We are grateful to Professor Stas Shvartsman for useful suggestions. NR 19 TC 17 Z9 17 U1 1 U2 8 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUN 28 PY 2009 VL 130 IS 24 AR 245104 DI 10.1063/1.3160546 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 465PX UT WOS:000267600400051 PM 19566185 ER PT J AU Sviridov, D Hortin, GL AF Sviridov, Denis Hortin, Glen L. TI Urine albumin measurement: Effects of urine matrix constituents SO CLINICA CHIMICA ACTA LA English DT Article DE Urine albumin; Microalbuminuria; Matrix effects; Urine composition ID HIPPURIC-ACID; MICROALBUMINURIA; EXCRETION; IMMUNOTURBIDIMETRY; CHROMATOGRAPHY; COMMUTABILITY; NEPHROPATHY; REACTIVITY; FORMS AB Background: There is increasing clinical interest in accurate measurement of urine albumin as an early indicator of kidney disease. However, urine is a highly variable sample matrix that may exert matrix effects on assays for urine albumin. Methods: Variation in urine composition was assessed-for components routinely measured in the clinical laboratory over 1 year. Solutions of representing different concentrations of urine components were prepared and spiked with a constant amount of albumin. Fourteen urine specimens of variable composition were ultrafiltered and spiked with a constant amount of albumin. Concentrations of albumin in solutions were determined with an immunoturbidimetric assay on the Beckman LX20 analyzer and with a competitive immunoassay on the Siemens Immulite analyzer. Results: Variation in concentrations of most constituents altered measured urine by <10%. High NaCl concentration increased assay values by 10% or more. Addition of 0.5% Triton X-100 increased values in the LX20 assay by about 20%. Most ultrafiltered urine specimens had <10% effect on measured albumin at a concentration near 20 mg/l. but one specimen was noted to decrease measured albumin by approximately 20% in the LX20 assay. Conclusions: Urine matrix components exert small but potentially significant effects on assays for urine albumin. Urine matrix effects should be considered in the design and evaluation of assays for albumin. Published by Elsevier B.V. C1 [Sviridov, Denis; Hortin, Glen L.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Hortin, GL (reprint author), Univ Florida, Dept Pathol, Lab Med & Immunol, Gainesville, FL 32611 USA. EM ghortin@pathology.ufl.edu FU Intramural NIH HHS NR 33 TC 14 Z9 15 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUN 27 PY 2009 VL 404 IS 2 BP 140 EP 143 DI 10.1016/j.cca.2009.03.034 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 461PB UT WOS:000267279100011 PM 19332047 ER PT J AU Chowell, G Munayco, CV Escalante, AA McKenzie, FE AF Chowell, Gerardo Munayco, Cesar V. Escalante, Ananias A. McKenzie, F. Ellis TI The spatial and temporal patterns of falciparum and vivax malaria in Peru: 1994-2006 SO MALARIA JOURNAL LA English DT Article ID POLYMERASE-CHAIN-REACTION; PLASMODIUM-FALCIPARUM; CLIMATE VARIABILITY; MEASLES EPIDEMICS; PARASITE DENSITY; WAVELET ANALYSIS; HIGH PREVALENCE; TIME-SERIES; INFECTIONS; TRANSMISSION AB Background: Malaria is the direct cause of approximately one million deaths worldwide each year, though it is both preventable and curable. Increasing the understanding of the transmission dynamics of falciparum and vivax malaria and their relationship could suggest improvements for malaria control efforts. Here the weekly number of malaria cases due to Plasmodium falciparum (1994-2006) and Plasmodium vivax (1999-2006) in Per at different spatial scales in conjunction with associated demographic, geographic and climatological data are analysed. Methods: Malaria periodicity patterns were analysed through wavelet spectral analysis, studied patterns of persistence as a function of community size and assessed spatial heterogeneity via the Lorenz curve and the summary Gini index. Results: Wavelet time series analyses identified annual cycles in the incidence of both malaria species as the dominant pattern. However, significant spatial heterogeneity was observed across jungle, mountain and coastal regions with slightly higher levels of spatial heterogeneity for P. vivax than P. falciparum. While the incidence of P. falciparum has been declining in recent years across geographic regions, P. vivax incidence has remained relatively steady in jungle and mountain regions with a slight decline in coastal regions. Factors that may be contributing to this decline are discussed. The time series of both malaria species were significantly synchronized in coastal (rho = 0.9, P < 0.0001) and jungle regions (rho = 0.76, P < 0.0001) but not in mountain regions. Community size was significantly associated with malaria persistence due to both species in jungle regions, but not in coastal and mountain regions. Conclusion: Overall, findings highlight the importance of highly refined spatial and temporal data on malaria incidence together with demographic and geographic information in improving the understanding of malaria persistence patterns associated with multiple malaria species in human populations, impact of interventions, detection of heterogeneity and generation of hypotheses. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo; McKenzie, F. Ellis] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Munayco, Cesar V.] Minist Hlth, Jesus Maria Luma 11, Peru. [Escalante, Ananias A.] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. EM gchowell@asu.edu; cmunayco@dge.gob.pe; Ananias.Escalante@asu.edu; mckenzel@mail.nih.gov RI Chowell, Gerardo/A-4397-2008; Munayco, Cesar/G-9990-2013; Chowell, Gerardo/F-5038-2012 OI Munayco, Cesar/0000-0001-7872-8913; Chowell, Gerardo/0000-0003-2194-2251 NR 59 TC 22 Z9 22 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JUN 27 PY 2009 VL 8 AR 142 DI 10.1186/1475-2875-8-142 PG 19 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 474YJ UT WOS:000268320800001 PM 19558695 ER PT J AU Tang, K Pugalenthi, G Suganthan, PN Lanczycki, CJ Chakrabarti, S AF Tang, Ke Pugalenthi, Ganesan Suganthan, P. N. Lanczycki, Christopher J. Chakrabarti, Saikat TI Prediction of functionally important sites from protein sequences using sparse kernel least squares classifiers SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Functionally important sites; Protein functional templates; Machine learning algorithms; Sparse kernel least squares classifiers ID SUPPORT VECTOR MACHINE; NEURAL-NETWORKS; IDENTIFICATION; RESIDUES; DATABASE; CONSERVATION AB Identification of functionally important sites (FIS) in proteins is a critical problem and can have profound importance where protein Structural information is limited. Machine learning techniques have been very useful in successful classification of many important biological problems. In this paper, we adopt the sparse kernel least squares classifiers (SKLSC) approach for classification and/or prediction of FIS using protein sequence derived features. The SKLSC algorithm was applied to 5435 FIS that have been extracted from 312 reliable alignments for a wide range of protein families. We obtained 68.28% sensitivity and 68.66% specificity for training dataset and 65.34% sensitivity and 66.88% specificity for testing dataset. Further, large scale benchmarking Study using alignments of 101 protein families containing 1899 FIS showed that our method achieved an average similar to 70% sensitivity in predicting different types of FIS, Such as active sites, metal, ligand or protein binding sites. Our findings also indicate that active sites and metal binding sites are comparably easier to predict compared to the ligand and protein binding sites. Despite moderate success, our results Suggest the usefulness and potential of SKLSC approach in prediction of FIS using only protein sequence derived information. (C) 2009 Elsevier Inc. All rights reserved. C1 [Lanczycki, Christopher J.; Chakrabarti, Saikat] NCBI, Natl Lib Med, NIH, Bethesda, MD 20892 USA. [Tang, Ke] Univ Sci & Technol China, Dept Comp Sci & Technol, NICAL, Hefei 230026, Anhui, Peoples R China. [Pugalenthi, Ganesan; Suganthan, P. N.] Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore, Singapore. RP Chakrabarti, S (reprint author), NCBI, Natl Lib Med, NIH, 8600 Rockville Pike, Bethesda, MD 20892 USA. EM chakraba@ncbi.nlm.nih.gov RI Suganthan, .Ponnuthurai /A-5023-2011; Tang, Ke/E-5656-2015 OI Suganthan, .Ponnuthurai /0000-0003-0901-5105; FU National Natural Science Foundation of China [60802036]; A*Star (Agency for Science, Technology and Research); National Library of Medicine at National Institutes of Health/DHHS FX KT is financially supported by a National Natural Science Foundation of China Grant (No. 60802036). G.P. and P.N.S. acknowledge the financial support offered by the A*Star (Agency for Science, Technology and Research). S.C. and C.J.L. acknowledge the support provided by the Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. NR 31 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 26 PY 2009 VL 384 IS 2 BP 155 EP 159 DI 10.1016/j.bbrc.2009.04.096 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 451HY UT WOS:000266462500005 PM 19394310 ER PT J AU Ryan, RM Compton, ELR Mindell, JA AF Ryan, Renae M. Compton, Emma L. R. Mindell, Joseph A. TI Functional Characterization of a Na(+)-dependent Aspartate Transporter from Pyrococcus horikoshii SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEURONAL GLUTAMATE TRANSPORTER; SCANNING MUTAGENESIS REVEALS; CHLORIDE PERMEATION PATHWAY; RAT-BRAIN; REENTRANT LOOP; SUBSTRATE-BINDING; ACID TRANSPORTER; ACTIVE-TRANSPORT; ION FLUXES; RECONSTITUTION AB Excitatory amino acid transporters (EAATs) are crucial in maintaining extracellular levels of glutamate, the most abundant excitatory neurotransmitter, below toxic levels. The recent three-dimensional crystal structure of Glt(Ph), an archaeal homolog of the EAATs, provides elegant structural details of this family of proteins, yet we know little about the mechanism of the bacterial transporter. Conflicting reports in the literature have described Glt(Ph) as an aspartate transporter driven by Na(+) or a glutamate transporter driven by either Na(+) or H(+). Here we use purified protein reconstituted into liposomes to thoroughly characterize the ion and substrate dependence of the Glt(Ph) transport. We confirm that Glt(Ph) is a Na(+)-dependent transporter that is highly selective for aspartate over other amino acids, and we show that transport is coupled to at least two Na(+) ions. In contrast to the EAATs, transport via Glt(Ph) is independent of H(+) and K(+). We propose a kinetic model of transport in which at least two Na(+) ions are coupled to the cotransport of each aspartate molecule by Glt(Ph), and where an ion-and substrate-free transporter reorients to complete the transport cycle. C1 [Ryan, Renae M.; Compton, Emma L. R.; Mindell, Joseph A.] NINDS, Membrane Transport Biophys Unit, Porter Neurosci Ctr, NIH, Bethesda, MD 20892 USA. RP Mindell, JA (reprint author), 35 Convent Dr,Bldg 35,MSC 3701, Bethesda, MD 20892 USA. EM mindellj@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247; Ryan, Renae/0000-0002-8680-4610 FU National Institutes of Health; Australian National Health and Medical Research Council [358779] FX This work was supported, in whole, or in part, by a National Institutes of Health grant from NINDS Intramural Program. This work was also supported by Australian National Health and Medical Research Council C. J. Martin Postdoctoral Fellowship 358779 (to R. M. R.). NR 36 TC 55 Z9 55 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 26 PY 2009 VL 284 IS 26 BP 17540 EP 17548 DI 10.1074/jbc.M109.005926 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 460QP UT WOS:000267202500020 PM 19380583 ER PT J AU Kehr, S Malinouski, M Finney, L Vogt, S Labunskyy, VM Kasaikina, MV Carlson, BA Zhou, Y Hatfield, DL Gladyshev, VN AF Kehr, Sebastian Malinouski, Mikalai Finney, Lydia Vogt, Stefan Labunskyy, Vyacheslav M. Kasaikina, Marina V. Carlson, Bradley A. Zhou, You Hatfield, Dolph L. Gladyshev, Vadim N. TI X-Ray Fluorescence Microscopy Reveals the Role of Selenium in Spermatogenesis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE selenium; X-ray fluorescence microscopy; spermatogenesis; male reproduction; trace elements ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; SPERM MATURATION; SELENOPROTEIN-P; DEVELOPMENTAL EXPRESSION; MITOCHONDRIAL CAPSULES; THIOREDOXIN REDUCTASE; MOUSE; SELENOCYSTEINE; PROTEIN; SUPPLEMENTATION AB Selenium (Se) is a trace element with important roles in human health. Several selenoproteins have essential functions in development. However, the cellular and tissue distribution of Se remains largely unknown because of the lack of analytical techniques that image this element with sufficient sensitivity and resolution. Herein, we report that X-ray fluorescence microscopy (XFM) can be used to visualize and quantify the tissue, cellular, and subcellular topography of Se. We applied this technique to characterize the role of Se in spermatogenesis and identified a dramatic Se enrichment specifically in late spermatids, a pattern that was not seen in any other elemental maps. This enrichment was due to elevated levels of the mitochondrial form of glutathione peroxidase 4 and was fully dependent on the supplies of Se by selenoprotein P. High-resolution scans revealed that Se concentrated near the lumen side of elongating spermatids, where structural components of sperm are formed. During spermatogenesis, maximal Se associated with decreased phosphorus, whereas Zn did not change. In sperm, Se was primarily in the midpiece and colocalized with Cu and Fe. XFM allowed quantification of Se in the midpiece (0.8 fg) and head (0.2 fg) of individual sperm cells, revealing the ability of sperm cells to handle the amounts of this element well above its toxic levels. Overall, the use of XFM allowed visualization of tissue and cellular Se and provided important insights in the role of this and other trace elements in spermatogenesis. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Kehr, Sebastian; Malinouski, Mikalai; Labunskyy, Vyacheslav M.; Kasaikina, Marina V.; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. [Kehr, Sebastian; Malinouski, Mikalai; Labunskyy, Vyacheslav M.; Kasaikina, Marina V.; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Finney, Lydia] Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. [Finney, Lydia; Vogt, Stefan] Argonne Natl Lab, Xray Sci Div, Argonne, IL 60439 USA. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, CCR,NIH, Bethesda, MD 20892 USA. [Zhou, You] Univ Nebraska, Ctr Biotechnol, Lincoln, NE 68588 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013; Vogt, Stefan/B-9547-2009; Vogt, Stefan/J-7937-2013 OI Vogt, Stefan/0000-0002-8034-5513; Vogt, Stefan/0000-0002-8034-5513 FU National Institutes of Health [GM065204]; Intramural Research Program of the Center for Cancer Research; National Cancer Institute; National Institutes of Health; Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX We thank Wayne Vogl for helpful discussion. We also thank Marcus Conrad for providing tissues from nGPx4 and mGPx4 knockout mice and Raymond Burk and Kristina Hill for tissues from Sell? knockout mice. This study was supported by National Institutes of Health Grant GM065204 (to V.N.G.) and the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (to D.L.H.). Use of the Advanced Photon Source was supported by the Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. NR 44 TC 41 Z9 43 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 26 PY 2009 VL 389 IS 5 BP 808 EP 818 DI 10.1016/j.jmb.2009.04.024 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 466OL UT WOS:000267671700002 PM 19379757 ER PT J AU Dougherty, MK Ritt, DA Zhou, M Specht, SI Monson, DM Veenstra, TD Morrison, DK AF Dougherty, Michele K. Ritt, Daniel A. Zhou, Ming Specht, Suzanne I. Monson, Daniel M. Veenstra, Timothy D. Morrison, Deborah K. TI KSR2 Is a Calcineurin Substrate that Promotes ERK Cascade Activation in Response to Calcium Signals SO MOLECULAR CELL LA English DT Article ID MAP KINASE PATHWAYS; PROTEIN-KINASE; SCAFFOLD PROTEINS; PHOSPHORYLATION SITES; 14-3-3 BINDING; GENE ENCODES; C-ELEGANS; RAS; TRANSDUCTION; IDENTIFICATION AB Protein scaffolds have emerged as important regulators of MAPK cascades, facilitating kinase activation and providing crucial spatio/temporal control to their signaling outputs. Using a proteomics approach to compare the binding partners of the two mammalian KSR scaffolds, we find that both KSR1 and KSR2 interact with the kinase components of the ERK cascade and have a common function in promoting RTK-mediated ERK signaling. Strikingly, we find that the protein phosphatase calcineurin selectively interacts with KSR2 and that KSR2 uniquely contributes to Ca(2+)-mediated ERK signaling. Calcineurin dephosphorylates KSR2 on specific sites in response to Ca(2+) signals, thus regulating KSR2 localization and activity. Moreover, we find that depletion of endogenous KSR2 impairs Ca(2+)-mediated ERK activation and ERK-dependent signaling responses in INS1 pancreatic beta-cells and NG108 neuroblastoma cells. These findings identify KSR2 as a Ca(2+)-regulated ERK scaffold and reveal a new mechanism whereby Ca(2+) impacts Ras to ERK pathway signaling. C1 [Dougherty, Michele K.; Ritt, Daniel A.; Specht, Suzanne I.; Monson, Daniel M.; Morrison, Deborah K.] NCI, SAIC Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Zhou, Ming; Veenstra, Timothy D.] NCI, SAIC Frederick Inc, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, SAIC Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM dmorrison@ncifcrf.gov FU National Cancer Institute; National Institutes of Health, DHHS [N01-CO-12400] FX We thank members of the Laboratory of Cell and Developmental Signaling for helpful discussions and comments. This project was supported with federal funds from the National Cancer Institute, National Institutes of Health, DHHS, in part under Contract N01-CO-12400. NR 46 TC 52 Z9 52 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 26 PY 2009 VL 34 IS 6 BP 652 EP 662 DI 10.1016/j.molcel.2009.06.001 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 464NH UT WOS:000267511300005 PM 19560418 ER PT J AU Das, R Mariano, J Tsai, YC Kalathur, RC Kostova, Z Li, J Tarasov, SG McFeeters, RL Altieri, AS Ji, XH Byrd, RA Weissman, AM AF Das, Ranabir Mariano, Jennifer Tsai, Yien Che Kalathur, Ravi C. Kostova, Zlatka Li, Jess Tarasov, Sergey G. McFeeters, Robert L. Altieri, Amanda S. Ji, Xinhua Byrd, R. Andrew Weissman, Allan M. TI Allosteric Activation of E2-RING Finger-Mediated Ubiquitylation by a Structurally Defined Specific E2-Binding Region of gp78 SO MOLECULAR CELL LA English DT Article ID UBIQUITIN-CONJUGATING ENZYME; RETICULUM-ASSOCIATED DEGRADATION; ENDOPLASMIC-RETICULUM; POLYUBIQUITIN CHAIN; PROTEIN LIGASES; E3 LIGASE; RING-TYPE; COMPLEX; DOMAIN; BINDING AB The activity of RING finger ubiquitin ligases (E3) is dependent on their ability to facilitate transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to substrates. The G2BR domain within the E3 gp78 binds selectively and with high affinity to the E2 Ube2g2. Through structural and functional analyses we determine that this occurs on a region of Ube2g2 distinct from binding sites for ubiquitin-activating enzyme (E1) and RING fingers. Binding to the G2BR results in conformational changes in Ube2g2 that affect ubiquitin loading. The Ube2g2:G2BR interaction also causes an similar to 50-fold increase in affinity between the E2 and RING finger. This results in markedly increased ubiquitylation by Ube2g2 and the gp78 RING finger. The significance of this G2BR effect is underscored by enhanced ubiquitylation observed when Ube2g2 is paired with other RING finger E3s. These findings uncover a mechanism whereby allosteric effects on an E2 enhance E2-RING finger interactions and, consequently, ubiquitylation. C1 [Das, Ranabir; Li, Jess; Tarasov, Sergey G.; McFeeters, Robert L.; Altieri, Amanda S.; Byrd, R. Andrew] NCI, Ctr Canc Res, Struct Biophys Lab, Frederick, MD 21702 USA. [Mariano, Jennifer; Tsai, Yien Che; Kostova, Zlatka; Weissman, Allan M.] NCI, Ctr Canc Res, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. [Kalathur, Ravi C.; Ji, Xinhua] NCI, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Ctr Canc Res, Struct Biophys Lab, Frederick, MD 21702 USA. EM rabyrd@ncifcrf.gov; amw@nih.gov RI Ji, Xinhua/C-9664-2012; Byrd, R. Andrew/F-8042-2015; Kalathur, Ravi/L-7696-2016 OI Ji, Xinhua/0000-0001-6942-1514; Tsai, Yien Che/0000-0001-9624-1092; Byrd, R. Andrew/0000-0003-3625-4232; Kalathur, Ravi/0000-0003-1669-9277 FU National Institutes of Health Intramural Research Program; Multiple Myeloma Research Foundation FX We thank Stanley Lipkowitz and Philip Ryan for critical reading of this manuscript, Mei Yang and Prasenjit Bhawmik for technical assistance, Kevin Lorick for assistance in initial studies, and Robert Gemmill, Kazuhiro Iwai, Amy Lam, and Emmanuel Wiertz for reagents. X-ray diffraction data were collected at the 22-ID beamline of SER-CAT, Advanced Photon Source, Argonne National Laboratory. Characterization of all proteins (CD and mass spectroscopy) and calorimetry were performed at the Biophysics Resource in the Structural Biophysics Laboratory. This work was supported by the National Institutes of Health Intramural Research Program and by a grant to A.M.W. from the Multiple Myeloma Research Foundation. NR 41 TC 85 Z9 86 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUN 26 PY 2009 VL 34 IS 6 BP 674 EP 685 DI 10.1016/j.molcel.2009.05.010 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 464NH UT WOS:000267511300007 PM 19560420 ER PT J AU Sleiman, PMA Healy, DG Muqit, MMK Yang, YX Van der Brug, M Holton, JL Revesz, T Quinn, NP Bhatia, K Diss, JKJ Lees, AJ Cookson, MR Latchman, DS Wood, NW AF Sleiman, P. M. A. Healy, D. G. Muqit, M. M. K. Yang, Y. X. Van der Brug, M. Holton, J. L. Revesz, T. Quinn, N. P. Bhatia, K. Diss, J. K. J. Lees, A. J. Cookson, M. R. Latchman, D. S. Wood, N. W. TI Characterisation of a novel NR4A2 mutation in Parkinson's disease brain SO NEUROSCIENCE LETTERS LA English DT Article DE NR4A2; Parkinsonism; Whole genome expression analysis; Allele specific expression analysis ID NURR1; GENE; MICE; TRANSCRIPTION; ASSOCIATION; DYSFUNCTION; NEURONS; ABSENCE; EXON-1 AB Objective: We performed a mutation screen of NR4A2 (also known as NURR1) in 409 Parkinson's disease (PD) patients. We identified a novel single base substitution in the 5'UTR of the NR4A2 (also known as NURR1) gene (c.-309C > T). Results: We have performed expression studies in neuronal cell lines showing that the c.-309C > T mutation reduces NR4A2 mRNA expression in vitro. We have confirmed this finding in vivo by performing allele specific real-time PCR from brain tissue harbouring the 309C > T mutation and show a 3.48 +/- 1.62 fold reduction in mRNA expression of the mutant allele compared to wild-type. In addition we have undertaken genome wide expression analysis of the mutant NR4A2 brain and shown underexpressed genes were significantly enriched for gene ontology categories in nervous system development and synaptic transmission and overexpressed genes were enriched for unfolded protein response and morphogenesis. Lastly we have shown that the c.-309C > T mutation abrogates the protective effect of wild-type NR4A2 against apoptopic stress. Conclusions: Our findings indicate the c.-309C > T mutation reduces NR4A2 expression resulting in the downregulation of genes involved in the development and maintenance of the nervous system and synaptic transmission. These downregulated pathways contained genes known to be transactivated by NR4A2 and were not disrupted in idiopathic PD brain suggesting causality of the mutation. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Sleiman, P. M. A.; Healy, D. G.; Muqit, M. M. K.; Holton, J. L.; Revesz, T.; Lees, A. J.; Wood, N. W.] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Muqit, M. M. K.; Yang, Y. X.; Diss, J. K. J.; Latchman, D. S.] Inst Child Hlth, Med Mol Biol Unit, London WC1N 1EH, England. [Van der Brug, M.; Cookson, M. R.] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Quinn, N. P.; Bhatia, K.; Diss, J. K. J.] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Lees, A. J.] Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England. [Latchman, D. S.] Univ London, London WC1E 7HX, England. [Sleiman, P. M. A.] UCL, Inst Neurol, Dept Clin Neurosci, London, England. RP Wood, NW (reprint author), Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England. EM n.wood@ion.ucl.ac.uk RI Wood, Nicholas/C-2505-2009; Diss, James/C-5994-2008; Holton, Janice/F-6831-2011; Lees, Andrew/A-6605-2009; Revesz, Tamas/A-8732-2010; OI Wood, Nicholas/0000-0002-9500-3348; Diss, James/0000-0003-4988-257X; Holton, Janice/0000-0002-3882-5249; Revesz, Tamas/0000-0003-2501-0259; Muqit, Miratul/0000-0001-9733-2404 FU Parkinson's Disease Society UK; Brain Research Trust FX We are grateful to the Queen Square Brain Bank for Neurological Disorders, UK, for the provision of the pathological specimens. We thank Dr Weidong Le and Dr Hiroshi Ichinose; Dr John Achermann and Dr Jacques Drouin for NR4A2 constructs; empty pCMX vector construct; and a POMC-luciferase construct respectively. The work was funded in part by the Parkinson's Disease Society UK and the Brain Research Trust. NR 25 TC 22 Z9 22 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 26 PY 2009 VL 457 IS 2 BP 75 EP 79 DI 10.1016/j.neulet.2009.03.021 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 449WF UT WOS:000266360400003 PM 19429166 ER PT J AU Guo, XZ Mak, KK Taketo, MM Yang, YZ AF Guo, Xizhi Mak, Kinglun Kingston Taketo, Makoto M. Yang, Yingzi TI The Wnt/beta-Catenin Pathway Interacts Differentially with PTHrP Signaling to Control Chondrocyte Hypertrophy and Final Maturation SO PLOS ONE LA English DT Article AB Sequential proliferation, hypertrophy and maturation of chondrocytes are required for proper endochondral bone development and tightly regulated by cell signaling. The canonical Wnt signaling pathway acts through beta-catenin to promote chondrocyte hypertrophy whereas PTHrP signaling inhibits it by holding chondrocytes in proliferating states. Here we show by genetic approaches that chondrocyte hypertrophy and final maturation are two distinct developmental processes that are differentially regulated by Wnt/beta-catenin and PTHrP signaling. Wnt/beta-catenin signaling regulates initiation of chondrocyte hypertrophy by inhibiting PTHrP signaling activity, but it does not regulate PTHrP expression. In addition, Wnt/beta-catenin signaling regulates chondrocyte hypertrophy in a non-cell autonomous manner and Gdf5/Bmp signaling may be one of the downstream pathways. Furthermore, Wnt/beta-catenin signaling also controls final maturation of hypertrophic chondrocytes, but such regulation is PTHrP signaling-independent. RP Guo, XZ (reprint author), NHGRI, Dev Genet Sect, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov FU Intramural NIH HHS NR 36 TC 36 Z9 38 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 26 PY 2009 VL 4 IS 6 AR e6067 DI 10.1371/journal.pone.0006067 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 463ID UT WOS:000267424600015 PM 19557172 ER PT J AU Daar, AS Nabel, EG Pramming, SK Anderson, W Beaudet, A Liu, DP Katoch, VM Borysiewicz, LK Glass, RI Bell, J AF Daar, Abdallah S. Nabel, Elizabeth G. Pramming, Stig K. Anderson, Warwick Beaudet, Alain Liu, Depei Katoch, V. M. Borysiewicz, Leszek K. Glass, Roger I. Bell, John TI The Global Alliance for Chronic Diseases SO SCIENCE LA English DT Letter C1 [Daar, Abdallah S.; Nabel, Elizabeth G.; Pramming, Stig K.; Bell, John] Oxford Hlth Alliance, Preparatory Comm, London, England. [Daar, Abdallah S.] Univ Toronto, UHN, McLaughlin Rotman Ctr Global Hlth, Toronto, ON, Canada. [Nabel, Elizabeth G.] NHLBI, Bethesda, MD 20892 USA. [Anderson, Warwick] Natl Hlth & Med Res Council, Canberra, ACT, Australia. [Beaudet, Alain] Canadian Inst Hlth Res, Ottawa, ON, Canada. [Liu, Depei] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Katoch, V. M.] Indian Council Med Res, New Delhi, India. [Borysiewicz, Leszek K.] MRC, London, England. [Glass, Roger I.] Fogarty Int Ctr, Bethesda, MD USA. RP Daar, AS (reprint author), Oxford Hlth Alliance, Preparatory Comm, London, England. EM a.daar@utoronto.ca NR 4 TC 19 Z9 20 U1 0 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD JUN 26 PY 2009 VL 324 IS 5935 BP 1642 EP 1642 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 462GE UT WOS:000267338200011 PM 19556484 ER PT J AU Alter, BP Giri, N Savage, SA Rosenberg, PS AF Alter, Blanche P. Giri, Neelam Savage, Sharon A. Rosenberg, Philip S. TI Cancer in dyskeratosis congenita SO BLOOD LA English DT Article ID BONE-MARROW FAILURE; FANCONI-ANEMIA; TELOMERE LENGTH; APLASTIC-ANEMIA; MUTATIONS; TRANSPLANTATION; CARCINOMA; COMPONENT; COMPLICATION; ASSOCIATION AB Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome. The spectrum of cancer susceptibility in this disorder of telomere biology has not been described. There were more than 500 cases of DC reported in the literature from 1910 to 2008; the National Cancer Institute (NCI) prospective DC cohort enrolled 50 cases from 2002 to 2007. Sixty cancers were reported in 52 literature cases, while 7 occurred among patients in the NCI DC cohort. The 2 cohorts were comparable in their median overall survival (42 years) and cumulative incidence of cancer (40%-50% by age 50 years). The most frequent solid tumors were head and neck squamous cell carcinomas (40% of patients in either cohort), followed by skin and anorectal cancer. The ratio of observed to expected cancers (O/E ratio) in the NCI cohort was 11-fold compared with the general population (P < .05). Significantly elevated O/E ratios were 1154 for tongue cancer and 195 for acute myeloid leukemia. Survival after bone marrow transplantation for aplastic anemia or leukemia was poor in both cohorts. The frequency and types of cancer in DC are surpassed only by those in Fanconi anemia (FA), indicating that FA and DC have similarly high risks of adverse hematologic and neoplastic events, and patients with these diseases should be counseled and monitored similarly. (Blood. 2009; 113: 6549-6557) C1 [Alter, Blanche P.; Giri, Neelam; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Rosenberg, Philip S.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Rm 7020, Rockville, MD 20852 USA. EM alterb@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural NIH HHS NR 70 TC 165 Z9 175 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD JUN 25 PY 2009 VL 113 IS 26 BP 6549 EP 6557 DI 10.1182/blood-2008-12-192880 PG 9 WC Hematology SC Hematology GA 468BY UT WOS:000267789600013 PM 19282459 ER PT J AU Chuk, MK McIntyre, E Small, D Brown, P AF Chuk, Meredith K. McIntyre, Emily Small, Donald Brown, Patrick TI Discordance of MLL-rearranged (MLL-R) infant acute lymphoblastic leukemia in monozygotic twins with spontaneous clearance of preleukemic clone in unaffected twin SO BLOOD LA English DT Article; Proceedings Paper CT 50th Annual Meeting of the American-Society-of-Hematology CY DEC 06-09, 2008 CL San Francisco, CA SP Amer Soc Hematol ID CHILDHOOD LEUKEMIA; GENE FUSION; CHROMOSOME TRANSLOCATIONS; IN-UTERO; ETIOLOGY; CHILDREN; ORIGIN; MICE AB Concordance of MLL-rearranged acute leukemia in infant monozygotic twins is thought to be 100% with a very short latency period, suggesting that either the MLL fusion itself is sufficient to cause leukemia or that it promotes the rapid acquisition of additional oncogenic events that result in overt disease. We report the first case of discordance in an infant monozygotic twin pair. Twin A presented at age 9 months with MLL-ENL(+) acute lymphoblastic leukemia and twin B remains healthy 3 years later. The presence and eventual clearance of a clonal population of MLL-ENL(+) cells was shown in the bone marrow and peripheral blood of twin B. Clearance of this clone was temporally associated with viral-induced cytopenias, suggesting an immune-mediated clearance of the clone before the development of leukemia. Thus, concordance of MLL-rearranged acute leukemia in infant monozygotic twins is not universal. The implications of this case for MLL-rearranged leukemogenesis are discussed. (Blood. 2009;113:6691-6694) C1 [Chuk, Meredith K.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Chuk, Meredith K.; McIntyre, Emily; Small, Donald; Brown, Patrick] Johns Hopkins Univ, Baltimore, MD USA. RP Brown, P (reprint author), CRB1 2M49,1650 Orleans St, Baltimore, MD 21231 USA. EM pbrown2@jhmi.edu FU NCI NIH HHS [K23 CA111728, R01 CA090668] NR 19 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 25 PY 2009 VL 113 IS 26 BP 6691 EP 6694 DI 10.1182/blood-2009-01-202259 PG 4 WC Hematology SC Hematology GA 468BY UT WOS:000267789600029 PM 19411627 ER PT J AU Hostomska, J Volfova, V Mu, JB Garfield, M Rohousova, I Volf, P Valenzuela, JG Jochim, RC AF Hostomska, Jitka Volfova, Vera Mu, Jianbing Garfield, Mark Rohousova, Iva Volf, Petr Valenzuela, Jesus G. Jochim, Ryan C. TI Analysis of salivary transcripts and antigens of the sand fly Phlebotomus arabicus SO BMC GENOMICS LA English DT Article ID LUTZOMYIA-LONGIPALPIS; LEISHMANIA-TROPICA; AEDES-AEGYPTI; VISCERAL LEISHMANIASIS; MIDGUT TRANSCRIPTOME; ANTIBODY-RESPONSE; NORTHERN ISRAEL; FEMALE MOSQUITO; CDNA CLONING; PROTEIN AB Background: Sand fly saliva plays an important role in blood feeding and Leishmania transmission as it was shown to increase parasite virulence. On the other hand, immunity to salivary components impedes the establishment of infection. Therefore, it is most desirable to gain a deeper insight into the composition of saliva in sand fly species which serve as vectors of various forms of leishmaniases. In the present work, we focused on Phlebotomus (Adlerius) arabicus, which was recently shown to transmit Leishmania tropica, the causative agent of cutaneous leishmaniasis in Israel. Results: A cDNA library from salivary glands of P. arabicus females was constructed and transcripts were sequenced and analyzed. The most abundant protein families identified were SP15-like proteins, ParSP25-like proteins, D7-related proteins, yellow-related proteins, PpSP32-like proteins, antigen 5-related proteins, and 34 kDa-like proteins. Sequences coding for apyrases, hyaluronidase and other putative secreted enzymes were also represented, including endonuclease, phospholipase, pyrophosphatase, amylase and trehalase. Mass spectrometry analysis confirmed the presence of 20 proteins predicted to be secreted in the salivary proteome. Humoral response of mice bitten by P. arabicus to salivary antigens was assessed and many salivary proteins were determined to be antigenic. Conclusion: This transcriptomic analysis of P. arabicus salivary glands is the first description of salivary proteins of a sand fly in the subgenus Adlerius. Proteomic analysis of P. arabicus salivary glands produced the most comprehensive account in a single sand fly species to date. Detailed information and phylogenetic relationships of the salivary proteins are provided, expanding the knowledge base of molecules that are likely important factors of sand fly-host and sand fly-Leishmania interactions. Enzymatic and immunological investigations further demonstrate the value of functional transcriptomics in advancing biological and epidemiological research that can impact leishmaniasis. C1 [Mu, Jianbing; Valenzuela, Jesus G.; Jochim, Ryan C.] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Hostomska, Jitka; Volfova, Vera; Rohousova, Iva; Volf, Petr] Charles Univ Prague, Fac Sci, Dept Parasitol, CR-12844 Prague 2, Czech Republic. [Garfield, Mark] NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. RP Valenzuela, JG (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM jitka.hostomska@centrum.cz; veravolf@seznam.cz; jmu@niaid.nih.gov; mgarfield@niaid.nih.gov; rohousova@seznam.cz; volf@cesnet.cz; jvalenzuela@niaid.nih.gov; rjochim@niaid.nih.gov RI Rohousova, Iva/B-4852-2011; Volf, Petr/C-4300-2012; Jochim, Ryan/C-6756-2013; Stafkova, Jitka/H-5775-2016 OI Rohousova, Iva/0000-0003-1830-0813; Volf, Petr/0000-0003-1790-1123; Stafkova, Jitka/0000-0002-7346-5445 FU Fulbright Scholar Program; MSM [MSM 0021620828, LC 06009]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases FX We thank Petr Jedelsky for help with the mass spectrometry analysis, Dr. Helena Kulikova and Dusan Eremias for helpful technical and administrative assistance. Participation of Iva Rohousova was supported by the Fulbright Scholar Program. The study was partially supported by projects MSM 0021620828, LC 06009, and The Division of Intramural Research, The National Institute of Allergy and Infectious Diseases. NR 61 TC 38 Z9 38 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 25 PY 2009 VL 10 AR 282 DI 10.1186/1471-2164-10-282 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 480RK UT WOS:000268754300001 PM 19555500 ER PT J AU Solomon, D Papillo, JL Davey, DD AF Solomon, Diane Papillo, Jacalyn L. Davey, Diane D. CA CETC TI Statement on Human Papillomavirus DNA Test Utilization SO CANCER CYTOPATHOLOGY LA English DT Editorial Material ID CANCER C1 [Solomon, Diane] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Papillo, Jacalyn L.] Fletcher Allen Hlth Care, Dept Anat Pathol, Burlington, VT USA. [Davey, Diane D.] Univ Cent Florida, Dept Med Educ, Coll Med, Orlando, FL 32816 USA. RP Solomon, D (reprint author), NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Execut Plaza N,Room 2130,6130 Execut Blvd, Rockville, MD 20852 USA. EM ds87v@nih.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUN 25 PY 2009 VL 117 IS 3 BP 154 EP 156 DI 10.1002/cncy.20031 PG 3 WC Oncology; Pathology SC Oncology; Pathology GA 459IT UT WOS:000267095900003 PM 19415756 ER PT J AU Collins, RN Zimmerberg, J AF Collins, Ruth N. Zimmerberg, Joshua TI CELL BIOLOGY A score for membrane fusion SO NATURE LA English DT Editorial Material ID VESICLE C1 [Collins, Ruth N.] Cornell Univ, Dept Mol Med, Ithaca, NY 14853 USA. [Zimmerberg, Joshua] Eunice Kennedy Shriver NICHHD, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Collins, RN (reprint author), Cornell Univ, Dept Mol Med, Ithaca, NY 14853 USA. EM rnc8@cornell.edu; zimmerbj@mail.nih.gov NR 14 TC 3 Z9 3 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 25 PY 2009 VL 459 IS 7250 BP 1065 EP 1066 DI 10.1038/4591065a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 466BX UT WOS:000267636700028 PM 19553985 ER PT J AU Deans, KJ Minneci, PC Chen, H Kern, SJ Logun, C Alsaaty, S Norsworthy, KJ Theel, SM Sennesh, JD Barb, JJ Munson, PJ Danner, RL Solomon, MA AF Deans, Katherine J. Minneci, Peter C. Chen, Hao Kern, Steven J. Logun, Carolea Alsaaty, Sara Norsworthy, Kelly J. Theel, Stephanie M. Sennesh, Joel D. Barb, Jennifer J. Munson, Peter J. Danner, Robert L. Solomon, Michael A. TI Impact of animal strain on gene expression in a rat model of acute cardiac rejection SO BMC GENOMICS LA English DT Article ID HEART-TRANSPLANT RECIPIENTS; ALLOGRAFT-REJECTION; HUMAN-POPULATIONS; DNA MICROARRAY; BLOOD; DIAGNOSIS; EXPERIENCE; PROFILES; BRAIN; PCR AB Background: The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway), microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC). Results: In heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC >= 3). Only 13 genes were affected by both strain and rejection, which was < 1% (13/1368) of all probesets differentially expressed in ACR. However, for PBMC, strain alone affected 265 probesets (FDR 10% and FC >= 3) and the addition of ACR had little further effect. Pathway analysis of these differentially expressed strain effect genes connected them with immune response, cell motility and cell death, functional themes that overlap with those related to ACR. After accounting for animal strain, additional analysis identified 30 PBMC candidate genes potentially associated with ACR. Conclusion: In ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes. C1 [Deans, Katherine J.; Minneci, Peter C.; Chen, Hao; Kern, Steven J.; Logun, Carolea; Alsaaty, Sara; Norsworthy, Kelly J.; Theel, Stephanie M.; Danner, Robert L.; Solomon, Michael A.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Barb, Jennifer J.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Sennesh, Joel D.] Inova Fairfax Hosp, Dept Pathol, Fairfax, VA USA. [Deans, Katherine J.; Minneci, Peter C.] Childrens Hosp Philadelphia, Dept Surg, Childrens Inst Surg Sci, Philadelphia, PA 19104 USA. [Minneci, Peter C.] Univ Penn, Sch Med, Dept Surg, Philadelphia, PA 19104 USA. [Deans, Katherine J.; Solomon, Michael A.] NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Solomon, MA (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. EM deansk@email.chop.edu; minneci@email.chop.edu; chenhao@cc.nih.gov; kernsj@cc.nih.gov; CLogun@cc.nih.gov; SAlsaaty@cc.nih.gov; kelly.norsworthy@gmail.com; smtheel@yahoo.com; Joel.Sennesh@inova.org; barbj@mail.nih.gov; munson@mail.nih.gov; RDanner@cc.nih.gov; msolomon@cc.nih.gov NR 43 TC 3 Z9 3 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 24 PY 2009 VL 10 AR 280 DI 10.1186/1471-2164-10-280 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 480RI UT WOS:000268754100002 PM 19552812 ER PT J AU Noben-Trauth, K Johnson, KR AF Noben-Trauth, Konrad Johnson, Kenneth R. TI Inheritance patterns of progressive hearing loss in laboratory strains of mice SO BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Meeting on the Mouse as an Instrument for Ear Research III CY SEP 18-21, 2008 CL Jackson Lab, Bar Harbor, ME HO Jackson Lab DE Hearing loss; Inbred strains; heterogeneous strains; Presbycusis ID QUANTITATIVE TRAIT LOCI; COCHLEAR HAIR-CELLS; PRODUCT OTOACOUSTIC EMISSIONS; INBRED MOUSE STRAINS; ANKLE-LINK COMPLEX; COPY NUMBER; DBA/2J MICE; EARLY-ONSET; GENE; IMPAIRMENT AB Positional cloning of mouse deafness mutations uncovered a plethora of proteins that have important functions in the peripheral auditory system in particular in the cochlear organ of Corti and stria vascularis. Most of these mutant variants follow a monogenic form of inheritance and are rare highly penetrant and deleterious alleles. Inbred and heterogenous strains of mice, in contrast, present with non-syndromic hearing impairment due to the effects of multiple genes and hypomorphic and less penetrant alleles that are often transmitted in a non-Mendelian manner. Here we review hearing loss inheritance patterns as they were discovered in different strains of mice and discuss the relevance of candidate genes to late-onset progressive hearing impairment in mouse and human. Published by Elsevier B.V. C1 [Noben-Trauth, Konrad] NIDCD, Neurogenet Sect, NIH, Rockville, MD 20850 USA. [Johnson, Kenneth R.] Jackson Lab, Bar Harbor, ME 04609 USA. RP Noben-Trauth, K (reprint author), NIDCD, Neurogenet Sect, NIH, 5 Res Court, Rockville, MD 20850 USA. EM nobentk@nidcd.nih.gov FU Intramural NIH HHS [Z01 DC000056-09]; NIDCD NIH HHS [DC005827, R01 DC005827, Z01 DC000056] NR 79 TC 25 Z9 26 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 24 PY 2009 VL 1277 BP 42 EP 51 DI 10.1016/j.brainres.2009.02.012 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 469OQ UT WOS:000267909600006 PM 19236853 ER PT J AU Scher, AI Gudmundsson, LS Sigurdsson, S Ghambaryan, A Aspelund, T Eiriksdottir, G van Buchem, MA Gudnason, V Launer, LJ AF Scher, Ann I. Gudmundsson, Larus S. Sigurdsson, Sigurdur Ghambaryan, Anna Aspelund, Thor Eiriksdottir, Gudny van Buchem, Mark A. Gudnason, Vilmundur Launer, Lenore J. TI Migraine Headache in Middle Age and Late-Life Brain Infarcts SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENE/ENVIRONMENT SUSCEPTIBILITY-REYKJAVIK; ISCHEMIC-STROKE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; GLOBAL BURDEN; RISK; WOMEN; EPIDEMIOLOGY; PATTERNS AB Context Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathologic changes in the brain, particularly in the cerebellum. Objective To determine whether individuals not reporting headache compared with individuals reporting migraine symptoms, particularly aura, in midlife are at increased risk of late-life infarct-like lesions found on magnetic resonance imaging (MRI) without consideration of clinical symptoms. Design, Setting, and Participants A population-based study of men and women in Reykjavik, Iceland (cohort born 1907-1935; n = 4689; 57% women) were followed up since 1967, examined, and interviewed about migraine symptoms in midlife (mean age, 51 years; range, 33-65 years). Between 2002 and 2006, more than 26 years later, brain MRIs were performed. Participants reporting headaches once or more per month were asked about migraine symptoms including nausea, unilateral location, photophobia, visual disturbance, and numbness. These individuals with headache were classified as having migraine without aura, migraine with aura, or nonmigraine headache. A comprehensive cardiovascular risk assessment was performed at both examinations. Main Outcome Measure Presence of infarct-like lesions (total) and specifically located in the cortical, subcortical, and cerebellar regions. Results Infarct-like lesions were present in 39.3% of men and 24.6% of women. After adjusting for age, sex, and follow-up time, compared with those not reporting headaches once or more per month (n = 3243), those with midlife migraine with aura (n = 361) had an increased risk of late-life infarct-like lesions (adjusted odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8) that specifically reflected an association with cerebellar lesions in women (prevalence of infarcts 23.0% for women with migraine with aura vs 14.5% for women not reporting headaches; adjusted OR, 1.9; 95% CI, 1.4-2.6 vs a 19.3% prevalence of infarcts for men with migraine with aura vs 21.3% for men not reporting headaches; adjusted OR, 1.0; 95% CI, 0.6-1.8; P < .04 for interaction by sex). Migraine without aura and nonmigraine headache were not associated with an increased risk. Conclusions Migraine with aura in midlife was associated with late-life prevalence of cerebellar infarct-like lesions on MRI. This association was statistically significant only for women. This is consistent with the hypothesis that migraine with aura in midlife is associated with late-life vascular disease in the cerebellum and in women. JAMA. 2009; 301(24):2563-2570 C1 [Launer, Lenore J.] NIA, LEDB, NIH, Bethesda, MD 20892 USA. [Scher, Ann I.; Ghambaryan, Anna] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Gudmundsson, Larus S.] Univ Iceland, Dept Pharmacol & Toxicol, Reykjavik, Iceland. [Sigurdsson, Sigurdur; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [van Buchem, Mark A.] Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. RP Launer, LJ (reprint author), NIA, LEDB, NIH, 7201 Wisconsin Ave,Ste 3C-309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 FU National Institutes of Health [N01-AG-12100]; National Institute on Aging Intramural Research Program, Hjartavernd; Althingi; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung, and Blood Institute FX Funding/Support: This study was funded by National Institutes of Health contract N01-AG-12100, the National Institute on Aging Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). Components of the study were also supported by the National Eye Institute, the National Institute on Deafness and Other Communication Disorders, and the National Heart, Lung, and Blood Institute. Funding in support of this analysis was provided by the Migraine Research Foundation. NR 34 TC 99 Z9 101 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 24 PY 2009 VL 301 IS 24 BP 2563 EP 2570 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 461KU UT WOS:000267266500021 PM 19549973 ER PT J AU Cheng, S Keyes, MJ Larson, MG McCabe, EL Newton-Cheh, C Levy, D Benjamin, EJ Vasan, RS Wang, TJ AF Cheng, Susan Keyes, Michelle J. Larson, Martin G. McCabe, Elizabeth L. Newton-Cheh, Christopher Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. Wang, Thomas J. TI Long-term Outcomes in Individuals With Prolonged PR Interval or First-Degree Atrioventricular Block SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; ATRIAL-FIBRILLATION; RISK-FACTORS; NATURAL-HISTORY; WAVE DURATION; CONDUCTION; REGURGITATION; POPULATION; PROGNOSIS; FEATURES AB Context Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice. Objective To determine the clinical significance of PR prolongation in ambulatory individuals. Design, Setting, and Participants Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 1968-1974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death. Main Outcome Measures Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. Results During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10 000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker implantation), and 2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22; P = .02) for AF, 1.22 (95% CI, 1.14-1.30; P < .001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P = .005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12; P < .001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P < .001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P = .01). Conclusion Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality. JAMA. 2009; 301(24):2571-2577 C1 [Cheng, Susan; McCabe, Elizabeth L.; Newton-Cheh, Christopher; Wang, Thomas J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cheng, Susan; Keyes, Michelle J.; Larson, Martin G.; McCabe, Elizabeth L.; Newton-Cheh, Christopher; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.; Wang, Thomas J.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02114 USA. [Cheng, Susan] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Clin Investigator Training Program, Boston, MA 02114 USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. [Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Wang, TJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, GRB 800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@partners.org OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [N01-HC-25195]; [K24-HL-04334] FX Funding/Support: The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195. Dr Vasan was supported in part by grant K24-HL-04334. NR 37 TC 197 Z9 202 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 24 PY 2009 VL 301 IS 24 BP 2571 EP 2577 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 461KU UT WOS:000267266500022 PM 19549974 ER PT J AU Kovacs, JA Masur, H AF Kovacs, Joseph A. Masur, Henry TI Evolving Health Effects of Pneumocystis One Hundred Years of Progress in Diagnosis and Treatment SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CARINII DIHYDROPTEROATE SYNTHASE; MAJOR SURFACE GLYCOPROTEIN; INFANT-DEATH-SYNDROME; TRIMETHOPRIM-SULFAMETHOXAZOLE; UNITED-STATES; AIDS PATIENTS; PNEUMONIA PROPHYLAXIS; S-ADENOSYLMETHIONINE; SULFONE PROPHYLAXIS AB 2009 marks the 100th anniversary of the first description of Pneumocystis, an organism that was ignored for much of its first 50 years but that has subsequently been recognized as an important pathogen of immunocompromised patients, especially patients infected with human immunodeficiency virus (HIV). We present a patient with chronic lymphocytic leukemia who died from Pneumocystis pneumonia (PCP) despite appropriate anti-Pneumocystis therapy. Although substantial advances in diagnosis, treatment, and prevention of PCP have decreased its frequency and improved prognosis, PCP continues to be seen in both HIV-infected patients and patients receiving immunosuppressive medications. Pneumocystis species comprise a family of fungi, each of which appears to be able to infect only 1 host species. Pneumocystis has a worldwide distribution. Immunocompetent hosts clear infection without obvious clinical consequences. Pneumocystis has been identified in patients with other diseases such as chronic obstructive pulmonary disease, although its clinical impact is uncertain. Immunocompromised patients develop disease as a consequence of reinfection and possibly reactivation of latent infection. In patients with HIV infection, the CD4 count is predictive of the risk for developing PCP, but such reliable markers are not available for other immunocompromised populations. In the majority of patients with PCP, multiple Pneumocystis strains can be identified using recently developed typing techniques. Because Pneumocystis cannot be cultured, diagnosis relies on detection of the organism by colorimetric or immunofluorescent stains or by polymerase chain reaction. Trimethoprim-sulfamethoxazole is the preferred drug regimen for both treatment and prevention of PCP, although a number of alternatives are also available. Corticosteroids are an important adjunct for hypoxemic patients. JAMA. 2009; 301(24):2578-2585 C1 [Kovacs, Joseph A.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Room 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@mail.nih.gov FU NIH Clinical Center, National Institutes of Health FX Funding/Support: This research was supported by the Intramural Research Program of the NIH Clinical Center, National Institutes of Health. NR 67 TC 55 Z9 60 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 24 PY 2009 VL 301 IS 24 BP 2578 EP 2585 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 461KU UT WOS:000267266500023 PM 19549975 ER PT J AU Ellis, RD Mullen, GED Pierce, M Martin, LB Miura, K Fay, MP Long, CA Shaffer, D Saul, A Miller, LH Durbin, AP AF Ellis, Ruth D. Mullen, Gregory E. D. Pierce, Mark Martin, Laura B. Miura, Kazutoyo Fay, Michael P. Long, Carole A. Shaffer, Donna Saul, Allan Miller, Louis H. Durbin, Anna P. TI A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel (R) with CPG 7909, using two different formulations and dosing intervals SO VACCINE LA English DT Article DE Malaria; Falciparum; Apical membrane antigen 1 ID APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM MALARIA; ANTIBODY-PRODUCTION; NORMAL VOLUNTEERS; CONTROLLED-TRIAL; AMA1 VACCINE; IN-VITRO; CHILDREN; EFFICACY; PROTECTION AB A Phase 1 study was conducted in 24 malaria naive adults to assess the safety and immunogenicity of the recombinant protein vaccine apical membrane antigen 1-Combination 1 (AMA1-C1)/Alhydrogel with CPG 7909 in two different formulations (phosphate buffer and saline), and given at two different dosing schedules, 0 and 1 month or 0 and 2 months. Both formulations were well tolerated and frequency of local reactions and solicited adverse events was similar among the groups. Peak antibody levels in the groups receiving CPG 7909 in saline were not significantly different than those receiving CPG 7909 in phosphate. Peak antibody levels in the groups vaccinated at a 0,2 month interval were 2.52-fold higher than those vaccinated at a 0,1 month interval (p=0.037, 95% CI 1.03, 4.28). In vitro growth inhibition followed the antibody level: median inhibition was 51% (0,1 month interval) versus 85%(0,2 month interval) in antibody from samples taken 2 weeks post-second vaccination (p = 0.056). Published by Elsevier Ltd. C1 [Ellis, Ruth D.; Mullen, Gregory E. D.; Pierce, Mark; Martin, Laura B.; Miura, Kazutoyo; Saul, Allan; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD 20852 USA. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Shaffer, Donna; Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Ellis, RD (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, Twinbrook 1, Rockville, MD 20852 USA. EM ellisru@niaid.nih.gov RI Saul, Allan/I-6968-2013; Martin, Laura/N-1789-2013 OI Saul, Allan/0000-0003-0665-4091; Martin, Laura/0000-0002-4431-4381 FU Intramural Division of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Division of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. We would also like to acknowledge Hong Zhou, Sam Moretz, Ababacar Diouf and Greg Tullo for the GIA work and the PATH/Malaria Vaccine Initiative for their support of the GIA Reference Center. Thanks to the study participants, the NIAID Data Safety and Monitoring Board for reviewing safety data from this study, Coley Pharmaceuticals, a Pfizer Company, who supplied CPG 7909, and Regina White and the entire study team. NR 28 TC 37 Z9 40 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUN 24 PY 2009 VL 27 IS 31 BP 4104 EP 4109 DI 10.1016/j.vaccine.2009.04.077 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 467YD UT WOS:000267778700003 PM 19410624 ER PT J AU Weinrich, M Rostovtseva, TK Bezrukov, SM AF Weinrich, Michael Rostovtseva, Tatiana K. Bezrukov, Sergey M. TI Lipid-Dependent Effects of Halothane on Gramicidin Channel Kinetics: A New Role for Lipid Packing Stress SO BIOCHEMISTRY LA English DT Article ID GENERAL-ANESTHESIA; BILAYERS; CHOLESTEROL; MEMBRANES; STIFFNESS; CONSTANTS AB We find that the sensitivity of gramicidin A channels to the anesthetic halothane is highly lipid dependent. Specifically, exposure of membranes made of lamellar DOPC to halothane in concentrations close to clinically relevant reduces channel lifetimes by 1 order of magnitude. At the same time, gramicidin channels in membranes of nonlamellar DOPE are affected little, if at all, by halothane. We attribute this difference in channel behavior to a difference in the stress of lipid packing into a planar lipid bilayer, wherein the higher stress of DOPE packing reduces the degree of halothane partitioning into the hydrophobic interior. C1 [Weinrich, Michael] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. [Rostovtseva, Tatiana K.; Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Weinrich, M (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Natl Ctr Med Rehabil Res, NIH, Bethesda, MD 20892 USA. EM weinricm@mail.nih.gov FU Intramural Research Program, National Institute of Child Health and Human Development; National Institutes of Health FX This study was supported by the Intramural Research Program, National Institute of Child Health and Human Development, National Institutes of Health. NR 23 TC 9 Z9 9 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 23 PY 2009 VL 48 IS 24 BP 5501 EP 5503 DI 10.1021/bi900494y PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 459QG UT WOS:000267117900001 PM 19405539 ER PT J AU Zhao, H Martin, BM Bisoffi, M Dunaway-Mariano, D AF Zhao, Hong Martin, Brian M. Bisoffi, Marco Dunaway-Mariano, Debra TI The Akt C-Terminal Modulator Protein Is an Acyl-CoA Thioesterase of the Hotdog-Fold Family SO BIOCHEMISTRY LA English DT Article ID PHOSPHORYLATION; PREDICTION; GENE AB Herein, we report on an in vitro kinetic activity analysis that demonstrates that the protein known as the Akt C-terminal modulator protein is a broad-range, high-activity acyl-CoA thioesterase. In vitro tests of possible activity regulation by product inhibition or by Akt1 binding gave negative results. Truncation mutants confined the thioesterase activity to the C-terminal, domain, consistent with our threading model. The N-terminal domain, of unknown fold and function was found to contribute to solubility. C1 [Zhao, Hong; Dunaway-Mariano, Debra] Univ New Mexico, Dept Chem & Biol Chem, Albuquerque, NM 87131 USA. [Martin, Brian M.] NIMH, Mol Struct Unit, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. [Bisoffi, Marco] Univ New Mexico, Dept Biochem & Mol Biol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Dunaway-Mariano, D (reprint author), Univ New Mexico, Dept Chem & Biol Chem, Albuquerque, NM 87131 USA. EM dd39@unm.edu RI ZHAO, HONG/C-6464-2013 FU National Institutes of Health [GM28688]; NIMH RP FX This work was supported by National Institutes of Health Grant GM28688 and by NIMH RP. NR 14 TC 11 Z9 12 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 23 PY 2009 VL 48 IS 24 BP 5507 EP 5509 DI 10.1021/bi900710w PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 459QG UT WOS:000267117900003 PM 19453107 ER PT J AU Shankavaram, UT Varma, S Kane, D Sunshine, M Chary, KK Reinhold, WC Pommier, Y Weinstein, JN AF Shankavaram, Uma T. Varma, Sudhir Kane, David Sunshine, Margot Chary, Krishna K. Reinhold, William C. Pommier, Yves Weinstein, John N. TI CellMiner: a relational database and query tool for the NCI-60 cancer cell lines SO BMC GENOMICS LA English DT Article ID GENE-EXPRESSION DATABASE; MOLECULAR PHARMACOLOGY; DRUG SCREEN; PANEL; MICROARRAY; PROFILES; SET AB Background: Advances in the high-throughput omic technologies have made it possible to profile cells in a large number of ways at the DNA, RNA, protein, chromosomal, functional, and pharmacological levels. A persistent problem is that some classes of molecular data are labeled with gene identifiers, others with transcript or protein identifiers, and still others with chromosomal locations. What has lagged behind is the ability to integrate the resulting data to uncover complex relationships and patterns. Those issues are reflected in full form by molecular profile data on the panel of 60 diverse human cancer cell lines ( the NCI-60) used since 1990 by the U. S. National Cancer Institute to screen compounds for anticancer activity. To our knowledge, CellMiner is the first online database resource for integration of the diverse molecular types of NCI-60 and related meta data. Description: CellMiner enables scientists to perform advanced querying of molecular information on NCI-60 ( and additional types) through a single web interface. CellMiner is a freely available tool that organizes and stores raw and normalized data that represent multiple types of molecular characterizations at the DNA, RNA, protein, and pharmacological levels. Annotations for each project, along with associated metadata on the samples and datasets, are stored in a MySQL database and linked to the molecular profile data. Data can be queried and downloaded along with comprehensive information on experimental and analytic methods for each data set. A Data Intersection tool allows selection of a list of genes ( proteins) in common between two or more data sets and outputs the data for those genes ( proteins) in the respective sets. In addition to its role as an integrative resource for the NCI-60, the CellMiner package also serves as a shell for incorporation of molecular profile data on other cell or tissue sample types. Conclusion: CellMiner is a relational database tool for storing, querying, integrating, and downloading molecular profile data on the NCI-60 and other cancer cell types. More broadly, it provides a template to use in providing such functionality for other molecular profile data generated by academic institutions, public projects, or the private sector. CellMiner is available online at http://discover.nci.nih.gov/cellminer/. C1 [Kane, David; Sunshine, Margot] SRA Int, Fairfax, VA USA. [Chary, Krishna K.] US FDA, Off Informat Technol, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Shankavaram, Uma T.; Varma, Sudhir; Reinhold, William C.; Pommier, Yves; Weinstein, John N.] NCI, Genom & Bioinformat Grp, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Shankavaram, UT (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Uma.Shankavaram@nih.hhs.gov; varmas@mail.nih.gov; David_Kane@sra.com; Margot.Sunshine@hhs.nih.gov; Krishna.Chary@fda.hhs.gov; William.Reinhold@nih.hhs.gov; Yves.Pommier@nih.hhs.gov; jweinste@mdanderson.org RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 NR 25 TC 67 Z9 69 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 23 PY 2009 VL 10 AR 277 DI 10.1186/1471-2164-10-277 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 480RH UT WOS:000268754000001 PM 19549304 ER PT J AU Lee, DS Gona, P Vasan, RS Larson, MG Benjamin, EJ Wang, TJ Tu, JV Levy, D AF Lee, Douglas S. Gona, Philimon Vasan, Ramachandran S. Larson, Martin G. Benjamin, Emelia J. Wang, Thomas J. Tu, Jack V. Levy, Daniel TI Relation of Disease Pathogenesis and Risk Factors to Heart Failure With Preserved or Reduced Ejection Fraction Insights From the Framingham Heart Study of the National Heart, Lung, and Blood Institute SO CIRCULATION LA English DT Article DE coronary disease; epidemiology; heart diseases; heart failure; hypertension; mortality; ventricles ID VENTRICULAR SYSTOLIC FUNCTION; CLINICAL DETERMINANTS; QRS DURATION; MORTALITY; POPULATION; CARDIOMYOPATHY; DYSFUNCTION; PREVALENCE; SURVIVAL; SPECTRUM AB Background-The contributions of risk factors and disease pathogenesis to heart failure with preserved ejection fraction (HFPEF) versus heart failure with reduced ejection fraction (HFREF) have not been fully explored. Methods and Results-We examined clinical characteristics and risk factors at time of heart failure onset and long-term survival in Framingham Heart Study participants according to left ventricular ejection fraction <= 45% (n = 314; 59%) versus >45% (n = 220; 41%) and hierarchical causal classification. Heart failure was attributed to coronary heart disease in 278 participants (52%), valvular heart disease in 42 (8%), hypertension in 140 (26%), or other/unknown causes in 74 (14%). Multivariable predictors of HFPEF (versus HFREF) included elevated systolic blood pressure (odds ratio [OR] = 1.13 per 10 mm Hg; 95% confidence interval [CI], 1.04 to 1.22), atrial fibrillation (OR = 4.23; 95% CI, 2.38 to 7.52), and female sex (OR = 2.29; 95% CI, 1.35 to 3.90). Conversely, prior myocardial infarction (OR = 0.32; 95% CI, 0.19 to 0.53) and left bundle-branch block QRS morphology (OR = 0.21; 95% CI, 0.10 to 0.46) reduced the odds of HFPEF. Long-term prognosis was grim, with a median survival of 2.1 years (5-year mortality rate, 74%), and was equally poor in men and women with HFREF or HFPEF. Conclusions-Among community patients with new-onset heart failure, there are differences in causes and time-of-onset clinical characteristics between those with HFPEF versus HFREF. In people with HFREF, mortality is increased when coronary heart disease is the underlying cause. These findings suggest that heart failure with reduced left ventricular systolic function and heart failure with preserved left ventricular systolic function are partially distinct entities, with potentially different approaches to early detection and prevention. (Circulation. 2009; 119: 3070-3077.) C1 [Gona, Philimon; Vasan, Ramachandran S.; Larson, Martin G.; Benjamin, Emelia J.; Wang, Thomas J.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Lee, Douglas S.; Tu, Jack V.] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Lee, Douglas S.] Univ Toronto, Univ Hlth Network, Toronto, ON, Canada. [Gona, Philimon; Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Tu, Jack V.] Univ Toronto, Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nih.gov RI Lee, Douglas/J-4315-2014; OI Larson, Martin/0000-0002-9631-1254; Tu, Jack/0000-0003-0111-722X; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health [N01-HL-25195]; Canadian Institutes of Health Research Operating Grant [MOP 86718]; Team Grant; Canadian Institutes of Health Research clinician-scientist award; Canada Research Chair in Health Services Research; National Heart, Lung, and Blood Institute [2K24 H-04334] FX This study was supported by National Institutes of Health contract N01-HL-25195 to the Framingham Heart Study, a Canadian Institutes of Health Research Operating Grant (MOP 86718) and Team Grant in Cardiovascular Outcomes Research, a Canadian Institutes of Health Research clinician-scientist award (D. S. L.), and a Canada Research Chair in Health Services Research (J. V. T.). Dr Vasan was supported in part by 2K24 H-04334 (National Heart, Lung, and Blood Institute). NR 25 TC 231 Z9 237 U1 4 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 23 PY 2009 VL 119 IS 24 BP 3070 EP 3077 DI 10.1161/CIRCULATIONAHA.108.815944 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 461PI UT WOS:000267279900006 PM 19506115 ER PT J AU Sarin, H Kanevsky, AS Wu, HT Sousa, AA Wilson, CM Aronova, MA Griffiths, GL Leapman, RD Vo, HQ AF Sarin, Hemant Kanevsky, Ariel S. Wu, Haitao Sousa, Alioscka A. Wilson, Colin M. Aronova, Maria A. Griffiths, Gary L. Leapman, Richard D. Vo, Howard Q. TI Physiologic upper limit of pore size in the blood-tumor barrier of malignant solid tumors SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID FROG MESENTERIC CAPILLARIES; BRAIN-BARRIER; ENDOTHELIAL GLYCOCALYX; VASCULAR-PERMEABILITY; TRANSPORT; PATHWAYS; VESSELS; MICROENVIRONMENT; MACROMOLECULES; EXTRAVASATION AB Background: The existence of large pores in the blood-tumor barrier (BTB) of malignant solid tumor microvasculature makes the blood-tumor barrier more permeable to macromolecules than the endothelial barrier of most normal tissue microvasculature. The BTB of malignant solid tumors growing outside the brain, in peripheral tissues, is more permeable than that of similar tumors growing inside the brain. This has been previously attributed to the larger anatomic sizes of the pores within the BTB of peripheral tumors. Since in the physiological state in vivo a fibrous glycocalyx layer coats the pores of the BTB, it is possible that the effective physiologic pore size in the BTB of brain tumors and peripheral tumors is similar. If this were the case, then the higher permeability of the BTB of peripheral tumor would be attributable to the presence of a greater number of pores in the BTB of peripheral tumors. In this study, we probed in vivo the upper limit of pore size in the BTB of rodent malignant gliomas grown inside the brain, the orthotopic site, as well as outside the brain in temporalis skeletal muscle, the ectopic site. Methods: Generation 5 (G5) through generation 8 (G8) polyamidoamine dendrimers were labeled with gadolinium (Gd)-diethyltriaminepentaacetic acid, an anionic MRI contrast agent. The respective Gd-dendrimer generations were visualized in vitro by scanning transmission electron microscopy. Following intravenous infusion of the respective Gd-dendrimer generations (Gd-G5, N = 6; Gd-G6, N = 6; Gd-G7, N = 5; Gd-G8, N = 5) the blood and tumor tissue pharmacokinetics of the Gd-dendrimer generations were visualized in vivo over 600 to 700 minutes by dynamic contrast-enhanced MRI. One additional animal was imaged in each Gd-dendrimer generation group for 175 minutes under continuous anesthesia for the creation of voxel-by-voxel Gd concentration maps. Results: The estimated diameters of Gd-G7 dendrimers were 11 +/- 1 nm and those of Gd-G8 dendrimers were 13 +/- 1 nm. The BTB of ectopic RG-2 gliomas was more permeable than the BTB of orthotopic RG-2 gliomas to all Gd-dendrimer generations except for Gd-G8. The BTB of both ectopic RG-2 gliomas and orthotopic RG-2 gliomas was not permeable to Gd-G8 dendrimers. Conclusion: The physiologic upper limit of pore size in the BTB of malignant solid tumor microvasculature is approximately 12 nanometers. In the physiologic state in vivo the luminal fibrous glycocalyx of the BTB of malignant brain tumor and peripheral tumors is the primary impediment to the effective transvascular transport of particles across the BTB of malignant solid tumor microvasculature independent of tumor host site. The higher permeability of malignant peripheral tumor microvasculature to macromolecules smaller than approximately 12 nm in diameter is attributable to the presence of a greater number of pores underlying the glycocalyx of the BTB of malignant peripheral tumor microvasculature. C1 [Sarin, Hemant; Sousa, Alioscka A.; Aronova, Maria A.; Leapman, Richard D.; Vo, Howard Q.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. [Sarin, Hemant; Kanevsky, Ariel S.; Vo, Howard Q.] NIH, Radiol & Imaging Sci Program, Ctr Clin, Bethesda, MD 20892 USA. [Wu, Haitao; Wilson, Colin M.; Griffiths, Gary L.] NHLBI, Imaging Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. RP Sarin, H (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM sarinh@mail.nih.gov; kanevskya@mail.nih.gov; wuh3@mail.nih.gov; sousaali@mail.nih.gov; wilsoncm@mail.nih.gov; aronovaa@mail.nih.gov; griffithsgl@mail.nih.gov; leapmanr@mail.nih.gov; voho@mail.nih.gov NR 41 TC 61 Z9 62 U1 2 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 23 PY 2009 VL 7 AR 51 DI 10.1186/1479-5876-7-51 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 473KE UT WOS:000268204100002 PM 19549317 ER PT J AU Hu, X Li, XG Valverde, K Fu, XQ Noguchi, C Qiu, Y Huang, SM AF Hu, Xin Li, Xingguo Valverde, Kristell Fu, Xueqi Noguchi, Constance Qiu, Yi Huang, Suming TI LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE H3K4 methylation; histone demethylation; transcriptional regulation; erythroid differentiation; stem cell leukemia (SCL) ID T-CELL LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; LOOP-HELIX PROTEIN; GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVITY; HISTONE DEMETHYLASE; ERYTHROID-CELLS; STEM-CELLS; LIM DOMAIN; DIFFERENTIATION AB TAL1 is a critical transcription factor required for hematopoiesis. However, perturbation of its activity often leads to T cell leukemia. Whether and how its transcriptional activities are regulated during hematopoiesis remains to be addressed. Here, we show that TAL1 is associated with histone demethylase complexes containing lysine-specific demethylase 1 (LSD1), RE1 silencing transcription factor corepressor (CoREST), histone deacetylase 1 (HDAC1), and histone deacetylase 2 in erythroleukemia and T cell leukemia cells. The enzymatic domain of LSD1 plays an important role in repressing the TAL1-directed transcription of GAL4 reporter linked to a thymidine kniase minimal promoter. Furthermore, we demonstrate that the TAL1-associated LSD1, HDAC1, and their enzymatic activities are coordinately down-regulated during the early phases of erythroid differentiation. Consistent with the rapid changes of TAL1-corepressor complex during differentiation, TAL1 recruits LSD1 to the silenced p4.2 promoter in undifferentiated, but not in differentiated, murine erythroleukemia (MEL) cells. Finally, shRNA-mediated knockdown of LSD1 in MEL cells resulted in derepression of the TAL1 target gene accompanied by increasing dimeH3K4 at the promoter region. Thus, our data revealed that histone lysine demethylase LSD1 may negatively regulate TAL1-mediated transcription and suggest that the dynamic regulation of TAL1-associated LSD1/HDAC1 complex may determine the onset of erythroid differentiation programs. C1 [Hu, Xin; Li, Xingguo; Valverde, Kristell; Huang, Suming] Univ Florida, Dept Biochem & Mol Biol, Coll Med, Gainesville, FL 32610 USA. [Qiu, Yi] Univ Florida, Dept Anat & Cell Biol, Coll Med, Gainesville, FL 32610 USA. [Huang, Suming] Univ Florida, Genet Inst, Coll Med, Gainesville, FL 32610 USA. [Qiu, Yi; Huang, Suming] Univ Florida, Shands Canc Ctr, Coll Med, Gainesville, FL 32610 USA. [Hu, Xin; Fu, Xueqi] Jilin Univ, Coll Life Sci, Changchun 130023, Peoples R China. [Noguchi, Constance] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. RP Huang, SM (reprint author), Univ Florida, Dept Biochem & Mol Biol, Coll Med, Gainesville, FL 32610 USA. EM sumingh@ufl.edu FU National Institutes of Health [HL090589, HL091929]; Bankhead-Coley Cancer Research Program; Intramural Research Program; National Institute of Diabetes, Digestive and Kidney Diseases FX We thank Jorg Bungert (University of Florida, Gainesville), Yoshihiro Nakatani (Dana-Farber Cancer Institute, Boston), Yang Shi (Harvard Medical School, Boston), and Eric So (The Institute of Cancer Research, London) for reagents and Jorg Bungert and Lizi Wu for helpful suggestions and comments on the manuscript. This work was supported by National Institutes of Health Grants HL090589 and HL091929 (to S. H.) and grants from the Bankhead-Coley Cancer Research Program (to S. H. and Y. Q). C. N. is supported by the Intramural Research Program, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health. NR 37 TC 64 Z9 69 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 2009 VL 106 IS 25 BP 10141 EP 10146 DI 10.1073/pnas.0900437106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 461SQ UT WOS:000267292200016 PM 19497860 ER PT J AU Rohani, P Breban, R Stallknecht, DE Drake, JM AF Rohani, Pejman Breban, Romulus Stallknecht, David E. Drake, John M. TI Environmental transmission of low pathogenicity avian influenza viruses and its implications for pathogen invasion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stochastic model; mathematical model; demographic stochasticity; waterfowl; epidemic ID SENTINEL DUCKS; H5N1 OUTBREAKS; SURFACE-WATER; A VIRUSES; TURKEYS; EVOLUTION; EPIZOOTIOLOGY; CONTAMINATION; INFECTIVITY; PERSISTENCE AB Understanding the transmission dynamics and persistence of avian influenza viruses (AIVs) in the wild is an important scientific and public health challenge because this system represents both a reservoir for recombination and a source of novel, potentially human-pathogenic strains. The current paradigm locates all important transmission events on the nearly direct fecal/oral bird-to-bird-pathway. In this article, on the basis of overlooked evidence, we propose that an environmental virus reservoir gives rise to indirect transmission. This transmission mode could play an important epidemiological role. Using a stochastic model, we demonstrate how neglecting environmentally generated transmission chains could underestimate the explosiveness and duration of AIV epidemics. We show the important pathogen invasion implications of this phenomenon: the nonnegligible probability of outbreak even when direct transmission is absent, the long-term infectivity of locations of prior outbreaks, and the role of environmental heterogeneity in risk. C1 [Rohani, Pejman; Breban, Romulus; Drake, John M.] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Rohani, Pejman] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Breban, Romulus] Inst Pasteur, Unite Epidemiol Malad Emergentes, F-75724 Paris, France. [Stallknecht, David E.] Univ Georgia, SE Cooperat Wildlife Dis Study, Athens, GA 30602 USA. RP Rohani, P (reprint author), Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. EM rohani@uga.edu RI Drake, John/D-6622-2012; OI Drake, John/0000-0003-4646-1235 FU Centers for Disease Control and Prevention [5U19Cl000401]; James S. McDonnell Foundation; Department of Homeland Security; National Institutes of Health FX We thank Andrew Park, Benjamin Roche, Kristzian Magori, and three anonymous reviewers for helpful comments on this article. This work was supported by Centers for Disease Control and Prevention Grant 5U19Cl000401 and by the James S. McDonnell Foundation. P. R. was supported by the Research and Policy in Infectious Disease Dynamics program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 37 TC 107 Z9 107 U1 5 U2 41 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 2009 VL 106 IS 25 BP 10365 EP 10369 DI 10.1073/pnas.0809026106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 461SQ UT WOS:000267292200054 PM 19497868 ER PT J AU Inglese, J Thorne, N Auld, DS AF Inglese, James Thorne, Natasha Auld, Douglas S. TI Reply to Peltz et al: Post-translational stabilization of the firefly luciferase reporter by PTC124 (Ataluren) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Inglese, James; Thorne, Natasha; Auld, Douglas S.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), NIH, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov NR 6 TC 5 Z9 5 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 23 PY 2009 VL 106 IS 25 BP E65 EP E65 DI 10.1073/pnas.0905457106 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 461SQ UT WOS:000267292200061 ER PT J AU Bezrukov, SM Kish, LB AF Bezrukov, Sergey M. Kish, Laszlo B. TI Deterministic multivalued logic scheme for information processing and routing in the brain SO PHYSICS LETTERS A LA English DT Article ID SUPERPOSITION; STATES; CODE AB Driven by analogies with state vectors of quantum informatics and noise-based logic, we propose a general scheme and elements of neural circuitry for processing and addressing information in the brain. Specifically, we consider random (e.g., Poissonian) trains of finite-duration spikes, and, using the idealized concepts of excitatory and inhibitory synapses, offer a procedure for generating 2(N) - 1 orthogonal vectors out of N partially overlapping trains ("neuro-bits"). We then show that these vectors can be used to construct 2(2N-1) - 1 different superpositions which represent the same number of logic values when carrying or routing information. In quantum informatics the above numbers are the same, however, the present logic scheme is more advantageous because it is deterministic in the sense that the presence of a vector in the spike train is detected by an appropriate coincidence circuit. For this reason it does not require time averaging or repeated measurements of the kind used in standard cross-correlation analysis or in quantum computing. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kish, Laszlo B.] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA. [Bezrukov, Sergey M.] NICHD, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Kish, LB (reprint author), Texas A&M Univ, Dept Elect & Comp Engn, Mailstop 3128, College Stn, TX 77843 USA. EM laszlo.kish@ece.tamu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; TAMU subcontract of the Army Research Office [W911 NF-08-C-0031] FX S.M.B. is indebted to Adrian Parsegian for fruitful suggestions and reading parts of the manuscript; L.B.K. appreciates discussions with Sunil Khatri, Mark Dykman, Ferdinand Peper, Swaminathan Sethuraman and Suhail Zubairy. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. S.M.B.'s visit of Texas A&M University (January 2009) and L.B.K.'s visit of NIH (November 2008) was partly supported by a TAMU subcontract of the Army Research Office grant under contract W911 NF-08-C-0031. L.B.K.'s visit was also supported by a TAMU travel grant for sabbatical leave. NR 11 TC 20 Z9 20 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0375-9601 J9 PHYS LETT A JI Phys. Lett. A PD JUN 22 PY 2009 VL 373 IS 27-28 BP 2338 EP 2342 DI 10.1016/j.physleta.2009.04.073 PG 5 WC Physics, Multidisciplinary SC Physics GA 462JQ UT WOS:000267348900006 ER PT J AU Aggarwal, P Hall, JB McLeland, CB Dobrovolskaia, MA McNeil, SE AF Aggarwal, Parag Hall, Jennifer B. McLeland, Christopher B. Dobrovolskaia, Marina A. McNeil, Scott E. TI Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE Nanoparticles; Protein binding; Immunology; Biodistribution; Biocompatibility ID SOLID-LIPID-NANOPARTICLES; HUMAN SERUM-ALBUMIN; POLY(D,L-LACTIC ACID) NANOPARTICLES; BLOOD-BRAIN-BARRIER; PERFUSED-RAT-LIVER; EQUILIBRIUM DIALYSIS; ADSORPTION PATTERNS; POLYMERIC NANOPARTICLES; COLLOIDAL CARRIERS; ENDOTHELIAL-CELLS AB Proteins bind the surfaces of nanoparticles, and biological materials in general, immediately upon introduction of the materials into a physiological environment. The further biological response of the body is influenced by the nanoparticle-protein complex. The nanoparticle's composition and surface chemistry dictate the extent and specificity of protein binding. Protein binding is one of the key elements that affects biodistribution of the nanoparticles throughout the body. Here we review recent research on nanoparticle physicochemical properties important for protein binding, techniques for isolation and identification of nanoparticle-bound proteins, and how these proteins can influence particle biodistribution and biocompatibility. Understanding the nanoparticle-protein complex is necessary for control and manipulation of protein binding. and allows for improved engineering of nanoparticles with favorable bioavailability and biodistribution. (C) 2009 Elsevier B.V. All rights reserved. C1 [Aggarwal, Parag; Hall, Jennifer B.; McLeland, Christopher B.; Dobrovolskaia, Marina A.; McNeil, Scott E.] NCI Frederick, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. RP Dobrovolskaia, MA (reprint author), NCI Frederick, SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM marina@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute, National Institutes of Health [N01 -CO-12400] FX We are grateful to Allen Kane for assistance with illustrations. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01 -CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 132 TC 647 Z9 654 U1 40 U2 301 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD JUN 21 PY 2009 VL 61 IS 6 BP 428 EP 437 DI 10.1016/j.addr.2009.03.009 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 464AN UT WOS:000267476600003 PM 19376175 ER PT J AU Dowsett, M Procter, M McCaskill-Stevens, W de Azambuja, E Dafni, U Rueschoff, J Jordan, B Dolci, S Abramovitz, M Stoss, O Viale, G Gelber, RD Piccart-Gebhart, M Leyland-Jones, B AF Dowsett, Mitch Procter, Marion McCaskill-Stevens, Worta de Azambuja, Evandro Dafni, Urania Rueschoff, Josef Jordan, Bruce Dolci, Stella Abramovitz, Mark Stoss, Oliver Viale, Giuseppe Gelber, Richard D. Piccart-Gebhart, Martine Leyland-Jones, Brian TI Disease-Free Survival According to Degree of HER2 Amplification for Patients Treated With Adjuvant Chemotherapy With or Without 1 Year of Trastuzumab: The HERA Trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 30th Annual San Antonio Breast Cancer Symposium CY DEC 13-16, 2007 CL San Antonio, TX SP San Antonio Canc Inst, Baylor Coll Med ID HER2-POSITIVE BREAST-CANCER; GENE; HER-2/NEU; ONCOGENE AB Purpose To determine whether (1) immunohistochemical (IHC) HER2 status (ie, 2+ or 3+), (2) degree of fluorescence in situ hybridization (FISH) amplification according to (2a) HER2/CEP17 ratio or (2b) HER2 gene copy number, or (3) polysomy significantly influenced clinical outcome for patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer enrolled in the Herceptin Adjuvant trial of trastuzumab versus no trastuzumab administered after completion of chemotherapy. Patients and Methods IHC and/or FISH analyses were performed locally and required central confirmation as indicating HER2 positivity for trial entry. FISH data from the central HER2 analysis on patients in the 1-year trastuzumab and no trastuzumab arms were assessed in relation to disease-free survival (DFS) after a median 2 years of follow-up. Results Central FISH results were available for 2,071 (61%) of the 3,401 patients randomized to the 2 arms. Among patients with FISH-positive disease, (1) the hazard ratios for trastuzumab versus no trastuzumab were 0.56 (95% CI, 0.32 to 0.99) for locally IHC2+ cases (n = 340) and 0.80 (95% CI, 0.40 to 1.61) for centrally IHC2+ cases (n = 299). There was no significant prognostic relationship between (2a) HER2 FISH ratio, (2b) HER2 copy number, or (3) polysomy and DFS in the control arm or predictive relationship defining differential benefit from trastuzumab. Conclusion There was no evidence for reduced benefit of trastuzumab in HER2 IHC2+ FISH+ cases. The degree of HER2 amplification does not influence prognosis or benefit from adjuvant trastuzumab in patients treated with prior adjuvant chemotherapy. J Clin Oncol 27: 2962-2969. (C) 2009 by American Society of Clinical Oncology C1 [Dowsett, Mitch] Royal Marsden Hosp, Dept Acad Biochem, London SW3 6JJ, England. Frontier Sci Scotland Ltd, Kincraig, Kingussie, Scotland. NCI, NIH, Bethesda, MD 20892 USA. Univ Libre Bruxelles, Inst Jules Bordet, Dept Med Oncol, Brussels, Belgium. Univ Libre Bruxelles, Inst Jules Bordet, Dept Med, Brussels, Belgium. Breast European Adjuvant Studies Team, Brussels, Belgium. Univ Athens, Sch Nursing, Dept Publ Hlth, Athens, Greece. TARGOS Mol Pathol GmbH, Kassel, Germany. F Hoffmann La Roche Ltd, Roche Profess Diagnost, Basel, Switzerland. VM Inst Res, Montreal, PQ, Canada. European Inst Oncol, Div Pathol & Lab Med, Milan, Italy. Univ Milan, Milan, Italy. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Emory Winship Canc Inst, Atlanta, GA USA. RP Dowsett, M (reprint author), Royal Marsden Hosp, Dept Acad Biochem, Fulham Rd, London SW3 6JJ, England. EM mitch.dowsett@icr.ac.uk NR 25 TC 106 Z9 111 U1 1 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 2962 EP 2969 DI 10.1200/JCO.2008.19.7939 PG 8 WC Oncology SC Oncology GA 459TP UT WOS:000267133300015 PM 19364966 ER PT J AU Kreitman, RJ Stetler-Stevenson, M Margulies, I Noel, P FitzGerald, DJP Wilson, WH Pastan, I AF Kreitman, Robert J. Stetler-Stevenson, Maryalice Margulies, Inger Noel, Pierre FitzGerald, David J. P. Wilson, Wyndham H. Pastan, Ira TI Phase II Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With Hairy Cell Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TERM-FOLLOW-UP; CYTOTOXIC ACTIVITY; CLADRIBINE; RITUXIMAB; 2-CHLORODEOXYADENOSINE; IDENTIFICATION; ANTIBODIES; EFFICACY; DISEASE AB Purpose To conduct a phase II trial in chemoresistant hairy cell leukemia (HCL) with BL22, a recombinant anti-CD22 immunotoxin which showed phase I activity in HCL. Patients and Methods Eligible patients had relapsed/refractory HCL and needed treatment based on blood counts. Patients were stratified into three groups: response to cladribine less than 1 year, those with a response lasting 1 to 4 years, or no response and uncontrolled infection. Patients received BL22 40 mu g/kg every other day for three doses on cycle 1. Those achieving hematologic remission (HR), defined as neutrophils >= 1,500/mm(3), hemoglobin >= 11 g/dL, and platelets >= 100,000/mm(3), were observed. Patients without HR were re-treated at 30 mu g/kg every other day for three doses every 4 weeks beginning at least 8 weeks after cycle 1. Results Thirty-six patients were enrolled including 26, nine, and one in groups 1 to 3. The response after one cycle (CR, 25%; PR, 25%) improved when 56% were re-treated (CR, 47%; PR, 25%). CR rate was similar in groups 1 and 2 (P = .7). Twenty-two with baseline spleen height lower than 200 mm had higher CR (64% v 21%; P = .019) and OR rates (95% v 36%; P = .0002) compared to 14 with spleens either absent or higher than 200 mm. The only serious toxicity was reversible grade 3 hemolytic uremic syndrome, not requiring plasmapheresis, in two patients (6%). High neutralizing antibodies were observed in four patients (11%) and prevented re-treatment. Conclusion BL22 activity in HCL is confirmed. Best responses to BL22 after cladribine failure are achieved before the patients develop massive splenomegaly or undergo splenectomy. C1 [Kreitman, Robert J.] NCI, Mol Biol Lab, Clin Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, Clin Pathol Lab, NIH, 9000 Rockville Pk,Bldg 37-5124B, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU Intramural Research Program; National Institutes of Health; National Cancer Institute; and MedImmune Inc FX Supported by the Intramural Research Program, National Institutes of Health, National Cancer Institute; and MedImmune Inc. NR 26 TC 114 Z9 116 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 2983 EP 2990 DI 10.1200/JCO.2008.20.2630 PG 8 WC Oncology SC Oncology GA 459TP UT WOS:000267133300018 PM 19414673 ER PT J AU Willett, CG Duda, DG di Tomaso, E Boucher, Y Ancukiewicz, M Sahani, DV Lahdenranta, J Chung, DC Fischman, AJ Lauwers, GY Shellito, P Czito, BG Wong, TZ Paulson, E Poleski, M Vujaskovic, Z Bentley, R Chen, HX Clark, JW Jain, RK AF Willett, Christopher G. Duda, Dan G. di Tomaso, Emmanuelle Boucher, Yves Ancukiewicz, Marek Sahani, Dushyant V. Lahdenranta, Johanna Chung, Daniel C. Fischman, Alan J. Lauwers, Gregory Y. Shellito, Paul Czito, Brian G. Wong, Terence Z. Paulson, Erik Poleski, Martin Vujaskovic, Zeljko Bentley, Rex Chen, Helen X. Clark, Jeffrey W. Jain, Rakesh K. TI Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID VASCULAR ENDOTHELIAL GROWTH; TYROSINE KINASE INHIBITOR; METASTATIC COLORECTAL-CANCER; ANTIANGIOGENIC THERAPY; TUMOR VASCULATURE; FACTOR RECEPTOR; CHEMORADIOTHERAPY; CHEMOTHERAPY; CARCINOMA; MARKERS AB Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. Conclusion Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen. J Clin Oncol 27: 3020-3026. (C) 2009 by American Society of Clinical Oncology C1 [Willett, Christopher G.] Duke Univ, Med Ctr, Dept Radiat Oncol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Nucl Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Willett, CG (reprint author), Duke Univ, Med Ctr, Dept Radiat Oncol, Box 3085, Durham, NC 27710 USA. EM christopher.willett@duke.edu FU National Institutes of Health [R21CA099237, P01CA80124, R01CA115767]; National Foundation for Cancer Research FX Supported by the Grants No. R21CA099237 (C. G. W.), P01CA80124, and R01CA115767 from the National Institutes of Health, and a grant from the National Foundation for Cancer Research (R. K. J.). NR 18 TC 274 Z9 284 U1 4 U2 18 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 3020 EP 3026 DI 10.1200/JCO.2008.21.1771 PG 7 WC Oncology SC Oncology GA 459TP UT WOS:000267133300023 PM 19470921 ER PT J AU Chaturvedi, AK Kleinerman, RA Hildesheim, A Gilbert, ES Storm, H Lynch, CF Hall, P Langmark, F Pukkala, E Kaijser, M Andersson, M Fossa, SD Joensuu, H Travis, LB Engels, EA AF Chaturvedi, Anil K. Kleinerman, Ruth A. Hildesheim, Allan Gilbert, Ethel S. Storm, Hans Lynch, Charles F. Hall, Per Langmark, Froydis Pukkala, Eero Kaijser, Magnus Andersson, Michael Fossa, Sophie D. Joensuu, Heikki Travis, Lois B. Engels, Eric A. TI Nonsmoking: A Surrogate Factor in Primary Lung Cancer in Survivors of Cervical Adenocarcinoma? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ORAL-CONTRACEPTIVES; CARCINOMA; WOMEN; RISK C1 [Chaturvedi, Anil K.; Kleinerman, Ruth A.; Hildesheim, Allan; Gilbert, Ethel S.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Storm, Hans; Andersson, Michael] Danish Canc Soc, Copenhagen, Denmark. [Lynch, Charles F.] Univ Iowa, Iowa City, IA USA. [Hall, Per; Kaijser, Magnus] Karolinska Inst, Stockholm, Sweden. [Langmark, Froydis; Fossa, Sophie D.] Canc Registry Norway, Oslo, Norway. [Pukkala, Eero] Finnish Canc Registry, FIN-00170 Helsinki, Finland. [Joensuu, Heikki] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Travis, Lois B.] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. RP Chaturvedi, AK (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 BP 3066 EP 3067 DI 10.1200/JCO.2009.22.5706 PG 3 WC Oncology SC Oncology GA 459TP UT WOS:000267133300034 ER PT J AU Cheng, S Dietrich, M Finnigan, S Sandler, A Crites, J Ferranti, L Wu, A Dilts, D AF Cheng, S. Dietrich, M. Finnigan, S. Sandler, A. Crites, J. Ferranti, L. Wu, A. Dilts, D. TI A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of CTEP-sponsored studies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Vanderbilt Univ, Med Ctr, Nashville, TN USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000030 ER PT J AU Croswell, JM Baker, SG Marcus, PM Clapp, JD Kramer, BS AF Croswell, J. M. Baker, S. G. Marcus, P. M. Clapp, J. D. Kramer, B. S. TI Cumulative risk for a false-positive test using low-dose computed tomography in lung cancer screening SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Natl Inst Hlth, Bethesda, MD USA. NCI, Bethesda, MD 20892 USA. IMS Inc, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000023 ER PT J AU Schuster, SJ Neelapu, SS Gause, BL Muggia, FM Gockerman, JP Sotomayor, EM Winter, JN Flowers, CR Stergiou, AM Kwak, LW AF Schuster, S. J. Neelapu, S. S. Gause, B. L. Muggia, F. M. Gockerman, J. P. Sotomayor, E. M. Winter, J. N. Flowers, C. R. Stergiou, A. M. Kwak, L. W. CA BiovaxID Phase III Study Investiga TI Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. NYU, Med Ctr, New York, NY 10016 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. Northwestern Univ, Chicago, IL 60611 USA. Emory Univ, Atlanta, GA 30322 USA. Biovest Int, New York, NY USA. RI Flowers, Christopher/F-1953-2010 OI Flowers, Christopher/0000-0002-9524-3990 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000008 ER PT J AU Wolmark, N Yothers, G O'Connell, MJ Sharif, S Atkins, JN Seay, TE Feherenbacher, L O'Reilly, S Allegra, CJ AF Wolmark, N. Yothers, G. O'Connell, M. J. Sharif, S. Atkins, J. N. Seay, T. E. Feherenbacher, L. O'Reilly, S. Allegra, C. J. TI A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Meeting Abstract CT 45th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 29-JUN 02, 2009 CL Orlando, FL SP Amer Soc Clin Oncol C1 Univ Florida, Gainesville, FL USA. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. SE Canc Control Consortium CCOP, Goldsboro, NC USA. Atlanta Canc Care, Atlanta, GA USA. Kaiser Permanente No Calif, Vallejo, CA USA. All Ireland Cooperat Oncol Res Grp, Dublin, Ireland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 20 PY 2009 VL 27 IS 18 SU S PG 2 WC Oncology SC Oncology GA 582OJ UT WOS:000276607000016 ER PT J AU Reynolds, SJ Quinn, TC Gray, RH Serwadda, D AF Reynolds, Steven J. Quinn, Thomas C. Gray, Ronald H. Serwadda, David TI Response to Castelnuovo et al. regarding our article 'Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda' SO AIDS LA English DT Letter C1 [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Gray, Ronald H.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Reynolds, SJ (reprint author), NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 19 PY 2009 VL 23 IS 10 BP 1296 EP 1296 DI 10.1097/QAD.0b013e32832cbd59 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 461PH UT WOS:000267279800017 ER PT J AU Fu, ZM Wang, MY Gucek, M Zhang, J Wu, J Jiang, LQ Monticone, RE Khazan, B Telljohann, R Mattison, J Sheng, SM Cole, RN Spinetti, G Pintus, G Liu, LJ Kolodgie, FD Virmani, R Spurgeon, H Ingram, DK Everett, AD Lakatta, EG Van Eyk, JE AF Fu, Zongming Wang, Mingyi Gucek, Marjan Zhang, Jing Wu, James Jiang, Liqun Monticone, Robert E. Khazan, Benjamin Telljohann, Richard Mattison, Julie Sheng, Simon Cole, Robert N. Spinetti, Gaia Pintus, Gianfranco Liu, Lijuan Kolodgie, Frank D. Virmani, Renu Spurgeon, Harold Ingram, Donald K. Everett, Allen D. Lakatta, Edward G. Van Eyk, Jennifer E. TI Milk Fat Globule Protein Epidermal Growth Factor-8 A Pivotal Relay Element Within the Angiotensin II and Monocyte Chemoattractant Protein-1 Signaling Cascade Mediating Vascular Smooth Muscle Cells Invasion SO CIRCULATION RESEARCH LA English DT Article DE MFG-E8; angiotensin II; monocyte chemoattractant protein-1; vascular smooth muscle cells; aging ID CARDIOVASCULAR-DISEASE ENTERPRISES; CYSTEINE-RICH PROTEIN-2; TRANSGENIC MOUSE MODEL; STE20-LIKE KINASE SLK; AGE-RELATED-CHANGES; NF-KAPPA-B; GENE-EXPRESSION; AGING PROCESS; TGF-BETA; CORONARY ATHEROSCLEROSIS AB Advancing age induces aortic wall thickening that results from the concerted effects of numerous signaling proteins, many of which have yet to be identified. To search for novel proteins associated with aortic wall thickening, we have performed a comprehensive quantitative proteomic study to analyze aortic proteins from young (8 months) and old (30 months) rats and identified 50 proteins that significantly change in abundance with aging. One novel protein, the milk fat globule protein epidermal growth factor 8 (MFG-E8), increases 2.3-fold in abundance in old aorta. Transcription and translation analysis demonstrated that aortic MFG-E8 mRNA and protein levels increase with aging in several mammalian species including humans. Dual immunolabeling shows that MFG-E8 colocalizes with both angiotensin II and monocyte chemoattractant protein (MCP)-1 within vascular smooth muscle cells (VSMCs) of the thickened aged aortic wall. Exposure of early passage VSMCs from young aorta to angiotensin II markedly increases MFG-E8 and enhances invasive capacity to levels observed in VSMCs from old rats. Treatment of VSMCs with MFG-E8 increases MCP-1 expression and VSMCs invasion that are inhibited by the MCP-1 receptor blocker vCCI. Silencing MFG-E8 RNA substantially reduces MFG-E8 expression and VSMCs invasion capacity. The data indicate that arterial MFG-E8 significantly increases with aging and is a pivotal relay element within the angiotensin II/MCP-1/VSMC invasion signaling cascade. Thus, targeting of MFG-E8 within this signaling axis pathway is a potential novel therapy for the prevention and treatment of the age-associated vascular diseases such as atherosclerosis. (Circ Res. 2009; 104: 1337-1346.) C1 [Fu, Zongming; Sheng, Simon; Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Liu, Lijuan] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Everett, Allen D.] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD USA. [Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD USA. [Wang, Mingyi; Jiang, Liqun; Monticone, Robert E.; Khazan, Benjamin; Telljohann, Richard; Spurgeon, Harold; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Mattison, Julie] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Zhang, Jing; Wu, James] Medstar Res Inst, Hyattsville, MD USA. [Spinetti, Gaia] IRCCS MultiMed, Milan, Italy. [Pintus, Gianfranco] Univ Sassari, Dept Biomed Sci, I-07100 Sassari, Italy. [Kolodgie, Frank D.; Virmani, Renu] Int Registry Pathol, CVPath, Gaithersburg, MD USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA USA. [Gucek, Marjan; Cole, Robert N.; Van Eyk, Jennifer E.] Johns Hopkins Univ, Johns Hopkins Bayview Prote Ctr, Baltimore, MD USA. RP Wang, MY (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM mingyiw@grc.nia.nih.gov OI Spinetti, Gaia/0000-0001-7996-6809 FU Intramural Research Program of the National Institute on Aging, NIH; National Heart, Lung and Blood Institute Proteomic Initiative [HV28120] FX This research was supported by the Intramural Research Program of the National Institute on Aging, NIH; and the National Heart, Lung and Blood Institute Proteomic Initiative (contract no. HV28120). NR 136 TC 31 Z9 33 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD JUN 19 PY 2009 VL 104 IS 12 BP 1337 EP 1346 DI 10.1161/CIRCRESAHA.108.187088 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 459WL UT WOS:000267143200004 PM 19443842 ER PT J AU Ozato, K AF Ozato, Keiko TI PLZF Outreach: A Finger in Interferon's Pie SO IMMUNITY LA English DT Editorial Material ID REPRESSION; PROTEIN AB In this issue of Immunity, Xu et al. (2009) find that the transcription factor PLZF activates interferon-stimulated genes and facilitates natural killer cell functions. Interferon-induced PLZF phosphorylation and histone deacetylase 1 recruitment probably mediates the repressor-to-activator conversion. C1 NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural NIH HHS [Z01 HD001310-21] NR 9 TC 6 Z9 6 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 19 PY 2009 VL 30 IS 6 BP 757 EP 758 DI 10.1016/j.immuni.2009.06.003 PG 2 WC Immunology SC Immunology GA 461MI UT WOS:000267270700002 PM 19538924 ER PT J AU Meng, GX Zhang, FP Fuss, I Kitani, A Strober, W AF Meng, Guangxun Zhang, Fuping Fuss, Ivan Kitani, Atsushi Strober, Warren TI A Mutation in the Nlrp3 Gene Causing Inflammasome Hyperactivation Potentiates Th17 Cell-Dominant Immune Responses SO IMMUNITY LA English DT Article ID IL-17-PRODUCING T-CELLS; NEUTROPHIL RECRUITMENT; CIAS1 MUTATIONS; INTERLEUKIN-1-BETA SECRETION; CASPASE-1 INFLAMMASOME; RHEUMATOID-ARTHRITIS; NALP3 INFLAMMASOME; CYTOKINE MILIEU; T(H)17 CELLS; TGF-BETA AB Missense mutations of the gene encoding NLRP3 are associated with autoinflammatory disorders characterized with excessive production of interleukin-1 beta (IL-1 beta). Here we analyzed the immune responses of gene-targeted mice carrying a mutation in the Nlrp3 gene equivalent to the human mutation associated with Muckle-Wells Syndrome. We found that antigen-presenting cells (APCs) from such mice produced massive amounts of IL-1 beta upon stimulation with microbial stimuli in the absence of ATP. This was likely due to a diminished inflammasome activation threshold that allowed a response to the small amount of agonist. Moreover, the Nlrp3 gene-targeted mice exhibited skin inflammation characterized by neutrophil infiltration and a Th17 cytokine-dominant response, which originated from hematopoietic cells. The inflammation of Nlrp3 gene-targeted mice resulted from excess IL-1 beta production from APCs, which augmented Th17 cell differentitation. These results demonstrate that the NLRP3 mutation leads to inflammasome hyperactivation and consequently Th17 cell-dominant immunopathology in autoinflammation. C1 [Meng, Guangxun; Zhang, Fuping; Fuss, Ivan; Kitani, Atsushi; Strober, Warren] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bldg 10-CRC,Room 5W3890,10 Ctr Dr, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov OI 孟, 广勋/0000-0002-4253-9675 FU Intramural NIH HHS [NIH0011985623]; PHS HHS [NIH0011985623] NR 49 TC 158 Z9 162 U1 2 U2 16 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 19 PY 2009 VL 30 IS 6 BP 860 EP 874 DI 10.1016/j.immuni.2009.04.012 PG 15 WC Immunology SC Immunology GA 461MI UT WOS:000267270700013 PM 19501001 ER PT J AU Brydges, SD Mueller, JL McGeough, MD Pena, CA Misaghi, A Gandhi, C Putnam, CD Boyle, DL Firestein, GS Horner, AA Soroosh, P Watford, WT O'Shea, JJ Kastner, DL Hoffman, HM AF Brydges, Susannah D. Mueller, James L. McGeough, Matthew D. Pena, Carla A. Misaghi, Amirhossein Gandhi, Chhavi Putnam, Chris D. Boyle, David L. Firestein, Gary S. Horner, Anthony A. Soroosh, Pejman Watford, Wendy T. O'Shea, John J. Kastner, Daniel L. Hoffman, Hal M. TI Inflammasome-Mediated Disease Animal Models Reveal Roles for Innate but Not Adaptive Immunity SO IMMUNITY LA English DT Article ID COLD AUTOINFLAMMATORY SYNDROME; INTERLEUKIN-1 RECEPTOR ANTAGONIST; MUCKLE-WELLS-SYNDROME; CIAS1 MUTATIONS; NALP3 INFLAMMASOME; ACTIVATION; MICE; CELL; PROTEIN; PYRIN AB NLRP3 nucleates the inflammasome, a protein complex responsible for cleavage of prointerleukin-1 beta (IL-1 beta) to its active form. Mutations in the NLRP3 gene cause the autoinflammatory disease spectrum cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1 beta in CAPS is supported by the response to IL-1-targeted therapy. We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various gene mutant backgrounds showed that the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1 beta, and was independent of T cells. These data suggest that CAPS are true inflammasome-mediated diseases and provide insight for more common inflammatory disorders. C1 [Brydges, Susannah D.; Gandhi, Chhavi; Boyle, David L.; Firestein, Gary S.; Horner, Anthony A.; Hoffman, Hal M.] Univ Calif San Diego, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA. [Mueller, James L.; McGeough, Matthew D.; Pena, Carla A.; Hoffman, Hal M.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. [Misaghi, Amirhossein; Putnam, Chris D.; Firestein, Gary S.; Horner, Anthony A.; Hoffman, Hal M.] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Watford, Wendy T.; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Brydges, Susannah D.; Kastner, Daniel L.] NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. [Mueller, James L.; Putnam, Chris D.; Hoffman, Hal M.] Ludwig Inst Canc Res, San Diego Branch, La Jolla, CA 92093 USA. [Soroosh, Pejman] La Jolla Inst Allergy & Immunol, Div Mol Immunol, La Jolla, CA 92037 USA. RP Hoffman, HM (reprint author), Univ Calif San Diego, Div Rheumatol Allergy & Immunol, La Jolla, CA 92093 USA. EM hahoffman@ucsd.edu FU NIH [R01-AI52430]; NIAMS; Regeneron and Novartis Pharmaceuticals FX The authors would like to thank R. Goldbach-Mansky for providing blood samples from CAPS patients, J. Hillman for luminex analysis, N. Ng and S. Lee for FACS analysis, and J.Y. Cho and S. Aceves for immunohistochemistry support. We also appreciate helpful advice from D. Cleveland, A. Silk, M. McAlonis-Downes, R. Kolodner, A. Laurence, M. Croft, T. Doherty, and D. Broide. The UCSD Cancer Center mouse transgenic and embryonic stem cell core (E. Kothari) and histology core (N. Varki) provided support, and the Ludwig Institute of Cancer Research San Diego branch provided DNA sequencing support. This work was funded by NIH R01-AI52430 and NIAMS. H.M.H. has received consultant fees from Regeneron and Novartis Pharmaceuticals. NR 45 TC 121 Z9 122 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 19 PY 2009 VL 30 IS 6 BP 875 EP 887 DI 10.1016/j.immuni.2009.05.005 PG 13 WC Immunology SC Immunology GA 461MI UT WOS:000267270700014 PM 19501000 ER PT J AU Araki, Y Wang, ZB Zang, CZ Wood, WH Schones, D Cui, KR Roh, TY Lhotsky, B Wersto, RP Peng, WQ Becker, KG Zhao, K Weng, NP AF Araki, Yasuto Wang, Zhibin Zang, Chongzhi Wood, William H., III Schones, Dustin Cui, Kairong Roh, Tae-Young Lhotsky, Brad Wersto, Robert P. Peng, Weiqun Becker, Kevin G. Zhao, Keji Weng, Nan-ping TI Genome-wide Analysis of Histone Methylation Reveals Chromatin State-Based Regulation of Gene Transcription and Function of Memory CD8(+) T Cells SO IMMUNITY LA English DT Article ID IFN-GAMMA LOCI; CUTTING EDGE; EXPRESSION; EFFECTOR; ACETYLATION; PROTEIN; DIFFERENTIATION; EOMESODERMIN; RECRUITMENT; HOMEOSTASIS AB Memory lymphocytes are characterized by their ability to exhibit a rapid response to the recall antigen, in which differential transcription is important, yet the underlying mechanism is not understood. We report here a genome-wide analysis of histone methylation on two histone H3 lysine residues (H3K4me3 and H3K27me3) and gene expression profiles in naive and memory CD8(+) T cells. We found that specific correlation exists between gene expression and the amounts of H3K4me3 (positive correlation) and H3K27me3 (negative correlation) across the gene body. These correlations displayed four distinct modes (repressive, active, poised, and bivalent), reflecting different functions of these genes in CD8(+) T cells. Furthermore, a permissive chromatin state of each gene was established by a combination of different histone modifications. Our findings reveal a complex regulation by histone methylation in differential gene expression and suggest that histone methylation may be responsible for memory CD8(+) T cell function. C1 [Wang, Zhibin; Schones, Dustin; Cui, Kairong; Roh, Tae-Young; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Araki, Yasuto; Weng, Nan-ping] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. [Wood, William H., III; Becker, Kevin G.] NIA, DNA Array Unit, NIH, Baltimore, MD 21224 USA. [Lhotsky, Brad] NIA, IT Sect, NIH, Baltimore, MD 21224 USA. [Wersto, Robert P.] NIA, Flow Cytometry Unit, NIH, Baltimore, MD 21224 USA. [Zang, Chongzhi; Peng, Weiqun] George Washington Univ, Dept Phys, Washington, DC 20052 USA. RP Zhao, K (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhaok@mail.nih.gov; wengn@mail.nih.gov RI Zang, Chongzhi/D-1445-2011; OI Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging and National Heart, Lung, and Blood Institute; National Institutes of Health (NIH) FX We thank R. Hodes and M. Pazin for critical reading the manuscript. We thank C. Nguyen of the Flow Cytometry Unit for cell sort, A. Sharov of Laboratory of Genetics for helping the microarray analysis, and the NIA Apheresis Unit for collecting blood samples. This research was supported by the Intramural Research Programs of the National Institute on Aging and National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). NR 49 TC 116 Z9 118 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN 19 PY 2009 VL 30 IS 6 BP 912 EP 925 DI 10.1016/j.immuni.2009.05.006 PG 14 WC Immunology SC Immunology GA 461MI UT WOS:000267270700017 PM 19523850 ER PT J AU Turu, G Varnai, P Gyombolai, P Szidonya, L Bagdy, G Kunos, G Hunyady, L AF Turu, Gabor Varnai, Peter Gyombolai, Pal Szidonya, Laszlo Bagdy, Gyoergy Kunos, George Hunyady, Laszlo TI Paracrine Transactivation of the CB1 Cannabinoid Receptor by AT(1) Angiotensin and Other G(q/11) Protein-coupled Receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-ARRESTIN BINDING; ENDOGENOUS CANNABINOIDS; ENDOCANNABINOID SYSTEM; SIGNALING PATHWAYS; ACTIVATION; PHARMACOLOGY; BRAIN; CELL; 2-ARACHIDONOYLGLYCEROL; PHOSPHORYLATION AB Intracellular signaling systems of G protein-coupled receptors are well established, but their role in paracrine regulation of adjacent cells is generally considered as a tissue-specific mechanism. We have shown previously that AT(1) receptor (AT(1)R) stimulation leads to diacylglycerol lipase-mediated transactivation of co-expressed CB(1)Rs in Chinese hamster ovary cells. In the present study we detected a paracrine effect of the endocannabinoid release from Chinese hamster ovary, COS7, and HEK293 cells during the stimulation of AT(1) angiotensin receptors by determining CB1 cannabinoid receptor activity with bioluminescence resonance energy transfer-based sensors of G protein activation expressed in separate cells. The angiotensin II-induced, paracrine activation of CB1 receptors was visualized by detecting translocation of green fluorescent protein-tagged beta-arrestin2. Mass spectrometry analyses have demonstrated angiotensin II-induced stimulation of 2-arachidonoylglycerol production, whereas no increase of anandamide levels was observed. Stimulation of G(q/11)-coupled M-1, M-3, M-5 muscarinic, V1 vasopressin, alpha(1a) adrenergic, B2 bradykinin receptors, but not G(i/o)-coupled M-2 and M-4 muscarinic receptors, also led to paracrine transactivation of CB1 receptors. These data suggest that, in addition to their retrograde neurotransmitter role, endocannabinoids have much broader paracrine mediator functions during activation of G(q/11)-coupled receptors. C1 [Hunyady, Laszlo] Semmelweis Univ, Dept Physiol, Fac Med, H-1444 Budapest, Hungary. [Bagdy, Gyoergy] Semmelweis Univ, Fac Pharm, Dept Pharmacodynam, H-1444 Budapest, Hungary. [Hunyady, Laszlo] Semmelweis Univ, Lab Neurobiochem & Mol Physiol, H-1444 Budapest, Hungary. [Bagdy, Gyoergy] Semmelweis Univ, Grp Neuropsychopharmacol, H-1444 Budapest, Hungary. [Bagdy, Gyoergy] Hungarian Acad Sci, Budapest, Hungary. [Szidonya, Laszlo; Kunos, George] NIAAA, Lab Psychol Studies, Bethesda, MD 20892 USA. RP Hunyady, L (reprint author), Semmelweis Univ, Dept Physiol, Fac Med, POB 259, H-1444 Budapest, Hungary. EM Hunyady@eok.sote.hu RI Szidonya, Laszlo/A-2271-2010; OI Turu, Gabor/0000-0002-4421-3812 FU Hungarian Scientific Research Fund [NK-072661, NF-68563, M-045341, T-034606]; Agency for Research Fund Management and Research Exploitation, Hungary [NKFP1-010/2005]; Hungarian Ministry of Public Health [ETT 447/2006, 460/2006]; EC [LSHM-CT-2004-503474] FX This work was supported by grants from the Hungarian Scientific Research Fund (OTKA Grants NK-072661, NF-68563, M-045341 and T-034606), the Anyos Jedlik program by the Agency for Research Fund Management and Research Exploitation, Hungary (Grants NKFP1-010/2005), the Hungarian Ministry of Public Health (Grants ETT 447/2006 and 460/2006) and the EC (Grant LSHM-CT-2004-503474). NR 53 TC 33 Z9 33 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 19 PY 2009 VL 284 IS 25 BP 16914 EP 16921 DI 10.1074/jbc.M109.003681 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457VM UT WOS:000266962400028 PM 19357084 ER PT J AU Adair, JE Stober, V Sobhany, M Zhuo, LS Roberts, JD Negishi, M Kimata, K Garantziotis, S AF Adair, Jennifer E. Stober, Vandy Sobhany, Mack Zhuo, Lisheng Roberts, John D. Negishi, Masahiko Kimata, Koji Garantziotis, Stavros TI Inter-alpha-trypsin Inhibitor Promotes Bronchial Epithelial Repair after Injury through Vitronectin Binding SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; SHAP-HYALURONAN COMPLEX; LUNG INJURY; CELLS; MIGRATION; INTEGRIN; PROVIDES; CD44; GENE; KEY AB Pulmonary epithelial injury is central to the pathogenesis of many lung diseases, such as asthma, pulmonary fibrosis, and the acute respiratory distress syndrome. Regulated epithelial repair is crucial for lung homeostasis and prevents scar formation and inflammation that accompany dysregulated healing. The extracellular matrix (ECM) plays an important role in epithelial repair after injury. Vitronectin is a major ECM component that promotes epithelial repair. However, the factors that modify cell-vitronectin interactions after injury and help promote epithelial repair are not well studied. Inter-alpha-trypsin inhibitor (IaI) is an abundant serum protein. IaI heavy chains contain von Willebrand A domains that can bind the arginine-glycine-aspartate domain of vitronectin. We therefore hypothesized that IaI can bind vitronectin and promote vitronectin-induced epithelial repair after injury. We show that IaI binds vitronectin at the arginine-glycine-aspartate site, thereby promoting epithelial adhesion and migration in vitro. Furthermore, we show that IaI-deficient mice have a dysregulated response to epithelial injury in vivo, consisting of decreased proliferation and epithelial metaplasia. We conclude that IaI interacts not only with hyaluronan, as previously reported, but also other ECM components like vitronectin and is an important regulator of cellular repair after injury. C1 [Garantziotis, Stavros] NIEHS, Res Triangle Pk, NC 27709 USA. [Zhuo, Lisheng; Kimata, Koji] Aichi Med Univ, Inst Mol Sci Med, Aichi 4801195, Japan. RP Garantziotis, S (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. EM garantziotis@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program. NR 29 TC 14 Z9 15 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 19 PY 2009 VL 284 IS 25 BP 16922 EP 16930 DI 10.1074/jbc.M808560200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457VM UT WOS:000266962400029 PM 19395377 ER PT J AU Kawada, J Zou, P Mazitschek, R Bradner, JE Cohen, JI AF Kawada, Junichi Zou, Ping Mazitschek, Ralph Bradner, James E. Cohen, Jeffrey I. TI Tubacin Kills Epstein-Barr Virus (EBV)-Burkitt Lymphoma Cells by Inducing Reactive Oxygen Species and EBV Lymphoblastoid Cells by Inducing Apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; BURKITTS-LYMPHOMA; IN-VIVO; MULTIPLE-MYELOMA; PROTEASOME; BORTEZOMIB; LINE; EXPRESSION; INDUCTION; ESTABLISHMENT AB Tubacin is a small molecule inhibitor of histone deacetylase 6 and blocks aggresome activity. We found that Epstein-Barr virus (EBV)-positive Burkitt lymphoma (BL) cells were generally killed by lower doses of tubacin than EBV-transformed lymphoblastoid cells (LCLs) or EBV-negative BL cells. Tubacin induced apoptosis of LCLs, which was inhibited by pretreatment with a pancaspase inhibitor but not by butylated hydroxyanisole, which inhibits reactive oxygen species. In contrast, tubacin killed EBV-positive BL cells in a caspase-3-independent pathway that involved reactive oxygen species and was blocked by butylated hydroxyanisole. Previously, we showed that bortezomib, a proteasome inhibitor, induces apoptosis of EBV LCLs and that LCLs are killed by lower doses of bortezomib than EBV-positive BL cells. Here we found that the combination of bortezomib and tubacin acted in synergy to kill EBV-positive BL cells and LCLs. Tubacin or the combination of bortezomib and tubacin did not induce EBV lytic replication. These findings suggest that the combination of a proteasome inhibitor and an HDAC6 inhibitor may represent a useful strategy for the treatment of certain EBV-associated B cell lymphomas. C1 [Kawada, Junichi; Zou, Ping; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Mazitschek, Ralph; Bradner, James E.] Harvard Univ, Broad Inst, Chem Biol Program, Cambridge, MA 02142 USA. [Mazitschek, Ralph; Bradner, James E.] MIT, Cambridge, MA 02142 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Bldg 10,Rm 11N234, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov RI Mazitschek, Ralph/E-3741-2013; Kawada, Jun-ichi/I-7322-2014 OI Mazitschek, Ralph/0000-0002-1105-689X; FU National Institutes of Health [K08CA128972, P01CA078048] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of NIAID and National Institutes of Health Grants K08CA128972 (to J. E. B.) and P01CA078048 (to R. M.). NR 35 TC 21 Z9 22 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 19 PY 2009 VL 284 IS 25 BP 17102 EP 17109 DI 10.1074/jbc.M809090200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 457VM UT WOS:000266962400048 PM 19386607 ER PT J AU Sereti, I Dunham, RM Spritzler, J Aga, E Proschan, MA Medvik, K Battaglia, CA Landay, AL Pahwa, S Fischl, MA Asmuth, DM Tenorio, AR Altman, JD Fox, L Moir, S Malaspina, A Morre, M Buffet, R Silvestri, G Lederman, MM AF Sereti, Irini Dunham, Richard M. Spritzler, John Aga, Evgenia Proschan, Michael A. Medvik, Kathy Battaglia, Catherine A. Landay, Alan L. Pahwa, Savita Fischl, Margaret A. Asmuth, David M. Tenorio, Allan R. Altman, John D. Fox, Lawrence Moir, Susan Malaspina, Angela Morre, Michel Buffet, Renaud Silvestri, Guido Lederman, Michael M. CA ACTG 5214 Study Team TI IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMATURE/TRANSITIONAL B-CELLS; CD127 EXPRESSION; ANTIRETROVIRAL THERAPY; INTERLEUKIN-7 RECEPTOR; DECREASED CD127; GAMMA-CHAIN; INDIVIDUALS; HOMEOSTASIS; DISEASE AB Interleukin 7 (IL- 7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL- 7 (rhIL- 7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL- 7 was well tolerated with biologic activity demonstrable at 3 mu g/kg and a maximum tolerated dose of 30 mu g/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671. (Blood. 2009; 113: 6304-6314) C1 [Sereti, Irini; Fox, Lawrence] NIAID, Div AIDS, Bethesda, MD 20892 USA. [Dunham, Richard M.; Silvestri, Guido] Univ Penn, Philadelphia, PA 19104 USA. [Spritzler, John; Aga, Evgenia] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Medvik, Kathy; Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp, Case Med Ctr, Cleveland, OH 44106 USA. [Battaglia, Catherine A.] AIDS Clin Trial Grp Operat Ctr, Silver Spring, MD USA. [Landay, Alan L.; Tenorio, Allan R.] Rush Univ, Ctr Med, Chicago, IL 60612 USA. [Pahwa, Savita; Fischl, Margaret A.] Univ Miami, Miller Sch Med, Coral Gables, FL 33124 USA. [Asmuth, David M.] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. [Altman, John D.] Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Morre, Michel; Buffet, Renaud] Cytheris, Paris, France. RP Sereti, I (reprint author), NIAID, Div AIDS, 10 Ctr Dr,Bldg 10,Rm 11B-107A, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Dunham, Richard/B-2012-2009 OI Dunham, Richard/0000-0003-4542-2330 FU National Institute of Allergy and Infectious Diseases; Statistical and Data Analysis Center [AI 38855]; AIDS Clinical Trials Units at Case Western Reserve University [AI 25879, AI 68636]; Northwestern University [AI 25915]; University of California, Davis Medical Center [AI 38858]; University of Miami [AI 27675]; National Institutes of Health; Concerned Parents for AIDS Research FX This study was supported in part by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases; the Statistical and Data Analysis Center (AI 38855); and the individual AIDS Clinical Trials Units at Case Western Reserve University (AI 25879, AI 68636), Northwestern University (AI 25915), University of California, Davis Medical Center (AI 38858), and University of Miami (AI 27675). This work was also supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Cytheris, Issy les Moulineaux, France. G. S. was supported by a grant from the Concerned Parents for AIDS Research. NR 41 TC 179 Z9 183 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 18 PY 2009 VL 113 IS 25 BP 6304 EP 6314 DI 10.1182/blood-2008-10-186601 PG 11 WC Hematology SC Hematology GA 459XV UT WOS:000267147400011 PM 19380868 ER PT J AU Almeida, JR Sauce, D Price, DA Papagno, L Shin, SY Moris, A Larsen, M Pancino, G Douek, DC Autran, B Saez-Ciron, A Appay, V AF Almeida, Jorge R. Sauce, Delphine Price, David A. Papagno, Laura Shin, So Youn Moris, Arnaud Larsen, Martin Pancino, Gianfranco Douek, Daniel C. Autran, Brigitte Saez-Ciron, Asier Appay, Victor TI Antigen sensitivity is a major determinant of CD8(+) T-cell polyfunctionality and HIV-suppressive activity SO BLOOD LA English DT Article ID ACTIVATION REFLECTS; FUNCTIONAL PROFILE; IMMUNE ESCAPE; AIDS VACCINE; VIRAL LOAD; HLA-B; INFECTION; AVIDITY; LYMPHOCYTES; RESPONSES AB CD8(+) T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8(+) T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8(+) T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8(+) T cells from infected donors. We report that attributes of CD8(+) T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8(+) T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8(+) T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy. (Blood. 2009; 113: 6351-6360) C1 [Almeida, Jorge R.; Sauce, Delphine; Papagno, Laura; Larsen, Martin; Autran, Brigitte; Appay, Victor] Univ Paris 06, Cellular Immunol Lab, Inserm U945, Avenir Grp,Hop Pitie Salpetriere, Paris, France. [Price, David A.; Douek, Daniel C.] NIAID, Vaccine Res Ctr, Human Immunol Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff, Wales. [Pancino, Gianfranco; Saez-Ciron, Asier] Unite Regulat Infect Retrovirales, Paris, France. [Moris, Arnaud] Inst Pasteur, Unite Virus & Immun, Paris, France. RP Appay, V (reprint author), Univ Paris 06, Cellular Immunol Lab, Inserm U945, Avenir Grp,Hop Pitie Salpetriere, Paris, France. EM victor.appay@upmc.fr RI Saez-Cirion, Asier/A-8640-2008; Pancino, Gianfranco/A-5519-2010; Price, David/C-7876-2013; sauce, delphine/H-1990-2014; Larsen, Martin/A-7316-2014; OI Price, David/0000-0001-9416-2737; sauce, delphine/0000-0003-4596-7373; Larsen, Martin/0000-0003-1375-4816; Ramos de Almeida, Jorge/0000-0002-5009-8478; Saez-Cirion, Asier/0000-0003-2406-7536; Moris, Arnaud/0000-0002-5052-1678 FU Inserm AVENIR; French ANRS; Sidaction; National Institutes of Health; Medical Research Council (MRC) of the United Kingdom; Fundacao para a ciencia e Tecnologia; Korea Science and Engineering Foundation and the Institut Pasteur Korea FX This work was supported by the Inserm AVENIR grant, the French ANRS, Sidaction, the National Institutes of Health, and the Medical Research Council (MRC) of the United Kingdom. D. A. P. is a MRC Senior Clinical Fellow. J.R.A. is supported by a fellowship from the Fundacao para a ciencia e Tecnologia. S.Y.S. is supported by Korea Science and Engineering Foundation and the Institut Pasteur Korea. NR 59 TC 132 Z9 133 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 18 PY 2009 VL 113 IS 25 BP 6351 EP 6360 DI 10.1182/blood-2009-02-206557 PG 10 WC Hematology SC Hematology GA 459XV UT WOS:000267147400017 PM 19389882 ER PT J AU Landgren, O Kyle, RA Hoppin, JA Freeman, LEB Cerhan, JR Katzmann, JA Rajkumar, SV Alavanja, MC AF Landgren, Ola Kyle, Robert A. Hoppin, Jane A. Freeman, Laura E. Beane Cerhan, James R. Katzmann, Jerry A. Rajkumar, S. Vincent Alavanja, Michael C. TI Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study SO BLOOD LA English DT Article ID MULTIPLE-MYELOMA; CANCER INCIDENCE; UNITED-STATES; IOWA FARMERS; LIFE-STYLE; OCCUPATION; MORTALITY; APPLICATORS; DEATH; MEN AB Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% Cl, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% Cl, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% Cl, 1.9- to 16.6-fold), 3.9-fold (95% Cl, 1.5- to 10.0-fold), and 2.4-fold (95% Cl, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis. (Blood. 2009; 113: 6386-6391) C1 [Landgren, Ola] NCI, Natl Inst Hlth, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. [Landgren, Ola; Freeman, Laura E. Beane; Alavanja, Michael C.] NCI, Natl Inst Hlth, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kyle, Robert A.; Cerhan, James R.; Katzmann, Jerry A.; Rajkumar, S. Vincent] Mayo Clin, Coll Med, Rochester, MN USA. [Hoppin, Jane A.] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Landgren, O (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, Med Oncol Branch, 9000 Rockville Pike,Bldg 10 Rm 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Cerhan, James/0000-0002-7482-178X; Rajkumar, S. Vincent/0000-0002-5862-1833 FU NCI [CA 62242, CA 107476, Z01-CP010119]; NIH; Division of Cancer Epidemiology and Genetics (DCEG); NIEHS [Z01-ES049030] FX This work was supported by NCI (research grants CA 62242 and CA 107476); the Intramural Research Program of the NIH, NCI, Division of Cancer Epidemiology and Genetics (DCEG); the NIEHS (Z01-ES049030); and the NCI (Z01-CP010119). NR 46 TC 61 Z9 61 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 18 PY 2009 VL 113 IS 25 BP 6386 EP 6391 DI 10.1182/blood-2009-02-203471 PG 6 WC Hematology SC Hematology GA 459XV UT WOS:000267147400021 PM 19387005 ER PT J AU Bhatia, H Hallock, JL Dutta, A Karkashon, S Sterner, LS Miyazaki, T Dean, A Little, JA AF Bhatia, Himanshu Hallock, Jennifer L. Dutta, Amrita Karkashon, Shay Sterner, Lauren S. Miyazaki, Toru Dean, Ann Little, Jane A. TI Short-chain fatty acid-mediated effects on erythropoiesis in primary definitive erythroid cells SO BLOOD LA English DT Article ID GLOBIN GENE-EXPRESSION; FETAL-HEMOGLOBIN INDUCTION; HISTONE DEACETYLASE INHIBITORS; YEAST ARTIFICIAL CHROMOSOME; PROPIONYL-COA CARBOXYLASE; LOCUS-CONTROL REGION; GAMMA-GLOBIN; COLON-CANCER; BETA-THALASSEMIA; TRANSGENIC MICE AB Short-chain fatty acids (SCFAs; butyrate and propionate) up-regulate embryonic/fetal globin gene expression through unclear mechanisms. In a murine model of definitive erythropoiesis, SCFAs increased embryonic beta-type globin gene expression in primary erythroid fetal liver cells (eFLCs) after 72 hours in culture, from 1.7% (+/- 1.2%) of total beta-globin gene expression at day 0 to 4.9% (+/- 2.2%) in propionate and 5.4% (+/- 3.4%) in butyrate; this effect was greater in butyrate plus insulin/erythropoietin (BIE), at 19.5% (+/- 8.3%) compared with 0.1% (+/- 0.1%) in ins/EPO alone (P<.05). Fetal gamma-globin gene expression was increased in human transgene-containing eFLCs, to 35.9% (+/- 7.0%) in BIE compared with 4.4% (+/- 4.2%) in ins/EPO only (P<.05). Embryonic globin gene expression was detectable in 11 of 15 single eFLCs treated with BIE, but in 0 of 15ins/EPO-only treated cells. Butyrate-treated [65.5% (+/- 9.9%)] and 77.5% (+/- 4.0%) propionate-treated eFLCs were highly differentiated in culture, compared with 21.5% (+/- 3.5%) in ins/EPO (P<.005). Importantly, signaling intermediaries, previously implicated in induced embryonic/fetal globin gene expression (STAT5, p42/44, and p38), were not differentially activated by SCFAs in eFLCs; but increased bulk histone (H3) acetylation was seen in SCFA-treated eFLCs. SCFAs induce embryonic globin gene expression in eFLCS, which are a useful short-term and physiologic primary cell model of embryonic/fetal globin gene induction during definitive erythropoiesis. (Blood. 2009; 113: 6440-6448) C1 [Bhatia, Himanshu; Dutta, Amrita; Karkashon, Shay; Little, Jane A.] Albert Einstein Coll Med, Div Hematol, Dept Med, Bronx, NY 10461 USA. [Hallock, Jennifer L.; Sterner, Lauren S.; Dean, Ann] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Miyazaki, Toru] Univ Tokyo, Fac Med, Div Mol Biomed Pathogenesis, Ctr Dis Biol & Integrat Med, Tokyo 113, Japan. RP Little, JA (reprint author), Albert Einstein Coll Med, Div Hematol, Dept Med, Ullman 505,1300 Morris Pk Ave, Bronx, NY 10461 USA. EM jlittle@aecom.yu.edu FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolic Phenotyping Center, Nashville, TN [U24, DK59637] FX We acknowledge with gratitude Dr Larry Swift and the Lipid Core, Vanderbilt- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Mouse Metabolic Phenotyping Center, Nashville, TN ( support: U24, DK59637) for propionate measurements; Dr J. Eric Russell, Department of Medicine and Pediatrics, School of Medicine, University of Pennsylvania, for analyzing embryonic hemoglobin protein; Galina Baibakova, Laboratory of Cellular and Developmental Biology ( LCDB; NIDDK, National Institutes of Health [ NIH]), for expert animal husbandry; and Drs Margaret Baron and Joan Isern, Departments of Medicine, Developmental and Regenerative Biology, Gene and Cell Medicine, and Oncological Sciences, Mt Sinai School of Medicine, for advice and for access to complementary experimental data. Support from the Department of Medicine, Albert Einstein College of Medicine ( H. B., A. Dutta, S. K, and J. A. L.), and the Intramural Program, NIDDK, NIH ( J. L. H., L. S. S., A. Dean, and J. A. L.) is gratefully acknowledged. We thank our colleagues in the Pasta and Red Cell Society of NewYork for critical review of the data. NR 52 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 18 PY 2009 VL 113 IS 25 BP 6440 EP 6448 DI 10.1182/blood-2008-09-171728 PG 9 WC Hematology SC Hematology GA 459XV UT WOS:000267147400027 PM 19380871 ER PT J AU Garcia-Ortiz, JE Pelosi, E Omari, S Nedorezov, T Piao, Y Karmazin, J Uda, M Cao, A Cole, SW Forabosco, A Schlessinger, D Ottolenghi, C AF Elias Garcia-Ortiz, Jose Pelosi, Emanuele Omari, Shakib Nedorezov, Timur Piao, Yulan Karmazin, Jesse Uda, Manuela Cao, Antonio Cole, Steve W. Forabosco, Antonino Schlessinger, David Ottolenghi, Chris TI Foxl2 functions in sex determination and histogenesis throughout mouse ovary development SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID GENE-EXPRESSION; TRANSCRIPTION FACTOR; GERM-CELL; DETERMINATION REVEALS; PRIMORDIAL FOLLICLE; MAMMALIAN OVARY; EMBRYONIC GONAD; BETA-CATENIN; IN-VITRO; DIFFERENTIATION AB Background: Partial loss of function of the transcription factor FOXL2 leads to premature ovarian failure in women. In animal models, Foxl2 is required for maintenance, and possibly induction, of female sex determination independently of other critical genes, e. g., Rspo 1. Here we report expression profiling of mouse ovaries that lack Foxl2 alone or in combination with Wnt4 or Kit/c-Kit. Results: Following Foxl2 loss, early testis genes (including Inhbb, Dhh, and Sox9) and several novel ovarian genes were consistently dysregulated during embryonic development. In the absence of Foxl2, expression changes affecting a large fraction of pathways were opposite those observed in Wnt4-null ovaries, reinforcing the notion that these genes have complementary actions in ovary development. Loss of one copy of Foxl2 revealed strong gene dosage sensitivity, with molecular anomalies that were milder but resembled ovaries lacking both Foxl2 alleles. Furthermore, a Foxl2 transgene disrupted embryonic testis differentiation and increased the levels of key female markers. Conclusion: The results, including a comprehensive principal component analysis, 1) support the proposal of dose-dependent Foxl2 function and anti-testis action throughout ovary differentiation; and 2) identify candidate genes for roles in sex determination independent of FOXL2 (e. g., the transcription factors IRX3 and ZBTB7C) and in the generation of the ovarian reserve downstream of FOXL2 (e. g., the cadherin-domain protein CLSTN2 and the sphingomyelin synthase SGMS2). The gene inventory is a first step toward the identification of the full range of pathways with partly autonomous roles in ovary development, and thus provides a framework to analyze the genetic bases of female fertility. C1 [Elias Garcia-Ortiz, Jose; Pelosi, Emanuele; Omari, Shakib; Nedorezov, Timur; Piao, Yulan; Karmazin, Jesse; Schlessinger, David; Ottolenghi, Chris] NIA, Genet Lab, NIH, IRP, Baltimore, MD 21224 USA. [Elias Garcia-Ortiz, Jose] CMNO IMSS, Ctr Invest Biomed Occidente, Div Genet, Guadalajara, Jalisco, Mexico. [Uda, Manuela; Cao, Antonio] Cittadella Univ Monserrato, CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Cole, Steve W.] Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Forabosco, Antonino] Univ Modena, Unita Genet Med, I-41100 Modena, Italy. RP Schlessinger, D (reprint author), NIA, Genet Lab, NIH, IRP, Baltimore, MD 21224 USA. EM egarcia@cucs.udg.mx; pelosie@grc.nia.nih.gov; shakib.omari@gmail.com; timur.nedorezov@gmail.com; piaoy@grc.nia.nih.gov; jkarmazi@ida.org; muda@mcweb.unica.it; acao@mcweb.unica.it; coles@ucla.edu; forabosc@unimo.it; schlessingerd@mail.nih.gov; chris.ottolenghi@inserm.fr FU National Institute on Aging; NIH FX We thank Dawood Dudekula for help with the microarray probe annotations. We are grateful for the high quality, consistent efforts of the NIA Comparative Medicine Section in breeding, genotyping, and providing all the analyzed mice. This research was supported entirely by the Intramural Research Program of the National Institute on Aging, NIH. NR 61 TC 58 Z9 62 U1 0 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD JUN 18 PY 2009 VL 9 AR 36 DI 10.1186/1471-213X-9-36 PG 21 WC Developmental Biology SC Developmental Biology GA 477SE UT WOS:000268538200001 PM 19538736 ER PT J AU Chou, JW Bushel, PR AF Chou, Jeff W. Bushel, Pierre R. TI Discernment of possible mechanisms of hepatotoxicity via biological processes over-represented by co-expressed genes SO BMC GENOMICS LA English DT Article ID EXPRESSION DATA; LIVER; IDENTIFICATION; MICROARRAY; SIGNATURES; PHENOTYPE; APOPTOSIS; PROFILES; EXPOSURE; STRESS AB Background: Hepatotoxicity is a form of liver injury caused by exposure to stressors. Genomic-based approaches have been used to detect changes in transcription in response to hepatotoxicants. However, there are no straightforward ways of using co-expressed genes anchored to a phenotype or constrained by the experimental design for discerning mechanisms of a biological response. Results: Through the analysis of a gene expression dataset containing 318 liver samples from rats exposed to hepatotoxicants and leveraging alanine aminotransferase (ALT), a serum enzyme indicative of liver injury as the phenotypic marker, we identified biological processes and molecular pathways that may be associated with mechanisms of hepatotoxicity. Our analysis used an approach called Coherent Co-expression Biclustering (cc-Biclustering) for clustering a subset of genes through a coherent (consistency) measure within each group of samples representing a subset of experimental conditions. Supervised biclustering identified 87 genes co-expressed and correlated with ALT in all the samples exposed to the chemicals. None of the over-represented pathways related to liver injury. However, biclusters with subsets of samples exposed to one of the 7 hepatotoxicants, but not to a non-toxic isomer, contained co-expressed genes that represented pathways related to a stress response. Unsupervised biclustering of the data resulted in 1) four to five times more genes within the bicluster containing all the samples exposed to the chemicals, 2) biclusters with co-expression of genes that discerned 1,4 dichlorobenzene (a non-toxic isomer at low and mid doses) from the other chemicals, pathways and biological processes that underlie liver injury and 3) a bicluster with genes up-regulated in an early response to toxic exposure. Conclusion: We obtained clusters of co-expressed genes that over-represented biological processes and molecular pathways related to hepatotoxicity in the rat. The mechanisms involved in the response of the liver to the exposure to 1,4-dichlorobenzene suggest non-genotoxicity whereas the exposure to the hepatotoxicants could be DNA damaging leading to overall genomic instability and activation of cell cycle check point signaling. In addition, key pathways and biological processes representative of an inflammatory response, energy production and apoptosis were impacted by the hepatotoxicant exposures that manifested liver injury in the rat. C1 [Chou, Jeff W.; Bushel, Pierre R.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Chou, Jeff W.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27157 USA. RP Bushel, PR (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM jchou@wfubmc.edu; bushel@niehs.nih.gov FU NIH; NIEHS FX We thank the National Center for Toxicogenomics at the National Institute of Environmental Health Sciences (NIEHS) for the hepatotoxicant compendium data. We also thank Jennifer Fostel and David Fargo for their critical review of the manuscript. This research was supported, in part by, the Intramural Research Program of the NIH and NIEHS. NR 33 TC 6 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUN 18 PY 2009 VL 10 AR 272 DI 10.1186/1471-2164-10-272 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 480RE UT WOS:000268753700002 PM 19538742 ER PT J AU Husain, FT Patkin, DJ Thai-Van, H Braun, AR Horwitz, B AF Husain, Fatima T. Patkin, Debra J. Thai-Van, Hung Braun, Allen R. Horwitz, Barry TI Distinguishing the processing of gestures from signs in deaf individuals: An fMRI study SO BRAIN RESEARCH LA English DT Article DE American Sign Language; Gesture; Deaf; Visual processing; Categorization; Linguistic; Brain; fMRI ID WORD FORM AREA; FUSIFORM GYRUS; FRONTAL-CORTEX; LANGUAGE; BRAIN; SYSTEMS; SPEECH AB Manual gestures occur on a continuum from co-speech gesticulations to conventionalized emblems to language signs. Our goal in the present study was to understand the neural bases of the processing of gestures along such a continuum. We studied four types of gestures, varying along linguistic and semantic dimensions: linguistic and meaningful American Sign Language (ASL), non-meaningful pseudo-ASL, meaningful emblematic, and nonlinguistic, non-meaningful made-up gestures. Pre-lingually deaf, native signers of ASL participated in the fMRI study and performed two tasks while viewing videos of the gestures: a visuo-spatial (identity) discrimination task and a category discrimination task. We found that the categorization task activated left ventral middle and inferior frontal gyrus, among other regions, to a greater extent compared to the visual discrimination task, supporting the idea of semantic-level processing of the gestures. The reverse contrast resulted in enhanced activity of bilateral intraparietal sulcus, supporting the idea of featural-level processing (analogous to phonological-level processing of speech sounds) of the gestures. Regardless of the task, we found that brain activation patterns for the nonlinguistic, non-meaningful gestures were the most different compared to the ASL gestures. The activation patterns for the emblems were most similar to those of the ASL gestures and those of the pseudo-ASL were most similar to the nonlinguistic, non-meaningful gestures. The fMRI results provide partial support for the conceptualization of different gestures as belonging to a continuum and the variance in the fMRI results was best explained by differences in the processing of gestures along the semantic dimension. Published by Elsevier B.V. C1 [Husain, Fatima T.] Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. [Husain, Fatima T.; Patkin, Debra J.; Thai-Van, Hung; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Brain imaging & Modeling Sect, NIH, Bethesda, MD USA. [Braun, Allen R.; Horwitz, Barry] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD USA. RP Husain, FT (reprint author), Univ Illinois, Dept Speech & Hearing Sci, Champaign, IL 61820 USA. EM husainf@illinois.edu FU NIH-NIDCD Intramural Research Program FX The research was supported by the NIH-NIDCD Intramural Research Program. The authors wish to thank Nathan Pajor, Jaymi Della and Madhav Nandipati for their help in performing the analysis of the behavioral data. David Quinto-Pozos and Christopher Grindrod also have our gratitude for carefully reading and commenting on preliminary versions of this article. NR 30 TC 8 Z9 8 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 18 PY 2009 VL 1276 BP 140 EP 150 DI 10.1016/j.brainres.2009.04.034 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 464PD UT WOS:000267516700016 PM 19397900 ER PT J AU Tudor, C Marchese, FP Hitti, E Aubareda, A Rawlinson, L Gaestel, M Blackshear, PJ Clark, AR Saklatvala, J Dean, JLE AF Tudor, Corina Marchese, Francesco P. Hitti, Edward Aubareda, Anna Rawlinson, Lesley Gaestel, Matthias Blackshear, Perry J. Clark, Andrew R. Saklatvala, Jeremy Dean, Jonathan L. E. TI The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages SO FEBS LETTERS LA English DT Article DE p38 Mitogen-activated protein kinase; Tristetraprolin; Interleukin-10; COX-2 ID ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; AU-RICH ELEMENTS; GENE-EXPRESSION; STABILITY; DEADENYLATION; CYCLOOXYGENASE-2; INVOLVEMENT; REGULATOR; ARTHRITIS AB p38 mitogen-activated protein kinase (MAPK) stabilises pro-inflammatory mediator mRNAs by inhibiting AU-rich element (ARE)-mediated decay. We show that in bone-marrow derived murine macrophages tristetraprolin (TTP) is necessary for the p38 MAPK-sensitive decay of several pro-inflammatory mRNAs, including cyclooxygenase-2 and the novel targets interleukin (IL)-6, and IL-1 alpha. TTP(-/-) macrophages also strongly overexpress IL-10, an anti-inflammatory cytokine that constrains the production of the IL-6 despite its disregulation at the post-transcriptional level. TTP directly controls IL-10 mRNA stability, which is increased and insensitive to inhibition of p38 MAPK in TTP(-/-) macrophages. Furthermore, TTP enhances deadenylation of an IL-10 3'-untranslated region RNA in vitro. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Tudor, Corina; Marchese, Francesco P.; Aubareda, Anna; Rawlinson, Lesley; Clark, Andrew R.; Saklatvala, Jeremy; Dean, Jonathan L. E.] Univ London Imperial Coll Sci Technol & Med, Kennedy Inst Rheumatol Div, London W6 8LH, England. [Hitti, Edward; Gaestel, Matthias] Hannover Med Sch, Inst Biochem, D-30625 Hannover, Germany. [Blackshear, Perry J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Dean, JLE (reprint author), Univ London Imperial Coll Sci Technol & Med, Kennedy Inst Rheumatol Div, 65 Aspenlea Rd, London W6 8LH, England. EM jonathan.dean@imperial.ac.uk OI Clark, Andy/0000-0003-4996-8322; Gaestel, Matthias/0000-0002-4944-4652 FU BBSRC; GlaxoSmithKline; MRC; ARC FX We thank M. Brook and J. Steitz for reagents. C. T. was supported by a CASE studentship from the BBSRC and GlaxoSmithKline. We are also grateful to the MRC and the ARC for support. NR 19 TC 52 Z9 54 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 18 PY 2009 VL 583 IS 12 BP 1933 EP 1938 DI 10.1016/j.febslet.2009.04.039 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 468EM UT WOS:000267797800019 PM 19416727 ER PT J AU Inoue, K Negishi, M AF Inoue, Kaoru Negishi, Masahiko TI Early growth response 1 loops the CYP2B6 promoter for synergistic activation by the distal and proximal nuclear receptors CAR and HNF4 alpha SO FEBS LETTERS LA English DT Article DE Nuclear receptor; Nuclear constitutive active/androstane receptor; Human cytochrome P450 2B6; Early growth response 1; Transcription; HNF4 alpha ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; LOCALIZATION SIGNAL; NGFI-A; GENE; HEPATIC-NUCLEAR-FACTOR-4-ALPHA; REPRESSION; ELEMENTS; MODULE; DOMAIN AB Nuclear xenobiotic receptor CAR activates transcription of the CYP2B6 gene by directly binding to the distal enhancer PB responsive enhancer module (PBREM). This CAR-mediated activation is synergized by transcription factors early growth response 1 (EGR1) and hepatocyte-enriched nuclear factor 4 alpha (HNF4 alpha) that bind to the proximal element OA response element KI (OARE(KI)) [Inoue, K., & Negishi, M. (2008). Nuclear receptor CAR requires early growth response 1 to activate the human cytochrome P450 2B6 gene. J. Biol. Chem. 283, 10425-10432]. Two additional EGR1 binding sites have now been found just downstream from PBREM. Internal deletion of EGR1 sites within the context of the -1.8 kb CYP2B6 promoter, which contains both PBREM and OARE(KI), revealed that the distal and proximal EGR1 sites are essential for EGR1 to synergize CAR-mediated transcription. Chromatin conformation capture 3C assays demonstrated that ERG1 may loop the distal PBREM towards the proximal OARE(KI) so that together, CAR and HNF4 alpha synergistically activate the CYP2B6 promoter. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Inoue, Kaoru; Negishi, Masahiko] NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU NIH [Z01ES71005-01]; NIEHS FX This work was supported by the Intramural Research Program (Z01ES71005-01) of the NIH and NIEHS. NR 17 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUN 18 PY 2009 VL 583 IS 12 BP 2126 EP 2130 DI 10.1016/j.febslet.2009.05.031 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 468EM UT WOS:000267797800051 PM 19467232 ER PT J AU Maddukuri, L Speina, E Christiansen, M Dudzinska, D Zaim, J Obtulowicz, T Kabaczyk, S Komisarski, M Bukowy, Z Szczegielniak, J Wojcik, A Kusmierek, JT Stevnsner, T Bohr, VA Tudek, B AF Maddukuri, Leena Speina, Elzbieta Christiansen, Mette Dudzinska, Dominika Zaim, Jolanta Obtulowicz, Tomasz Kabaczyk, Sylwia Komisarski, Marek Bukowy, Zuzanna Szczegielniak, Jadwiga Wojcik, Andrzej Kusmierek, Jaroslaw T. Stevnsner, Tinna Bohr, Vilhelm A. Tudek, Barbara TI Cockayne syndrome group B protein is engaged in processing of DNA adducts of lipid peroxidation product trans-4-hydroxy-2-nonenal SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE Lipid peroxidation; HNE adducts; Transcription inhibition; NER; CSB; CSB ATPase mutations ID BASE EXCISION-REPAIR; RNA-POLYMERASE-II; COUPLING FACTOR CSB/ERCC6; HUMAN P53 GENE; OXIDATIVE STRESS; CSB PROTEIN; HUMAN-CELLS; ATPASE DOMAIN; IN-VIVO; DAMAGE AB Cockayne syndrome complementation group B (CSB) protein is engaged in transcription-coupled repair (TCR) of UV induced DNA damage and its deficiency leads to progressive multisystem degeneration and premature aging. Here, we show that human CSB-deficient cells are hypersensitive to physiological concentrations (1-10 mu M) of a lipid peroxidation product, trans-4-hydroxy-2-nonenal (HNE), and in response to HNE they develop a higher level of sister chromatid exchanges (SCEs) in comparison to the wild-type cells. HNE-DNA adducts block in vitro transcription by T7 RNA polymerase, as well as by HeLa cell-free extracts. Treatment of wild-type cells with 1-20 mu M HNE causes dephosphorylation of the CSB protein, which stimulates its ATPase activity necessary for TCR. However, high HNE concentrations (100-200 mu M) inhibit in vitro CSB ATPase activity as well as the transcription machinery in HeLa cell-free extracts. Cell lines expressing CSB protein mutated in different ATPase domains exhibit different sensitivities to HNE. The motif II mutant, which binds ATP but is defective in ATP hydrolysis was as sensitive to HNE as CSB-null cells. In contrast, motif V mutant cells were as sensitive to HNE as were the cells bearing wild-type protein, while motif VI mutant cells showed intermediate sensitivity to HNE. These mutants exhibit decreased ATP binding, but retain residual ATPase activity. Homology modeling suggested that amino acids mutated in motifs II and VI are localized closer to the ATP binding site than amino acids mutated in ATPase motif V. These results suggest that HNE-DNA adducts are extremely toxic endogenous DNA lesion, and that their processing involves CSB. When these lesions are not removed from the transcribed DNA strand due to CSB gene mutation or CSB protein inactivation by high, pathological HNE concentrations, they may contribute to accelerated aging. (c) 2009 Elsevier B.V. All rights reserved. C1 [Maddukuri, Leena; Speina, Elzbieta; Zaim, Jolanta; Obtulowicz, Tomasz; Komisarski, Marek; Bukowy, Zuzanna; Szczegielniak, Jadwiga; Kusmierek, Jaroslaw T.; Tudek, Barbara] Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. [Maddukuri, Leena] Postgrad Sch Mol Med, Warsaw, Poland. [Christiansen, Mette; Stevnsner, Tinna; Bohr, Vilhelm A.] Aarhus Univ, Danish Ctr Mol Gerontol, Aarhus, Denmark. [Christiansen, Mette; Stevnsner, Tinna; Bohr, Vilhelm A.] Danish Aging Res Ctr, Aarhus, Denmark. [Dudzinska, Dominika; Obtulowicz, Tomasz; Kabaczyk, Sylwia; Tudek, Barbara] Warsaw Univ, Inst Genet & Biotechnol, Warsaw, Poland. [Wojcik, Andrzej] Inst Nucl Chem & Technol, PL-03195 Warsaw, Poland. [Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Tudek, B (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Pawinskiego 5A, PL-02106 Warsaw, Poland. EM tudek@ibb.waw.pl FU Polish Ministry of Science and Higher Education [N N303 328834] FX This work was supported by the grants of the Polish Ministry of Science and Higher Education N N303 328834 (awarded for years 2001-2008) and N N303 391436 (awarded for years 2009-2012), Danish Cancer Society (grant no: DP03131) and the Lundbeck Foundation (grant no: 329/06). M.C. was supported by The Carlsberg Foundation (04/0169/20). NR 62 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 18 PY 2009 VL 666 IS 1-2 BP 23 EP 31 DI 10.1016/j.mrfmmm.2009.03.007 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 463VX UT WOS:000267462100004 PM 19481676 ER PT J AU Celniker, SE Dillon, LAL Gerstein, MB Gunsalus, KC Henikoff, S Karpen, GH Kellis, M Lai, EC Lieb, JD MacAlpine, DM Micklem, G Piano, F Snyder, M Stein, L White, KP Waterston, RH AF Celniker, Susan E. Dillon, Laura A. L. Gerstein, Mark B. Gunsalus, Kristin C. Henikoff, Steven Karpen, Gary H. Kellis, Manolis Lai, Eric C. Lieb, Jason D. MacAlpine, David M. Micklem, Gos Piano, Fabio Snyder, Michael Stein, Lincoln White, Kevin P. Waterston, Robert H. CA modENCODE Consortium TI Unlocking the secrets of the genome SO NATURE LA English DT Article ID GENE-EXPRESSION MAP; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; FUNCTIONAL ELEMENTS; RNAI LIBRARY; C-ELEGANS; DISCOVERY; NETWORKS; PROJECT; IDENTIFICATION C1 [Celniker, Susan E.] Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Genome Biol, Berkeley, CA 94720 USA. [Dillon, Laura A. L.] NHGRI, Div Extramural Res, NIH, Bethesda, MD 20892 USA. [Gerstein, Mark B.] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA. [Gerstein, Mark B.] Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA. [Gerstein, Mark B.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Gunsalus, Kristin C.; Piano, Fabio] NYU, Ctr Genom & Syst Biol, New York, NY 10003 USA. [Henikoff, Steven] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. [Karpen, Gary H.] Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Mol & Cell Biol, Dept Genome & Computat Biol, Berkeley, CA 94720 USA. [Kellis, Manolis] MIT, Broad Inst, Cambridge, MA 02140 USA. [Kellis, Manolis] Harvard Univ, Cambridge, MA 02140 USA. [Kellis, Manolis] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Lai, Eric C.] Sloan Kettering Inst, New York, NY 10065 USA. [Lieb, Jason D.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Lieb, Jason D.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA. [MacAlpine, David M.] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. [Micklem, Gos] Cambridge Syst Biol Ctr, Cambridge CB2 1QR, England. [Micklem, Gos] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Snyder, Michael] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06824 USA. [Stein, Lincoln] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11542 USA. [White, Kevin P.] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [White, Kevin P.] Argonne Natl Lab, Inst Genom & Syst Biol, Argonne, IL 60439 USA. [Waterston, Robert H.] Dept Genome Sci, Seattle, WA 98195 USA. [Waterston, Robert H.] Univ Washington, Sch Med, Seattle, WA 98195 USA. RP Celniker, SE (reprint author), Univ Calif Berkeley, Lawrence Berkeley Lab, Dept Genome Biol, Berkeley, CA 94720 USA. EM celniker@fruitfly.org RI Brenner, Steven/A-8729-2008; OI Brenner, Steven/0000-0001-7559-6185; Brown, Christopher/0000-0002-3785-5008; Micklem, Gos/0000-0002-6883-6168; Edsall, Lee Elizabeth/0000-0002-0326-2829 FU NHGRI NIH HHS [R01 HG004037, R01 HG004037-02, U01 HG004258, U01 HG004258-03, U01 HG004279]; NIGMS NIH HHS [R01 GM066272] NR 35 TC 392 Z9 398 U1 7 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD JUN 18 PY 2009 VL 459 IS 7249 BP 927 EP 930 DI 10.1038/459927a PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458XS UT WOS:000267063500031 PM 19536255 ER PT J AU Miller, MA Viboud, C Balinska, M Simonsen, L AF Miller, Mark A. Viboud, Cecile Balinska, Marta Simonsen, Lone TI The Signature Features of Influenza Pandemics - Implications for Policy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Miller, Mark A.; Viboud, Cecile; Balinska, Marta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Simonsen, Lone] George Washington Univ, Sch Publ Hlth & Hlth Serv, Dept Global Hlth, Washington, DC USA. RP Miller, MA (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. OI Simonsen, Lone/0000-0003-1535-8526 NR 5 TC 167 Z9 176 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 18 PY 2009 VL 360 IS 25 BP 2595 EP 2598 DI 10.1056/NEJMp0903906 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 458WR UT WOS:000267060000002 PM 19423872 ER PT J AU Ahmet, I Spangler, E Shukitt-Hale, B Juhaszova, M Sollott, SJ Joseph, JA Ingram, DK Talan, M AF Ahmet, Ismayil Spangler, Edward Shukitt-Hale, Barbara Juhaszova, Magdalena Sollott, Steven J. Joseph, James A. Ingram, Donald K. Talan, Mark TI Blueberry-Enriched Diet Protects Rat Heart from Ischemic Damage SO PLOS ONE LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; OXIDATIVE STRESS; CARDIOVASCULAR INJURY; CARDIAC MYOCYTES; MYOCARDIAL-INFARCTION; BEHAVIORAL DEFICITS; BASIC MECHANISMS; RABBIT HEARTS; FREE-RADICALS; BRAIN-DAMAGE AB Objectives: to assess the cardioprotective properties of a blueberry enriched diet (BD). Background: Reactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. The attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results precipitating the interest in natural products. Blueberries are readily available product with the highest antioxidant capacity among fruits and vegetables. Methods and Results: Following 3-mo of BD or a regular control diet (CD), the threshold for mitochondrial permeability transition (tMPT) was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001) of ROS indexed t(MPT). The remaining animals were subjected to a permanent ligation of the left descending coronary artery. 24 hrs later resulting myocardial infarction (MI) in rats on BD was 22% less than in CD rats (p<0.01). Significantly less TUNEL(+) cardiomyocytes (2% vs 9%) and 40% less inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.01). In the subgroup of rats, after coronary ligation the original diet was either continued or switched to the opposite one, and cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Measurements suggested that continuation of BD or its withdrawal after MI attenuated or accelerated rates of post MI cardiac remodeling and MI expansion. Conclusion: A blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure. RP Ahmet, I (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov FU Intramural NIH HHS NR 51 TC 25 Z9 25 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUN 18 PY 2009 VL 4 IS 6 AR e5954 DI 10.1371/journal.pone.0005954 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 459DE UT WOS:000267079500004 PM 19536295 ER PT J AU Kimura, T Cheng, K Rice, KC Gawrisch, K AF Kimura, Tomohiro Cheng, Kejun Rice, Kenner C. Gawrisch, Klaus TI Location, Structure, and Dynamics of the Synthetic Cannabinoid Ligand CP-55,940 in Lipid Bilayers SO BIOPHYSICAL JOURNAL LA English DT Article ID SOLID-STATE H-2-NMR; X-RAY-DIFFRACTION; NOESY CROSS-RELAXATION; MAGNETIC-RESONANCE; PHOSPHATIDYLCHOLINE BILAYERS; BIOLOGICAL-MEMBRANES; CRYSTAL-STRUCTURE; RECEPTOR-LIGAND; ACHATIN-I; NMR AB The widely used hydrophobic cannabinoid ligand CP-55,940 partitions with high efficiency into biomembranes. We studied the location, orientation, and dynamics of CP-55,940 in POPC bilayers by solid-state NMR. Chemical-shift perturbation of POPC protons from the aromatic ring-current effect, as well as (1)H NMR cross-relaxation rates, locate the hydroxyphenyl ring of the ligand near the lipid glycerol, carbonyls, and upper acyl-chain methylenes. Order parameters of the hydroxyphenyl ring determined by the (1)H-(13)C DIPSHIFT experiment indicate that the bond between the hydroxyphenyl and hydroxycyclohexyl rings is oriented perpendicular to the bilayer normal. (2)H NMR order parameters of the nonyl tail are very low, indicating that the hydrophobic chain maintains a high level of conformational flexibility in the membrane. Lateral diffusion rates of CP-55,940 and POPC were measured by (1)H magic-angle spinning NMR with pulsed magnetic field gradients. The rate of CP-55,940 diffusion is comparable to the rate of lipid diffusion. The magnitude of cross-relaxation and diffusion rates suggests that associations between CP-55,940 and lipids are with lifetimes of a fraction of a microsecond. With its flexible hydrophobic tail, CP-55,940 may efficiently approach the binding site of the cannabinoid receptor from the lipid-water interface by lateral diffusion. C1 [Kimura, Tomohiro; Gawrisch, Klaus] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. [Cheng, Kejun; Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, Bethesda, MD USA. [Cheng, Kejun; Rice, Kenner C.] NIAAA, NIH, Bethesda, MD USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD USA. EM gawrisch@helix.nih.gov FU National Institutes of Health FX This work was Supported by the Intramural Research Program of the National Institute oil Alcohol Abuse and Alcoholism, National Institutes of Health. NR 49 TC 21 Z9 22 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN 17 PY 2009 VL 96 IS 12 BP 4916 EP 4924 DI 10.1016/j.bpj.2009.03.033 PG 9 WC Biophysics SC Biophysics GA 460NO UT WOS:000267194600015 PM 19527650 ER PT J AU Borlongan, CV Hayashi, T Oeltgen, PR Su, TP Wang, Y AF Borlongan, Cesar V. Hayashi, Teruo Oeltgen, Peter R. Su, Tsung-Ping Wang, Yun TI Hibernation-like state induced by an opioid peptide protects against experimental stroke SO BMC BIOLOGY LA English DT Article ID CEREBRAL-ARTERY OCCLUSION; NEUROTROPHIC FACTOR; DOPAMINERGIC-NEURONS; BRAIN-DAMAGE; IN-VITRO; RATS; ISCHEMIA; GDNF; DELTA; MICE AB Background: Delta opioid peptide [D-ala2,D-leU5] enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system. Results: Adult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h x 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals. Conclusion: These results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection. C1 [Borlongan, Cesar V.; Hayashi, Teruo; Su, Tsung-Ping; Wang, Yun] NIDA, NIH, Intramural Res Program, Cellular Neurobiol Branch, Baltimore, MD USA. [Oeltgen, Peter R.] Univ Kentucky, Dept Pathol, Lexington, KY USA. RP Borlongan, CV (reprint author), NIDA, NIH, Intramural Res Program, Cellular Neurobiol Branch, Baltimore, MD USA. EM cborlong@health.usf.edu; THAYASHI@intra.nida.nih.gov; proelt1@email.uky.edu; tsu@mail.nih.gov; ywang@intra.nida.nih.gov OI Borlongan, Cesar/0000-0002-2966-9782 FU Intramural Research Program, Division of Basic Research, NIDA/NIH FX We are grateful to Dr Barry J Hoffer for his critical comments during the preparation of the manuscript. The authors also thank Ms EunKyung Bae for excellent technical assistance in manuscript preparation. This study was supported by Intramural Research Program, Division of Basic Research, NIDA/NIH. NR 37 TC 36 Z9 37 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD JUN 17 PY 2009 VL 7 AR 31 DI 10.1186/1741-7007-7-31 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 476OF UT WOS:000268451200001 PM 19534760 ER PT J AU Smink, JJ Begay, V Schoenmaker, T Sterneck, E de Vries, TJ Leutz, A AF Smink, Jeske J. Begay, Valerie Schoenmaker, Ton Sterneck, Esta de Vries, Teun J. Leutz, Achim TI Transcription factor C/EBP beta isoform ratio regulates osteoclastogenesis through MafB SO EMBO JOURNAL LA English DT Article DE bone homeostasis; CCAAT/enhancer binding protein beta; MafB; mTOR; osteoclast ID BINDING-PROTEIN-BETA; GENE-EXPRESSION; HOMOLOGOUS PROTEIN; BONE-FORMATION; TNF-ALPHA; OSTEOBLAST DIFFERENTIATION; ADIPOCYTE DIFFERENTIATION; INHIBITORY PROTEIN; SEGMENTATION GENE; CAUSES OSTEOPENIA AB Disequilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts is central to many bone diseases. Here, we show that dysregulated expression of translationally controlled isoforms of CCAAT/enhancer-binding protein beta (C/EBP beta) differentially affect bone mass. Alternative translation initiation that is controlled by the mammalian target of rapamycin (mTOR) pathway generates long transactivating (LAP*, LAP) and a short repressive (LIP) isoforms from a single C/EBPb transcript. Rapamycin, an inhibitor of mTOR signalling increases the ratio of LAP over LIP and inhibits osteoclastogenesis in wild type (WT) but not in C/EBP beta null (c/ebp beta(-/-)) or in LIP knock-in (L/L) osteoclast precursors. C/EBP beta mutant mouse strains exhibit increased bone resorption and attenuated expression of MafB, a negative regulator of osteoclastogenesis. Ectopic expression of LAP and LIP in monocytes differentially affect the MafB promoter activity, MafB gene expression and dramatically affect osteoclastogenesis. These data show that mTOR regulates osteoclast formation by modulating the C/EBP beta isoform ratio, which in turn affects osteoclastogenesis by regulating MafB expression. The EMBO Journal (2009) 28, 1769-1781. doi:10.1038/emboj.2009.127; Published online 14 May 2009 C1 [Leutz, Achim] Humboldt Univ, Inst Biol, Max Delbrueck Ctr Mol Med, Berlin Brandenburg Ctr Regenerat Therapies, D-13125 Berlin, Germany. [Schoenmaker, Ton; de Vries, Teun J.] Univ Amsterdam, Acad Ctr Dent Amsterdam, Dept Periodontol, Amsterdam, Netherlands. [Schoenmaker, Ton; de Vries, Teun J.] Univ Amsterdam, Acad Ctr Dent Amsterdam, Dept Oral Cell Biol, Amsterdam, Netherlands. [Schoenmaker, Ton; de Vries, Teun J.] Vrije Univ Amsterdam, Amsterdam, Netherlands. [Sterneck, Esta] NCI, Ctr Canc Res, Frederick, MD 21701 USA. RP Leutz, A (reprint author), Humboldt Univ, Inst Biol, Max Delbrueck Ctr Mol Med, Berlin Brandenburg Ctr Regenerat Therapies, Robert Roessle Str 10, D-13125 Berlin, Germany. EM aleutz@mdc-berlin.de RI Leutz, Achim/K-9643-2013 OI Leutz, Achim/0000-0001-8259-927X FU European Community [MEIF-CT-2005-009611]; Berliner Krebsgesellschaft [LEFF200708] FX We are indebted to Drs C Birchmeier and T Muller (MDC, Berlin, Germany) for providing reagents, advice and help with targeted mouse genetics. We are grateful to Dr J-P David (German Rheumatism Research Center Berlin, Germany) and Dr GR Burmester (Charite, University Medicine Berlin, Germany) for providing Etanercept, Dr M Sakai (Department of Biochemistry, Hokkaido University School of Medicine, Sapporo Japan) for providing the MafB luciferase reporter construct. Furthermore, we thank Dr H-P Rahn (MDC, Berlin, Germany) for FACS sorting, R Zarmstorff and P Gossen-Heinrich for technical assistance. We also thank Dr BCJ van der Eerden (Erasmus Medical Center, Rotterdam, The Netherlands) for helpful discussions and advice as well as Dr K Zaragoza, Dr K Wethmar and the other members of the Leutz lab for discussions. This work was supported by an individual Marie Curie fellowship from the European Community to JJS (MEIF-CT-2005-009611) and the Berliner Krebsgesellschaft (LEFF200708). NR 75 TC 71 Z9 77 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 17 PY 2009 VL 28 IS 12 BP 1769 EP 1781 DI 10.1038/emboj.2009.127 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 458TI UT WOS:000267046000010 PM 19440205 ER PT J AU Risch, N Herrell, R Lehner, T Liang, KY Eaves, L Hoh, J Griem, A Kovacs, M Ott, J Merikangas, KR AF Risch, Neil Herrell, Richard Lehner, Thomas Liang, Kung-Yee Eaves, Lindon Hoh, Josephine Griem, Andrea Kovacs, Maria Ott, Jurg Merikangas, Kathleen Ries TI Interaction Between the Serotonin Transporter Gene (5-HTTLPR), Stressful Life Events, and Risk of Depression A Meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID X ENVIRONMENT INTERACTION; THREATENING EXPERIENCES; POLYMORPHISM 5-HTTLPR; PSYCHIATRIC-DISORDERS; PROMOTER POLYMORPHISM; MALTREATED CHILDREN; MAJOR DEPRESSION; REGION 5-HTTLPR; SOCIAL SUPPORTS; HUMAN-DISEASES AB Context Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression. Objective To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data. Data Sources Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis. Study Selection Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, >= 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data. Data Extraction Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14 250 participants, 1769 were classified as having depression; 12 481 as not having depression. Results In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI, 1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data. Conclusion This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined. JAMA. 2009; 301(23):2462-2471 C1 [Merikangas, Kathleen Ries] NIMH, Genet Epidemiol Res Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Risch, Neil] Univ Calif San Francisco, Inst Human Genet, Oakland, CA USA. [Risch, Neil] Kaiser Permanente No Calif Div Res, Oakland, CA USA. [Liang, Kung-Yee] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Eaves, Lindon] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA 23284 USA. [Eaves, Lindon] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA 23284 USA. [Hoh, Josephine] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Kovacs, Maria] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Ott, Jurg] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. RP Merikangas, KR (reprint author), NIMH, Genet Epidemiol Res Branch, Intramural Res Program, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov RI Liang, Kung-Yee/F-8299-2011 FU National Institutes of Health; National Institute of Mental Health; Intramural Research Program; Division of Developmental Translational Research; Division of Neuroscience and Basic Behavioral Science FX Funding/Support: This work was supported in part by the National Institutes of Health, National Institute of Mental Health, Intramural Research Program, Division of Developmental Translational Research, and Division of Neuroscience and Basic Behavioral Science. Disclaimer: The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations or agencies or the US government. Additional Information: Online tables are available at http://www.jama.com. NR 72 TC 896 Z9 912 U1 17 U2 162 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 17 PY 2009 VL 301 IS 23 BP 2462 EP 2471 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 458MO UT WOS:000267028100024 PM 19531786 ER PT J AU Tahara, H Sato, M Thurin, M Wang, E Butterfield, LH Disis, ML Fox, BA Lee, PP Khleif, SN Wigginton, JM Ambs, S Akutsu, Y Chaussabel, D Doki, Y Eremin, O Fridman, WH Hirohashi, Y Imai, K Jacobson, J Jinushi, M Kanamoto, A Kashani-Sabet, M Kato, K Kawakami, Y Kirkwood, JM Kleen, TO Lehmann, PV Liotta, L Lotze, MT Maio, M Malyguine, A Masucci, G Matsubara, H Mayrand-Chung, S Nakamura, K Nishikawa, H Palucka, AK Petricoin, EF Pos, Z Ribas, A Rivoltini, L Sato, N Shiku, H Slingluff, CL Streicher, H Stroncek, DF Takeuchi, H Toyota, M Wada, H Wu, XF Wulfkuhle, J Yaguchi, T Zeskind, B Zhao, YD Zocca, MB Marincola, FM AF Tahara, Hideaki Sato, Marimo Thurin, Magdalena Wang, Ena Butterfield, Lisa H. Disis, Mary L. Fox, Bernard A. Lee, Peter P. Khleif, Samir N. Wigginton, Jon M. Ambs, Stefan Akutsu, Yasunori Chaussabel, Damien Doki, Yuichiro Eremin, Oleg Fridman, Wolf Herve Hirohashi, Yoshihiko Imai, Kohzoh Jacobson, James Jinushi, Masahisa Kanamoto, Akira Kashani-Sabet, Mohammed Kato, Kazunori Kawakami, Yutaka Kirkwood, John M. Kleen, Thomas O. Lehmann, Paul V. Liotta, Lance Lotze, Michael T. Maio, Michele Malyguine, Anatoli Masucci, Giuseppe Matsubara, Hisahiro Mayrand-Chung, Shawmarie Nakamura, Kiminori Nishikawa, Hiroyoshi Palucka, A. Karolina Petricoin, Emanuel F. Pos, Zoltan Ribas, Antoni Rivoltini, Licia Sato, Noriyuki Shiku, Hiroshi Slingluff, Craig L. Streicher, Howard Stroncek, David F. Takeuchi, Hiroya Toyota, Minoru Wada, Hisashi Wu, Xifeng Wulfkuhle, Julia Yaguchi, Tomonori Zeskind, Benjamin Zhao, Yingdong Zocca, Mai-Britt Marincola, Francesco M. TI Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; CD8(+) T-CELLS; EPSTEIN-BARR-VIRUS; TUMOR-INFILTRATING LYMPHOCYTES; CHRONIC HEPATITIS-C; NASOPHARYNGEAL CARCINOMA NPC; POSITRON-EMISSION-TOMOGRAPHY; CUTANEOUS MALIGNANT-MELANOMA; INTERFERON-STIMULATED GENES; RESISTANT PROSTATE-CANCER AB Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28(th) 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions. C1 [Tahara, Hideaki; Sato, Marimo; Jinushi, Masahisa; Kanamoto, Akira] Univ Tokyo, Inst Med Sci, Dept Surg & Bioengn, Adv Clin Res Ctr, Tokyo, Japan. [Thurin, Magdalena] NCI, Canc Diag Program, NIH, Rockville, MD 20852 USA. [Wang, Ena; Pos, Zoltan; Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Ena; Pos, Zoltan; Marincola, Francesco M.] NIH, CHI, Bethesda, MD 20892 USA. [Butterfield, Lisa H.; Kirkwood, John M.] Univ Pittsburgh, Inst Canc, Div Hematol Oncol, Dept Med, Pittsburgh, PA 15213 USA. [Butterfield, Lisa H.; Kirkwood, John M.] Univ Pittsburgh, Inst Canc, Div Hematol Oncol, Dept Surg, Pittsburgh, PA 15213 USA. [Butterfield, Lisa H.; Kirkwood, John M.] Univ Pittsburgh, Inst Canc, Div Hematol Oncol, Dept Immunol, Pittsburgh, PA 15213 USA. [Disis, Mary L.] Univ Washington, Tumor Vaccine Grp, Ctr Translat Med Womens Hlth, Seattle, WA 98195 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97213 USA. [Fox, Bernard A.] Oregon Hlth & Sci Univ, Earle A Chiles Res Inst, Robert Franz Res Ctr, Providence Portland Med Ctr, Portland, OR 97213 USA. [Lee, Peter P.] Stanford Univ, Div Hematol, Dept Med, Stanford, CA 94305 USA. [Khleif, Samir N.] NCI, Canc Vaccine Sect, NIH, Bethesda, MD 20892 USA. [Wigginton, Jon M.] Bristol Myers Squibb Inc, Discovery Med Oncol, Princeton, NJ USA. [Ambs, Stefan] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Akutsu, Yasunori; Matsubara, Hisahiro] Chiba Univ, Grad Sch Med, Dept Frontier Surg, Chiba, Japan. [Chaussabel, Damien; Palucka, A. Karolina] Baylor Inst Immunol Res, Dallas, TX 75204 USA. [Chaussabel, Damien; Palucka, A. Karolina] Baylor Res Inst, Dallas, TX 75204 USA. [Doki, Yuichiro; Wada, Hisashi] Osaka Univ, Grad Sch Med, Dept Surg, Osaka, Japan. [Eremin, Oleg] Univ Nottingham, Survey Sect, Biomed Res Unit, Nottingham Digest Dis Ctr, Nottingham NG7 2UH, England. [Fridman, Wolf Herve] Paris Descarte Univ, INSERM, Ctr Res Cordeliers, F-75270 Paris, France. [Kashani-Sabet, Mohammed] Univ Calif San Francisco, Melanoma Clin, San Francisco, CA 94143 USA. [Kato, Kazunori; Nakamura, Kiminori] Sapporo Med Univ, Sch Med, Dept Mol Med, Sapporo, Hokkaido, Japan. [Kawakami, Yutaka; Yaguchi, Tomonori] Keio Univ, Sch Med, Inst Adv Med Res, Div Cellular Signaling, Tokyo, Japan. [Kleen, Thomas O.; Lehmann, Paul V.] Cellular Technol Ltd, Shaker Hts, OH 44122 USA. [Liotta, Lance; Petricoin, Emanuel F.; Wulfkuhle, Julia] George Mason Univ, Ctr Appl Prote & Mol Med, Dept Microbiol & Mol Pathol, Manassas, VA USA. [Lotze, Michael T.] Univ Pittsburgh, Illman Canc Ctr, Pittsburgh, PA 15213 USA. [Maio, Michele] Hosp Siena, Ist Toscano Tumori, Dept Oncol, Siena, Italy. [Maio, Michele] IRCCS, Ctr Riferimento Oncol, Dept Med Oncol, Canc Bioimmunotherapy Unit, I-53100 Aviano, Italy. [Malyguine, Anatoli] NCI, SAIC Frederick Inc, Lab Cell Mediated Immun, Frederick, MD 21702 USA. [Masucci, Giuseppe] Karolinska Inst, Dept Oncol Pathol, S-17176 Stockholm, Sweden. [Mayrand-Chung, Shawmarie] NIH, BC, Publ Private Partnership Program, Off Director, Bethesda, MD 20892 USA. [Nishikawa, Hiroyoshi; Shiku, Hiroshi] Mie Univ, Grad Sch Med, Dept Immunogene Therapy, Dept Canc Vaccine, Tsu, Mie, Japan. [Ribas, Antoni] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Los Angeles, CA 90095 USA. [Rivoltini, Licia] Ist Nazl Tumori, IRCCS Fdn, Unit Immunotherapy Human Tumors, I-20100 Milan, Italy. [Sato, Noriyuki] Sapporo Med Univ, Sch Med, Dept Pathol, Sapporo, Hokkaido, Japan. [Slingluff, Craig L.] Univ Virginia, Sch Med, Div Surg Oncol, Dept Surg, Charlottesville, VA 22908 USA. [Streicher, Howard] NCI, Canc Therapy Evaluat Program, DCTD, NIH, Bethesda, MD 20892 USA. [Stroncek, David F.] NIH, CTS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Takeuchi, Hiroya] Keio Univ, Sch Med, Dept Surg, Tokyo 160, Japan. [Toyota, Minoru] Sapporo Med Univ, Sch Med, Dept Biochem, Sapporo, Hokkaido, Japan. [Wu, Xifeng] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Zeskind, Benjamin] Immuneering Corp, Boston, MA 02215 USA. [Zhao, Yingdong] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Zocca, Mai-Britt] DanDritt Biotech AS, DK-2100 Copenhagen, Denmark. RP Tahara, H (reprint author), Univ Tokyo, Inst Med Sci, Dept Surg & Bioengn, Adv Clin Res Ctr, Tokyo, Japan. EM tahara@ims.u-tokyo.ac.jp; marimo@ims.u-tokyo.ac.jp; thurinm@mail.nih.gov; Ewang@mail.cc.nih.gov; butterfieldl@upmc.edu; ndisis@u.washington.edu; foxb@foxlab.org; ppl@stanford.edu; khleif@nih.gov; jon.wigginton@bms.com; ambss@mail.nih.gov; yakutsu@faculty.chiba-u.jp; damienc@baylorhealth.edu; ydoki@gesurg.med.osaka-u.ac.jp; val.elliott@ulh.nhs.uk; herve.fridman@crc.jussieu.fr; hirohash@sapmed.ac.jp; imai@sapmed.ac.jp; jacobsoj@mail.nih.gov; jinushi@ims.u-tokyo.ac.jp; kanamoto@ims.u-tokyo.ac.jp; cascllar@derm.ucsf.edu; kakazu@sapmed.ac.jp; yutakawa@sc.itc.keio.ac.jp; kirkwoodjm@upmc.edu; thomas.kleen@immunospot.com; pvl@immunospot.com; lliotta@gmu.edu; lotzemt@upmc.edu; mmaio@cro.it; malyguinea@mail.nih.hov; giuseppe.masucci@ki.se; matsuhm@faculty.chiba-u.jp; Mayrands@mail.nih.gov; kiminori@sapmed.ac.jp; nisihiro@clin.medic.mie-u.ac.jp; karolinp@BaylorHealth.edu; epetrico@gmu.edu; posz@cc.nih.gov; aribas@mednet.ucla.edu; licia.rivoltini@istitutotumori.mi.it; nsatou@sapmed.ac.jp; shiku@clin.medic.mie-u.ac.jp; GRW3K@hscmail.mcc.virginia.edu; hs30c@nih.gov; dstroncek@mail.cc.nih.gov; htakeuch@sc.itc.keio.ac.jp; mtoyota@sapmed.ac.jp; hwada@gesurg.med.osaka-u.ac.jp; xwu@mdanderson.org; jwulfkuh@gmu.edu; beatless@rr.iij4u.or.jp; bzeskind@immuneering.com; zhaoy@mail.nih.gov; mbz@dandrit.com; fmarincola@mail.cc.nih.gov RI Jinushi, Masahisa/A-4311-2012; Pos, Zoltan/C-3623-2014; Kawakami, Yutaka /E-7429-2013; OI Pos, Zoltan/0000-0002-2574-7616; Kawakami, Yutaka /0000-0003-4836-2855; Masucci, Giuseppe/0000-0002-9583-2306; coral, sandra/0000-0002-1308-3082; Rivoltini, Licia/0000-0002-2409-6225; Chaussabel, Damien/0000-0002-6131-7242 NR 285 TC 28 Z9 29 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUN 17 PY 2009 VL 7 AR 45 DI 10.1186/1479-5876-7-45 PG 25 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 485TJ UT WOS:000269146900001 PM 19534815 ER PT J AU Hassan, MM Osman, OF El-Raba'a, FMA Schallig, HDFH Elnaiem, DEA AF Hassan, Mo'awia M. Osman, Omran F. El-Raba'a, Fathi M. A. Schallig, Henk D. F. H. Elnaiem, Dia-Eldin A. TI Role of the domestic dog as a reservoir host of Leishmania donovani in eastern Sudan SO PARASITES & VECTORS LA English DT Article ID DIRECT AGGLUTINATION-TEST; VISCERAL LEISHMANIASIS; KALA-AZAR; PHLEBOTOMUS-ORIENTALIS; LUTZOMYIA-LONGIPALPIS; SOUTHERN SUDAN; INFECTION; IDENTIFICATION; EPIDEMIOLOGY; PREFERENCE AB Background: The study aims to determine the role of domestic dogs in transmission of visceral leishmaniasis in eastern Sudan. A cross-sectional survey was conducted in 10 villages along the River Rahad in eastern Sudan to elucidate the role of domestic dogs (Canis familiaris, Linnaeus, 1758) as a reservoir host of Leishmania donovani. In this study, 87 dogs were screened for infection by Leishmania donovani. Blood and lymph node samples were taken from 87 and 33 dogs respectively and subsequently screened by the Polymerase Chain Reaction (PCR) and Direct Agglutination Test (DAT) test. Additional lymph node smears were processed for microscopy and parasite culture. Host preference of the visceral leishmaniasis (VL) vector in the area, Phlebotomus orientalis, and other sandflies for the Nile rat (Arvicanthis niloticus, E. Geoffrey, 1803), the genet (Genetta genetta, Linnaeus, 1758), the mongoose (Herpeistes ichneumon, Linnaeus, 1758), and the domestic dog were determined by counting numbers of sand flies attracted to CDC traps that were baited by these animals. Results: DAT on blood samples detected anti-Leishmania antibodies in 6 samples (6.9%). Two out of 87 (2.3%) blood samples tested were PCR positive, giving an amplification product of 560 bp. The two positive samples by PCR were also positive by DAT. However, none of the 33 lymph nodes aspirates were Leishmania positive when screened by microscopy, culture and genus-specific PCR. The dog-baited trap significantly attracted the highest number of P. orientalis and sand fly species (P < 0.001). This was followed by the Egyptian mongoose baited trap and less frequently by the genet baited trap. Conclusion: It is concluded that the results obtained from host attraction studies indicate that dog is more attractive for P. orientalis than Egyptian mongoose, common genet and Nile rat. C1 [Hassan, Mo'awia M.] Natl Res Ctr, Res Inst Trop Med, Dept Epidemiol, Minist Sci & Technol, Khartoum, Sudan. [Osman, Omran F.; El-Raba'a, Fathi M. A.] Univ Khartoum, Dept Zool, Khartoum, Sudan. [Schallig, Henk D. F. H.] Royal Trop Inst KIT, NL-1105 AZ Amsterdam, Netherlands. [Elnaiem, Dia-Eldin A.] NIAID, NIH, Rockville, MD 20852 USA. RP Hassan, MM (reprint author), Natl Res Ctr, Res Inst Trop Med, Dept Epidemiol, Minist Sci & Technol, POB 1304, Khartoum, Sudan. EM moawia65@hotmail.com; omrann@hotmail.com; fathielrabaa@yahoo.com; H.Schallig@kit.nl; elnaiemd@niaid.nih.gov FU Khartoum College of Medical Sciences; UNICEF/UNDP/World Bank WHO; WHO [A 4190-TDR] FX We would like to thank Prof. Suad M. Suliman of (TMRI) and Prof. Nasr Eldin A. Mahmoud Dean Faculty of Khartoum College of Medical Sciences who provided financial support for this work. Also, thanks are due to people of the surveyed villages who helped patiently in sample collection. Many thanks to Mr. Breema Musa ( Faculty of Science, University of Khartoum), for help and support in fieldwork. This Investigation received financial support from UNICEF/UNDP/World Bank WHO. Special programme for Research and Training in Tropical Disease (TDR). Grant (Osman: A 4190-TDR, WHO). NR 37 TC 19 Z9 19 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD JUN 17 PY 2009 VL 2 AR 26 DI 10.1186/1756-3305-2-26 PG 7 WC Parasitology SC Parasitology GA 475RL UT WOS:000268378100001 PM 19534802 ER PT J AU Yanovski, JA Parikh, SJ Yanoff, LB Denkinger, BI Calis, KA Reynolds, JC Sebring, NG McHugh, T AF Yanovski, Jack A. Parikh, Shamik J. Yanoff, Lisa B. Denkinger, Blakeley I. Calis, Karim A. Reynolds, James C. Sebring, Nancy G. McHugh, Teresa TI Effects of Calcium Supplementation on Body Weight and Adiposity in Overweight and Obese Adults A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRES; VITAMIN-D SUPPLEMENTATION; DIETARY CALCIUM; UNITED-STATES; DAIRY CALCIUM; FAT LOSS; PRESCHOOL-CHILDREN; MILK CONSUMPTION; BLOOD-PRESSURE; MASS INDEX AB Background: Some data suggest that increasing calcium intake may help prevent weight gain. Objective: To test the hypothesis that calcium supplementation can prevent weight gain in persons who are overweight or obese. Design: Randomized, placebo-controlled trial. Randomization was computer-generated, and allocation was assigned by pharmacy personnel who prepared intervention and placebo capsules. Participants, providers, and those who assessed outcomes were blinded to study group assignment. Setting: Single research center. Participants: 340 overweight (body mass index [BMI], 25 to <30 kg/m(2)) and obese (BMI >= 30 kg/m(2)) adults (mean age, 38.8 years [SD, 10.5]). Intervention: Calcium carbonate (elemental calcium, 1500 mg/d) (n = 170) or placebo (n = 170) with meals for 2 years. Measurements: Changes in body weight and fat mass (primary outcomes). Results: Seventy-five percent of participants completed the trial (78% received calcium; 73% received placebo). There were no statistically or clinically significant differences between the calcium and placebo groups in change in body weight (difference, 0.02 kg [95% CI, -1.64 to 1.69 kg]; P = 0.98), BMI (difference, 0.32 kg/m(2) [CI, -0.41 to 1.02 kg/m(2)]; P = 0.39), or body fat mass (difference, 0.39 kg [CI, -1.04 to 1.92 kg]; P = 0.55). Parathyroid hormone concentrations decreased in the calcium group compared with the placebo group (difference, -0.71 pmol/L [CI, -1.28 to -0.13 pmol/L]). Limitation: The study took place at a research center, and its sample was mostly women. Conclusion: Dietary supplementation with elemental calcium, 1500 mg/d, for 2 years had no statistically or clinically significant effects on weight in overweight and obese adults. Calcium supplementation is unlikely to have clinically significant efficacy as a preventive measure against weight gain in such patients. C1 [Yanovski, Jack A.] NIH, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NIH, Hatfield Clin Res Ctr, 9000 Rockville Pike,Room 1-3330, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU National Institutes of Health [Z01-HD-000641, OD-2067] FX By the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health ( grant Z01-HD-000641) ( Dr. Yanovski), and the Office of Dietary Supplements, National Institutes of Health ( grant OD-2067) ( Dr. Yanovski). NR 83 TC 43 Z9 45 U1 2 U2 4 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 16 PY 2009 VL 150 IS 12 BP 821 EP U17 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 460CX UT WOS:000267164800001 PM 19528561 ER PT J AU Warren, JL Klabunde, CN Mariotto, AB Meekins, A Topor, M Brown, ML Ransohoff, DF AF Warren, Joan L. Klabunde, Carrie N. Mariotto, Angela B. Meekins, Angela Topor, Marie Brown, Martin L. Ransohoff, David F. TI Adverse Events After Outpatient Colonoscopy in the Medicare Population SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID SERVICES TASK-FORCE; COLORECTAL-CANCER; SCREENING COLONOSCOPY; BOWEL PREPARATION; DIAGNOSTIC YIELD; UNITED-STATES; LOW-RISK; COMPLICATIONS; GUIDELINES; RECOMMENDATION AB Background: Although use of colonoscopy has increased substantially among elderly Medicare beneficiaries, no one has described colonoscopy-related adverse events in a representative sample of Medicare patients. Objective: To determine risk for adverse events after outpatient colonoscopy in elderly patients. Design: Population-based, matched cohort study. Setting: Surveillance, Epidemiology, and End Results cancer registry areas. Patients: Random 5% sample of Medicare beneficiaries, age 66 to 95 years, who underwent outpatient colonoscopy between 1 July 2001 and 31 October 2005 (n = 53 220), matched with beneficiaries who did not have colonoscopy. Measurements: Medicare claims were used to measure the rate of serious gastrointestinal events (bleeding and perforation), other gastrointestinal events, and cardiovascular events resulting in a hospitalization or emergency department visit within 30 days after colonoscopy compared with matched beneficiaries who did not have colonoscopy. Logistic regression was used to estimate adjusted predictive risks for adverse events and to assess whether these events varied by age, comorbid conditions, or type of colonoscopy. Results: Persons undergoing colonoscopy had a higher risk for adverse gastrointestinal events than their matched group. Rates of adverse events after colonoscopy increased with age. Patients having polypectomy had higher risk for all adverse events compared with their matched group and with the screening and diagnostic colonoscopy groups. Comorbid conditions increased the risk for adverse events. Patients with a history of stroke, chronic obstructive pulmonary disease, atrial fibrillation, or congestive heart failure had significantly higher risk for serious gastrointestinal events. Limitation: The analysis relied on the diagnosis and procedure codes recorded on the Medicare claims. Conclusion: Risks for adverse events after outpatient colonoscopy among elderly Medicare beneficiaries were low; however, they increased with age with specific comorbid conditions and depending on whether polypectomy was done. These data may inform decisions on whether to perform colonoscopy in persons of advanced age or those with comorbid conditions. C1 [Warren, Joan L.] NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. Univ N Carolina, Chapel Hill, NC USA. RP Warren, JL (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Room 4005,6130 Execut Blvd,MSC 734, Bethesda, MD 20892 USA. EM joan_warren@nih.gov NR 50 TC 161 Z9 165 U1 0 U2 3 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 16 PY 2009 VL 150 IS 12 BP 849 EP U51 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 460CX UT WOS:000267164800004 PM 19528563 ER PT J AU Shewmaker, F Kryndushkin, D Chen, B Tycko, R Wickner, RB AF Shewmaker, Frank Kryndushkin, Dmitry Chen, Bo Tycko, Robert Wickner, Reed B. TI Two Prion Variants of Sup35p Have In-Register Parallel beta-Sheet Structures, Independent of Hydration SO BIOCHEMISTRY LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; HET-S PRION; AMYLOID FIBRILS; SACCHAROMYCES-CEREVISIAE; TRANSLATION TERMINATION; SECONDARY STRUCTURE; STRAIN VARIATION; POLAR ZIPPERS; URE3 PRION AB The [PSI(+)] prion is a self-propagating amyloid of the Sup35 protein, normally a subunit of the translation termination factor, but impaired in this vital function when in the amyloid form. The Sup35 N, M, and C domains are the amino-terminal prion domain, a connecting polar domain, and the essential C-terminal domain resembling eukaryotic elongation factor 1 alpha respectively. Different [PSI(+)] isolates (prion variants) may have distinct biological properties, associated with different amyloid structures. Here we use solid state NMR to examine the structure of infectious Sup35NM amyloid fibrils of two prion variants. We find that both variants have an in-register parallel beta-sheet structure, both in the fully hydrated form and in the lyophilized form. Moreover, we confirm that some leucine residues in the M domain participate in the in-register parallel P-sheet structure. Transmission of the [PSI(+)] prion by amyloid fibrils of Sup35NM and transmission of the [URE3] prion by amyloid fibrils of recombinant full-length Ure2p are similar whether they have been lyophilized or not (wet or dry). C1 [Shewmaker, Frank; Kryndushkin, Dmitry; Wickner, Reed B.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Chen, Bo; Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Bldg 8,Room 225,NIH 8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov RI Chen, Bo/F-3573-2015 FU Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 65 TC 49 Z9 50 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 16 PY 2009 VL 48 IS 23 BP 5074 EP 5082 DI 10.1021/bi900345q PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 456PX UT WOS:000266860400005 PM 19408895 ER PT J AU Hozumi, K Suzuki, N Uchiyama, Y Katagiri, F Kikkawa, Y Nomizu, M AF Hozumi, Kentaro Suzuki, Nobuharu Uchiyama, Yoshihiko Katagiri, Fumihiko Kikkawa, Yamato Nomizu, Motoyoshi TI Chain-Specific Heparin-Binding Sequences in the Laminin alpha Chain LG45 Modules SO BIOCHEMISTRY LA English DT Article ID EPITHELIAL BRANCHING MORPHOGENESIS; G-DOMAIN; BIOLOGICAL-ACTIVITY; KERATINOCYTE MIGRATION; SUBMANDIBULAR-GLAND; SYNTHETIC PEPTIDES; LOOP REGION; IDENTIFICATION; SITES; EXPRESSION AB Laminin alpha chains contain five tandem globular modules (LG 1-5) at the C-terminus. Here, we focused oil the LG45 module, which play a critical biological role via binding to heparin/heparan sulfate, and examined their chain-specific heparin-binding affinity. The relative heparin-binding affinity of recombinant laminin alpha chain LG45 proteins was as, follows: alpha 5 > alpha 4 > alpha 1 > alpha 2 and alpha 3. The alpha 5 chain LG45 module also promoted the strongest cell attachment. We screened heparin-binding sequences using the recombinant alpha 5LG45 protein and 43 synthetic peptides. Four peptides, A5G71 (GPLPSYLQFVGI) (IC(50) = 91.8 mu M), A5G77 (LVLFLNHGHFVA) (IC(50) = 7.0 mu M), A5G81 (AGQWHRVSVRWG) (IC(50) = 5.9 mu M), and A5G94 (KMPYVSLELEMR) (IC(50) = 0.84 mu M), inhibited the heparin-binding of rec-alpha 5LG45. Additionally, the same four peptides exhibited dose-dependent heparin-binding activity in a solid-phase assay. We found that the alpha 5 chain LG45 module contains four heparin-binding sequences, and this number is higher than that of the other LG45 modules (alpha 2 and alpha 3, one sequence; alpha 1 and alpha 4, two sequences). The data suggest that the active sequences identified from the synthetic peptide screening contribute to the heparin-binding activity of the LG45 module. Most of the heparin-binding sequences in the LG45 modules are located in the N-terminal regions of the LG4 module within the loop regions in the proteins. The data suggest that the N-terminal loop regions of the LG4 module are mainly involved in the heparin/heparan sulfate-mediated biological functions. C1 [Nomizu, Motoyoshi] Tokyo Univ Pharm & Life Sci, Lab Clin Biochem, Sch Pharm, Tokyo 1920392, Japan. [Suzuki, Nobuharu] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Nomizu, M (reprint author), Tokyo Univ Pharm & Life Sci, Lab Clin Biochem, Sch Pharm, 1432-1 Horinouchi, Tokyo 1920392, Japan. EM nomizu@toyaku.ac.jp RI Kikkawa, Yamato/D-1503-2010 FU Ministry of Education, Cultures, Sports, Science and Technology of Japan [17390024, 17014081, 21750174] FX This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Cultures, Sports, Science and Technology of Japan (17390024, 17014081, and 21750174). NR 41 TC 12 Z9 12 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 16 PY 2009 VL 48 IS 23 BP 5375 EP 5381 DI 10.1021/bi900542u PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 456PX UT WOS:000266860400037 PM 19415899 ER PT J AU Bilski, PJ Karriker, B Chignell, CF AF Bilski, P. J. Karriker, B. Chignell, C. F. TI Quenching and generation of singlet oxygen by hydroethidine and related chromophores SO CHEMICAL PHYSICS LETTERS LA English DT Article ID SOLVENT MIXTURES; SUPEROXIDE; PRODUCT; FLUORESCENCE; OXIDATION; ETHIDIUM; PLANTS AB We have found that the oxidative probe hydroethidine (HE) is an efficient (1)O(2) quencher with k(q) = 1.1 x 10(9) M (1) s (1) in CH(3)CN. The structurally related MitoSOX Red had k(q) = 2.1 x 10(9) M (1) s (1) in D(2)O-CH(3)CN containing DNA. Ethidium cation, the main oxidation product, and three model compounds, 5-ethyl-5,6-dihydro-3,8-dinitro-6-phenyl-6-phenanthridinol, 3-amino-2-naphthenol, and 2-aminophenol, were lesser (1)O(2) quenchers. Another product, 2-OH-ethidium cation, quenched (1)O(2) with k(q) = 5.5 x 10(8) M (1) s (1) in a D(2)O-CH(3)CN mixture. Interestingly, both ethidium and 2-OH-ethidium cations are weak (1)O(2) photosensitizers with quantum yields of (1)O(2) production in CH(3)CN of 0.06 and 0.03, respectively. Thus, (1)O(2) can be involved in photochemical experiments with MitoSOX Red and HE. (c) 2009 Published by Elsevier B.V. C1 [Bilski, P. J.; Karriker, B.; Chignell, C. F.] NIEHS, Pharmacol Lab, ETP, NIH, Res Triangle Pk, NC 27709 USA. RP Bilski, PJ (reprint author), NIEHS, Pharmacol Lab, ETP, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM bilski@niehs.nih.gov FU NIH; NIEHS FX This research was supported by the Intramural Research Program of the NIH, NIEHS. NR 24 TC 6 Z9 6 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD JUN 16 PY 2009 VL 475 IS 1-3 BP 116 EP 119 DI 10.1016/j.cplett.2009.05.032 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 454HS UT WOS:000266673600024 ER PT J AU Reeve, BB Potosky, AL Smith, AW Han, PK Hays, RD Davis, WW Arora, NK Haffer, SC Clauser, SB AF Reeve, Bryce B. Potosky, Arnold L. Smith, Ashley Wilder Han, Paul K. Hays, Ron D. Davis, William W. Arora, Neeraj K. Haffer, Samuel C. Clauser, Steven B. TI Impact of Cancer on Health-Related Quality of Life of Older Americans SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID LOCALIZED PROSTATE-CANCER; PROPENSITY-SCORE; MANAGED CARE; OUTCOMES-SURVEY; BREAST-CANCER; NURSES HEALTH; MEDICARE; SURVIVORS; DIFFERENCE; CARCINOMA AB The impact of cancer on health-related quality of life (HRQOL) is poorly understood because of the lack of baseline HRQOL status before cancer diagnosis. To our knowledge, this is the first population-based study to quantify the nature and extent of HRQOL changes from before to after cancer diagnosis for nine types of cancer patients and to compare their health with individuals without cancer. The Surveillance, Epidemiology, and End Results cancer registry data were linked with the Medicare Health Outcomes Survey (MHOS) data; data were collected from Medicare beneficiaries who were aged 65 years and older from 1998 through 2003. Cancer patients (n = 1432; with prostate, breast, colorectal, lung, bladder, endometrial, or kidney cancers; melanoma; or non-Hodgkin lymphoma [NHL]) were selected whose first cancer diagnosis occurred between their baseline and follow-up MHOS assessments. Control subjects without cancer (n = 7160) were matched to cancer patients by use of propensity scores that were estimated from demographics and comorbid medical conditions. Analysis of covariance models were used to estimate changes in HRQOL as assessed with the Medical Outcomes Study Short Form-36 survey (mean score = 50, SD = 10). All statistical tests were two-sided. Patients with all cancer types (except melanoma and endometrial cancer) reported statistically significant declines in physical health (mean scores: prostate cancer = -3.4, 95% confidence interval [CI] = -2.5 to -4.2; breast cancer = -3.5, 95% CI = -2.5 to -4.5; bladder cancer = -4.3, 95% CI = -2.5 to -6.1; colorectal cancer = -4.4, 95% CI = -3.3 to -5.5; kidney cancer = -5.7, 95% CI = -3.2 to -8.2; NHL = -6.7, 95% CI = -4.4 to -9.1; and lung cancer = -7.5, 95% CI = -5.9 to -9.2) compared with the control subjects (mean score = -1.8, 95% CI = -1.6 to -2.0) (all P < .05). However, only lung (mean score = -5.4, 95% CI = -3.5 to -7.2), colorectal (mean score = -3.5, 95% CI = -2.2 to -4.7), and prostate (mean score = -2.8, 95% CI = -1.8 to -3.7) cancer patients showed statistically significant decreases in mental health relative to the mean change of the control subjects (mean score = -1.2, 95% CI = -0.9 to -1.4) (all P < .05). These findings provide validation of the specific deleterious effects of cancer on HRQOL and an evidence base for future research and clinical interventions aimed at understanding and remediating these effects. C1 [Reeve, Bryce B.; Smith, Ashley Wilder; Han, Paul K.; Arora, Neeraj K.; Clauser, Steven B.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Davis, William W.] NCI, Statistician Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Potosky, Arnold L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Canc Control Program, Washington, DC 20007 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Div Gen Internal Med, Los Angeles, CA 90024 USA. [Hays, Ron D.] Univ Calif Los Angeles, Dept Med, Hlth Serv Res, Los Angeles, CA 90024 USA. [Haffer, Samuel C.] Ctr Medicare Serv, Off Res Dev & Informat, Baltimore, MD USA. [Haffer, Samuel C.] Ctr Medicaid Serv, Off Res Dev & Informat, Baltimore, MD USA. RP Reeve, BB (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM reeveb@mail.nih.gov RI Hays, Ronald/D-5629-2013; OI Han, Paul/0000-0003-0165-1940 FU The National Cancer Institute; Centers for Medicare & Medicaid Services; Medicare Health Outcomes Survey FX The National Cancer Institute funded the collection of cancer data from the Surveillance, Epidemiology, and End Results registry, and the Centers for Medicare & Medicaid Services supported the Medicare Health Outcomes Survey. No grants were awarded for this study. NR 43 TC 87 Z9 87 U1 4 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 16 PY 2009 VL 101 IS 12 BP 860 EP 868 DI 10.1093/jnci/djp123 PG 9 WC Oncology SC Oncology GA 460XH UT WOS:000267225000008 PM 19509357 ER PT J AU Belyantseva, IA Perrin, BJ Sonnemann, KJ Zhu, M Stepanyan, R Mcgee, J Frolenkov, GI Walsh, EJ Friderici, KH Friedman, TB Ervasti, JM AF Belyantseva, Inna A. Perrin, Benjamin J. Sonnemann, Kevin J. Zhu, Mei Stepanyan, Ruben McGee, JoAnn Frolenkov, Gregory I. Walsh, Edward J. Friderici, Karen H. Friedman, Thomas B. Ervasti, James M. TI gamma-Actin is required for cytoskeletal maintenance but not development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin; cytoskeleton; hearing ID COCHLEAR HAIR-CELLS; DROSOPHILA BRISTLES; HEARING-LOSS; BETA-ACTIN; F-ACTIN; MOLECULAR TREADMILL; FILAMENT TURNOVER; INNER-EAR; BUNDLES; STEREOCILIA AB beta(cyto)-Actin and gamma(cyto)-actin are ubiquitous proteins thought to be essential building blocks of the cytoskeleton in all non-muscle cells. Despite this widely held supposition, we show that gamma(cyto)-actin null mice (Actg1(-/-)) are viable. However, they suffer increased mortality and show progressive hearing loss during adulthood despite compensatory up-regulation of beta(cyto)-actin. The surprising viability and normal hearing of young Actg1(-/-) mice means that beta(cyto)-actin can likely build all essential non-muscle actin-based cytoskeletal structures including mechanosensory stereocilia of hair cells that are necessary for hearing. Although gamma(cyto)-actin-deficient stereocilia form normally, we found that they cannot maintain the integrity of the stereocilia actin core. In the wild-type, gamma(cyto)-actin localizes along the length of stereocilia but re-distributes to sites of F-actin core disruptions resulting from animal exposure to damaging noise. In Actg1(-/-) stereocilia similar disruptions are observed even without noise exposure. We conclude that gamma(cyto)-actin is required for reinforcement and long-term stability of F-actin-based structures but is not an essential building block of the developing cytoskeleton. C1 [Perrin, Benjamin J.; Sonnemann, Kevin J.; Ervasti, James M.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. [Belyantseva, Inna A.; Friedman, Thomas B.] NIDCD, Genet Mol Lab, NIH, Rockville, MD 20850 USA. [Zhu, Mei; Friderici, Karen H.] Michigan State Univ, E Lansing, MI 48824 USA. [Stepanyan, Ruben; Frolenkov, Gregory I.] Univ Kentucky, Dept Physiol, Lexington, KY 40536 USA. [Frolenkov, Gregory I.] NIDCD, Mol Biol & Genet Sect, NIH, Rockville, MD 20850 USA. [McGee, JoAnn; Walsh, Edward J.] Boys Town Natl Res Hosp, Dev Auditory Physiol Lab, Omaha, NE 68131 USA. RP Ervasti, JM (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM jervasti@umn.edu OI Frolenkov, Gregory/0000-0002-9810-5024 FU National Institutes of Health (NIH) [Z01-DC-000060, DC004568, F32 DC009539, R01 AR049899]; DRF; NOHR Foundation FX We thank J. Bartles and C. Bulinski for providing anti-espin antibody and one of the anti-gamma cyto-actin antibodies, respectively; D. Catts and P. Diers for technical assistance; D. Drayna, R. Chadwick, N. Gavara, A. Griffith, J. Bird, and R. Morell for critically reading the manuscript; P. Belyantsev for Fig. 1 drawing; and K. Prins, S. Ikeda, and A. Ikeda for preliminary analysis of Actg1-/- mice. The work was supported by intramural funds 1 Z01 DC000048-11 LMG (to T.B.F.), NIH intramural funds Z01-DC-000060 (to Andrew J. Griffith), funds from the DRF and NOHR Foundation (to G.I.F.), and NIH grants DC004568 (to K.H.F.), F32 DC009539 (to B. J. P.), and a R01 AR049899 (to J. M. E.). NR 31 TC 66 Z9 66 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 16 PY 2009 VL 106 IS 24 BP 9703 EP 9708 DI 10.1073/pnas.0900221106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458TD UT WOS:000267045500030 PM 19497859 ER PT J AU Than, NG Romero, R Goodman, M Weckle, A Xing, J Dong, Z Xu, Y Tarquini, F Szilagyi, A Gal, P Hou, ZC Tarca, AL Kim, CJ Kim, JS Haidarian, S Uddin, M Bohn, H Benirschke, K Santolaya-Forgas, J Grossman, LI Erez, O Hassan, SS Zavodszky, P Papp, Z Wildman, DE AF Than, Nandor Gabor Romero, Roberto Goodman, Morris Weckle, Amy Xing, Jun Dong, Zhong Xu, Yi Tarquini, Federica Szilagyi, Andras Gal, Peter Hou, Zhuocheng Tarca, Adi L. Kim, Chong Jai Kim, Jung-Sun Haidarian, Saied Uddin, Monica Bohn, Hans Benirschke, Kurt Santolaya-Forgas, Joaquin Grossman, Lawrence I. Erez, Offer Hassan, Sonia S. Zavodszky, Peter Papp, Zoltan Wildman, Derek E. TI A primate subfamily of galectins expressed at the maternal-fetal interface that promote immune cell death SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adaptive evolution; glycocode; maternal-fetal immune tolerance; PP13; preeclampsia ID LEYDEN CRYSTAL PROTEIN; REGULATORY T-CELLS; PHYLOGENETIC ANALYSIS; PLACENTAL EXPRESSION; EUTHERIAN MAMMALS; EVOLUTION; TOLERANCE; PREECLAMPSIA; LYSOPHOSPHOLIPASE; PREGNANCY AB Galectins are proteins that regulate immune responses through the recognition of cell-surface glycans. We present evidence that 16 human galectin genes are expressed at the maternal-fetal interface and demonstrate that a cluster of 5 galectin genes on human chromosome 19 emerged during primate evolution as a result of duplication and rearrangement of genes and pseudogenes via a birth and death process primarily mediated by transposable long interspersed nuclear elements (LINEs). Genes in the cluster are found only in anthropoids, a group of primate species that differ from their strep-sirrhine counterparts by having relatively large brains and long gestations. Three of the human cluster genes (LGALS13, -14, and -16) were found to be placenta-specific. Homology modeling revealed conserved three-dimensional structures of galectins in the human cluster; however, analyses of 24 newly derived and 69 publicly available sequences in 10 anthropoid species indicate functional diversification by evidence of positive selection and amino acid replacements in carbohydrate-recognition domains. Moreover, we demonstrate altered sugar-binding capacities of 6 recombinant galectins in the cluster. We show that human placenta-specific galectins are predominantly expressed by the syncytiotrophoblast, a primary site of metabolic exchange where, early during pregnancy, the fetus comes in contact with immune cells circulating in maternal blood. Because ex vivo functional assays demonstrate that placenta-specific galectins induce the apoptosis of T lymphocytes, we propose that these galectins reduce the danger of maternal immune attacks on the fetal semiallograft, presumably conferring additional immune tolerance mechanisms and in turn sustaining hemochorial placentation during the long gestation of anthropoid primates. C1 [Than, Nandor Gabor; Romero, Roberto; Weckle, Amy; Xing, Jun; Dong, Zhong; Xu, Yi; Tarquini, Federica; Tarca, Adi L.; Kim, Chong Jai; Kim, Jung-Sun; Grossman, Lawrence I.; Erez, Offer; Hassan, Sonia S.; Wildman, Derek E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI 48201 USA. [Romero, Roberto; Goodman, Morris; Weckle, Amy; Xing, Jun; Hou, Zhuocheng; Haidarian, Saied; Uddin, Monica; Grossman, Lawrence I.; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Romero, Roberto; Erez, Offer; Hassan, Sonia S.; Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Goodman, Morris] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Kim, Chong Jai; Kim, Jung-Sun] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Szilagyi, Andras; Gal, Peter] Hungarian Acad Sci, Inst Enzymol, H-1113 Budapest, Hungary. [Bohn, Hans] Behringwerke AG, D-35041 Marburg, Germany. [Benirschke, Kurt] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Santolaya-Forgas, Joaquin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1088 Budapest, Hungary. RP Romero, R (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; mgoodwayne@aol.com; dwildman@med.wayne.edu RI Szilagyi, Andras/A-3561-2008; Gal, Peter/B-5886-2011 OI Szilagyi, Andras/0000-0002-1773-6861; FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health, Department of Health and Human Services; National Science Foundation [BCS-0751508, BCS-0550209]; Hungarian Scientific Research Fund [NK77978, PD73096] FX We thank Dr. Prasenjit Das, Sivasakthy Sivalogan, and Hong Meng for assistance; Dr. Sue Land (Wayne State University, Applied Genomic Technology Center) for running qRT-PCR; Drs. Howard Petty, Sally Madsen- Bouterse, Maik Huttemann, and Raghavendra Navath for helpful advice; and Sara Tipton for critically reading the manuscript. We also thank Drs. Caro-Beth Stewart (State University of New York, Albany, NY) and Kathy Neiswanger (University of Pittsburgh, Pittsburgh, PA), the New England Regional Primate Center (Southborough, MA), and the Duke University Primate Center (Durham, NC) for providing DNA and/or tissue samples. This research was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services; by National Science Foundation Grants BCS-0751508 (to D.E.W.) and BCS-0550209 (to M. G.); and by the Hungarian Scientific Research Fund (OTKA) Grants NK77978 (to P.Z.) and PD73096 (to A.Sz.). NR 52 TC 72 Z9 81 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 16 PY 2009 VL 106 IS 24 BP 9731 EP 9736 DI 10.1073/pnas.0903568106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458TD UT WOS:000267045500035 PM 19497882 ER PT J AU Stanika, RI Pivovarova, NB Brantner, CA Watts, CA Winters, CA Andrews, SB AF Stanika, Ruslan I. Pivovarova, Natalia B. Brantner, Christine A. Watts, Charlotte A. Winters, Christine A. Andrews, S. Brian TI Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE extrasynaptic receptors; hippocampal neurons; mitochondria; NMDA receptor; synaptic activation ID HIPPOCAMPAL-NEURONS; NMDA RECEPTORS; IN-VITRO; CULTURED NEURONS; OXIDATIVE STRESS; CELL-DEATH; NEUROTOXICITY; ROLES; VULNERABILITY; MECHANISMS AB Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca(2+) overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, over-activation of only extrasynaptic NMDARs resulted in Ca(2+) entry strong enough to promote Ca(2+) overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca(2+) loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca(2+) overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca(2+) entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca(2+) spikes and modest, nondamaging mitochondrial Ca(2+) accumulation. The results-showing that the various routes of excitotoxic Ca(2+) entry converge on a common pathway involving Ca(2+) overload-induced mitochondrial dysfunction-reconcile and unify many aspects of the "route-specific'' and "calcium load-dependent'' views of exitotoxic injury. C1 [Stanika, Ruslan I.; Pivovarova, Natalia B.; Brantner, Christine A.; Watts, Charlotte A.; Winters, Christine A.; Andrews, S. Brian] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Andrews, SB (reprint author), NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. EM sba@helix.nih.gov OI Brantner, Christine/0000-0001-8172-901X FU Intramural Research Program of the National Institutes of Health; National Institute of Neurological Disorders and Stroke (NINDS) FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS). The authors are indebted to Dr. J. A. Galbraith and to the NINDS Electron Microscopy Facility for excellent technical assistance. NR 38 TC 89 Z9 93 U1 4 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 16 PY 2009 VL 106 IS 24 BP 9854 EP 9859 DI 10.1073/pnas.0903546106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458TD UT WOS:000267045500056 PM 19482936 ER PT J AU Driscoll, CA Macdonald, DW O'Brien, SJ AF Driscoll, Carlos A. Macdonald, David W. O'Brien, Stephen J. TI From wild animals to domestic pets, an evolutionary view of domestication SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE artificial selection; sympatric divergence ID MITOCHONDRIAL-DNA; CRANIOLOGICAL DIFFERENTIATION; ANCIENT DNA; ORIGINS; CAT; MULTIPLE; PHYLOGEOGRAPHY; AGRICULTURE; RADIATION; GENETICS AB Artificial selection is the selection of advantageous natural variation for human ends and is the mechanism by which most domestic species evolved. Most domesticates have their origin in one of a few historic centers of domestication as farm animals. Two notable exceptions are cats and dogs. Wolf domestication was initiated late in the Mesolithic when humans were nomadic hunter-gatherers. Those wolves less afraid of humans scavenged nomadic hunting camps and over time developed utility, initially as guards warning of approaching animals or other nomadic bands and soon thereafter as hunters, an attribute tuned by artificial selection. The first domestic cats had limited utility and initiated their domestication among the earliest agricultural Neolithic settlements in the Near East. Wildcat domestication occurred through a self-selective process in which behavioral reproductive isolation evolved as a correlated character of assortative mating coupled to habitat choice for urban environments. Eurasian wildcats initiated domestication and their evolution to companion animals was initially a process of natural, rather than artificial, selection over time driven during their sympatry with forbear wildcats. C1 [Driscoll, Carlos A.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Driscoll, Carlos A.; Macdonald, David W.] Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Tubney OX13 5QL, Oxon, England. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov OI Driscoll, Carlos/0000-0003-2392-505X NR 90 TC 93 Z9 97 U1 45 U2 304 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 16 PY 2009 VL 106 SU 1 BP 9971 EP 9978 DI 10.1073/pnas.0901586106 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 458TP UT WOS:000267046700006 PM 19528637 ER PT J AU Wall, EA Zavzavadjian, JR Chang, MS Randhawa, B Zhu, XC Hsueh, RC Liu, J Driver, A Bao, XR Sternweis, PC Simon, MI Fraser, IDC AF Wall, Estelle A. Zavzavadjian, Joelle R. Chang, Mi Sook Randhawa, Baljinder Zhu, Xiaocui Hsueh, Robert C. Liu, Jamie Driver, Adrienne Bao, Xiaoyan Robert Sternweis, Paul C. Simon, Melvin I. Fraser, Iain D. C. TI Suppression of LPS-Induced TNF-alpha Production in Macrophages by cAMP Is Mediated by PKA-AKAP95-p105 SO SCIENCE SIGNALING LA English DT Article ID NF-KAPPA-B; PROTEIN-KINASE-A; NECROSIS-FACTOR-ALPHA; VASOACTIVE-INTESTINAL-PEPTIDE; CYCLIC-AMP; ANCHORING PROTEIN; RNA INTERFERENCE; INNATE IMMUNITY; SIGNALING COMPLEXES; MONOCYTIC CELLS AB The activation of macrophages through Toll-like receptor (TLR) pathways leads to the production of a broad array of cytokines and mediators that coordinate the immune response. The inflammatory potential of this response can be reduced by compounds, such as prostaglandin E(2), that induce the production of cyclic adenosine monophosphate (cAMP). Through experiments with cAMP analogs and multigene RNA interference (RNAi), we showed that key anti-inflammatory effects of cAMP were mediated specifically by cAMP-dependent protein kinase (PKA). Selective inhibitors of PKA anchoring, time-lapse microscopy, and RNAi screening suggested that differential mechanisms of PKA action existed. We showed a specific role for A kinase-anchoring protein 95 in suppressing the expression of the gene encoding tumor necrosis factor-alpha, which involved phosphorylation of p105 (also known as Nfkb1) by PKA at a site adjacent to the region targeted by inhibitor of nuclear factor kappa B kinases. These data suggest that crosstalk between the TLR4 and cAMP pathways in macrophages can be coordinated through PKA-dependent scaffolds that localize specific pools of the kinase to distinct substrates. C1 [Wall, Estelle A.; Zavzavadjian, Joelle R.; Chang, Mi Sook; Randhawa, Baljinder; Zhu, Xiaocui; Liu, Jamie; Driver, Adrienne; Bao, Xiaoyan Robert; Simon, Melvin I.; Fraser, Iain D. C.] CALTECH, Div Biol, Pasadena, CA 91125 USA. [Hsueh, Robert C.; Sternweis, Paul C.] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA. RP Fraser, IDC (reprint author), NIAID, Program Syst Immunol & Infect Dis Modeling, NIH, Bldg 33,Rm 3W20B-4,33 N Dr,MSC-8180, Bethesda, MD 20892 USA. EM fraseri@niaid.nih.gov FU National Institute of General Medical Sciences [U54 GM062114] FX This work was supported by National Institute of General Medical Sciences Grant U54 GM062114. We thank L. Cheadle for excellent technical assistance and Alliance for Cellular Signaling colleagues for insight and advice. We are grateful to M. Covert and D. Baltimore for provision of the GFP-p65 construct, V. Coghlan for AKAP95 antisera, and W. Frankel and Y. Yang for the AKAP95GT mice. NR 75 TC 89 Z9 92 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD JUN 16 PY 2009 VL 2 IS 75 AR ra28 DI 10.1126/scisignal.2000202 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567VR UT WOS:000275475500003 PM 19531803 ER PT J AU Kapetanovic, IM Crowell, JA Krishnaraj, R Zakharov, A Lindeblad, M Lyubimov, A AF Kapetanovic, I. M. Crowell, J. A. Krishnaraj, R. Zakharov, A. Lindeblad, M. Lyubimov, A. TI Exposure and toxicity of green tea polyphenols in fasted and non-fasted dogs SO TOXICOLOGY LA English DT Article DE Green tea; Toxicity; Polyphenols; (-)-Epigallocatechin gallate (EGCG); Dogs; Fasted ID EPIGALLOCATECHIN-GALLATE EGCG; CAMELLIA-SINENSIS; ORAL BIOAVAILABILITY; HEALTHY-INDIVIDUALS; MEDICINAL BENEFITS; INDUCED ASTHMA; CATECHINS; CANCER; HEPATOTOXICITY; SUPPLEMENTS AB Standardized green tea extract was evaluated for exposure and toxicity in Beagle dogs following oral dosing by capsules. The main component (-)-epigallocatechin gallate (EGCG) accounted for 56-72% of the material. A 9-month chronic study (0, 200, 500. and 1000 mg/kg/day) was done in fasted dogs to take advantage of the reported improved catechin bioavailability with fasting. Extensive morbidity, mortality, and pathology of many major organs led to its early termination at 6.5 months and prevented identification of the toxicity mechanisms. A follow-up 13-week study examined the exposure to and toxicity of the extract. In general. toxicities were less severe than in the chronic study during the same interval. Dosing in a fed state resulted in considerably lower and less variable exposure than found under fasted conditions. Toxicity was less frequent and of lesser severity with lower exposure but limited sample size and large variability prevented reaching that definitive conclusion. Differences in mortality and morbidity between the preliminary terminated chronic and follow-up subchronic studies with the same dose of the same drug lot and similar exposure were not fully resolved as there may be other as yet unclear confounding factors. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Kapetanovic, I. M.; Crowell, J. A.] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Krishnaraj, R.; Zakharov, A.; Lindeblad, M.; Lyubimov, A.] Univ Illinois, Toxicol Res Lab, Chicago, IL 60612 USA. RP Kapetanovic, IM (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, 6130 Execut Blvd,Rm 2116, Bethesda, MD 20892 USA. EM kapetani@mail.nih.gov FU [N01-CN-43306] FX The work was conducted under contract N01-CN-43306. NR 38 TC 33 Z9 34 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUN 16 PY 2009 VL 260 IS 1-3 BP 28 EP 36 DI 10.1016/j.tox.2009.03.007 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 460BX UT WOS:000267161000004 PM 19464566 ER PT J AU Preis, SR Hwang, SJ Fox, CS Massaro, JM Levy, D Hoffmann, U O'Donnell, CJ AF Preis, Sarah Rosner Hwang, Shih-Jen Fox, Caroline S. Massaro, Joseph M. Levy, Daniel Hoffmann, Udo O'Donnell, Christopher J. TI Eligibility of Individuals With Subclinical Coronary Artery Calcium and Intermediate Coronary Heart Disease Risk for Reclassification (from the Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ELECTRON-BEAM TOMOGRAPHY; C-REACTIVE PROTEIN; COMPUTED-TOMOGRAPHY; EVENTS; PREDICTION; COHORT; ADULTS; AGE; REPRODUCIBILITY; QUANTIFICATION AB Coronary artery calcium (CAC) predicts risk for coronary heart disease (CRD) events and perhaps CAC testing may further stratify risk in individuals at intermediate CHD risk. We sought to determine the percentage of participants at intermediate CHD risk who could potentially be reclassified as having a high CHD risk based on the presence of a high CAC score and the prevalence, treatment, and control of CHD risk factors in this group. Framingham Heart Study Offspring and Third Generation cohort participants underwent multidetector computed tomography (n = 3,529, mean age 51 years, 48% women). High CAC was defined as >= 90th age- and gender-specific percentiles based on a healthy reference group or by an absolute modified Agatston score of 100 HU. Prevalence of CHD risk factors (hypertension, hypercholesterolemia, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, smoking, and obesity), their treatment, and control was compared between nondiabetic participants with and without high CAC. Of the 595 participants at intermediate CHD risk, 22% had CAC 90th percentile and 39% had CAC 100 and could be eligible for reclassification as having a high CHD risk based on the presence of a high CAC score. There were no statistically significant differences in prevalence, treatment, and control of risk factors between those with and without high CAC. In conclusion, prevalence of CHD risk factors did not differ between intermediate-risk participants with and without high CAC. Approximately 25% of intermediate-risk individuals have high CAC scores and may be eligible for reclassification into a higher-risk category. (C) 2009 Published by Elsevier Inc. (Am J Cardiol 2009;103:1710-1715) C1 [Preis, Sarah Rosner; Hwang, Shih-Jen; Fox, Caroline S.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,MGH Cardiac MR PET CT Prog, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp,Dept Med, Boston, MA 02115 USA. RP O'Donnell, CJ (reprint author), NHLBI, Ctr Populat Studies, Framingham Heart Study, Framingham, MA USA. EM codonnell@nih.gov OI Preis, Sarah/0000-0002-9360-4166; Massaro, Joseph/0000-0002-2682-4812 FU Intramural NIH HHS [ZIA HL006002-04, Z99 HL999999]; NHLBI NIH HHS [N01-HC-25195, N01HC25195, N01 HC025195] NR 28 TC 18 Z9 19 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2009 VL 103 IS 12 BP 1710 EP 1715 DI 10.1016/j.amjcard.2009.02.020 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 463CS UT WOS:000267407000014 PM 19539080 ER PT J AU Ma, XM Lim, U Park, Y Mayne, ST Wang, R Hartge, P Hollenbeck, AR Schatzkin, A AF Ma, Xiaomei Lim, Unhee Park, Yikyung Mayne, Susan T. Wang, Rong Hartge, Patricia Hollenbeck, Albert R. Schatzkin, Arthur TI Obesity, Lifestyle Factors, and Risk of Myelodysplastic Syndromes in a Large US Cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE life style; myelodysplastic syndromes; obesity; smoking ID WORLD-HEALTH-ORGANIZATION; UNITED-STATES; BODY-WEIGHT; CANCER-RISK; CLASSIFICATION; OVERWEIGHT; HEMATOPOIESIS; ASSOCIATION; DISEASES; SMOKING AB The etiology of myelodysplastic syndromes (MDS) is not well understood. The authors examined the relations of obesity and lifestyle factors to MDS in a cohort of 471,799 persons aged 50-71 years who were recruited into the National Institutes of Health-AARP Diet and Health Study, a large US prospective study, in 1995-1996. Incident MDS was diagnosed in 193 persons during 2001-2003. A significant positive association was observed between body mass index (BMI; weight (kg)/height (m)(2)) at baseline and MDS. Compared with persons with a BMI less than 25.0, the hazard ratios for persons with BMIs of 25.0-< 30.0 and >= 30.0 were 1.15 (95% confidence interval (CI): 0.81, 1.64) and 2.18 (95% CI: 1.51, 3.17; P for trend < 0.001), respectively. The association was not affected by physical activity, cigarette smoking, or alcohol intake. As reported in previous studies, the risk of MDS was elevated among former smokers (hazard ratio = 1.68, 95% CI: 1.17, 2.41) and current smokers (hazard ratio = 3.17, 95% CI: 2.02, 4.98) as compared with never smokers. Physical activity, alcohol consumption, meat intake, and fruit and vegetable intake did not appear to significantly influence the risk of MDS in this analysis. This prospective investigation of MDS implicates both obesity and smoking as modifiable risk factors. C1 [Ma, Xiaomei; Mayne, Susan T.; Wang, Rong] Yale Sch Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT 06520 USA. [Lim, Unhee] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Park, Yikyung; Hartge, Patricia; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Ma, XM (reprint author), Yale Sch Publ Hlth, Div Chron Dis Epidemiol, 60 Coll St,Box 208034, New Haven, CT 06520 USA. EM xiaomei.ma@yale.edu RI Wang, Rong/H-3112-2011; OI Wang, Rong/0000-0002-2169-4174; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute [K07 CA119108] FX This work was supported by grant K07 CA119108 from the National Cancer Institute. NR 32 TC 21 Z9 21 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2009 VL 169 IS 12 BP 1492 EP 1499 DI 10.1093/aje/kwp074 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 457SN UT WOS:000266953700011 PM 19395696 ER PT J AU Manini, TM Everhart, JE Patel, KV Schoeller, DA Cummings, S Mackey, DC Bauer, DC Simonsick, EM Colbert, LH Visser, M Tylavsky, F Newman, AB Harris, TB AF Manini, Todd M. Everhart, James E. Patel, Kushang V. Schoeller, Dale A. Cummings, Steve Mackey, Dawn C. Bauer, Douglas C. Simonsick, Eleanor M. Colbert, Lisa H. Visser, Marjolein Tylavsky, Frances Newman, Anne B. Harris, Tamara B. CA Hlth Aging & Body Composition Stud TI Activity Energy Expenditure and Mobility Limitation in Older Adults: Differential Associations by Sex SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aging; disability evaluation; energy metabolism; exercise; mobility limitation; motor activity; sex ID CORONARY-HEART-DISEASE; DOUBLY LABELED WATER; PHYSICAL-ACTIVITY; ACTIVITY THERMOGENESIS; KNEE OSTEOARTHRITIS; FUNCTIONAL STATUS; MORTALITY; LIFE; EXERCISE; WOMEN AB In this study, the authors aimed to determine whether higher activity energy expenditure, assessed by using doubly labeled water, was associated with a reduced decline in mobility limitation among 248 older community-dwelling US adults aged 70-82 years enrolled in 1998-1999. Activity energy expenditure was calculated as total energy expenditure (assessed over 2 weeks by using doubly labeled water) minus resting metabolic rate (measured with indirect calorimetry), with adjustment for the thermic effect of food. Across sex-specific tertiles of activity energy expenditure, men in the lowest activity group experienced twice the rate of mobility limitation as men in the highest activity group (41% (n = 18) vs. 18% (n = 8)). Conversely, women in the lowest and highest activity groups exhibited similarly high rates of mobility limitation (40% (n = 16) vs. 38% (n = 15)). After adjustment for potential confounders, men with higher activity energy expenditure levels continued to show reduced risk of mobility limitation (per standard deviation (284 kcal/day): hazard ratio = 0.61, 95% confidence interval: 0.41, 0.92). Women showed no association (per standard deviation (226 kcal/day): hazard ratio = 1.34, 95% confidence interval: 0.98, 1.85). Greater energy expenditure from any and all physical activity was significantly associated with reduced risk of developing mobility limitation among men, but not among women. C1 [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Patel, Kushang V.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Everhart, James E.] NIDDK, Epidemiol & Data Syst Program, Bethesda, MD USA. [Schoeller, Dale A.] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. [Colbert, Lisa H.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53706 USA. [Visser, Marjolein] Vrije Univ Amsterdam, Inst Hlth Sci, Fac Earth & Life Sci, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam, Med Ctr, Inst Res Extramural Med, Amsterdam, Netherlands. [Tylavsky, Frances] Univ Tennessee, Dept Biostat & Epidemiol, Memphis, TN USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Cummings, Steve; Mackey, Dawn C.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. RP Manini, TM (reprint author), 210 E Mowry Rd,POB 112610, Gainesville, FL 32611 USA. EM tmanini@aging.ufl.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institute on Aging [NO1-AG-6-2101, NO1-AG-6-2103, NO1AG-6-2106]; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported by National Institute on Aging contracts NO1-AG-6-2101, NO1-AG-6-2103, and NO1AG-6-2106. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 51 TC 18 Z9 19 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 15 PY 2009 VL 169 IS 12 BP 1507 EP 1516 DI 10.1093/aje/kwp069 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 457SN UT WOS:000266953700013 PM 19383938 ER PT J AU Kim, RD Greenberg, DE Olivier, KN Holland, SM AF Kim, Richard D. Greenberg, David E. Olivier, Kenneth N. Holland, Steven M. TI Pathogenesis of Lady Windermere Syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter C1 [Kim, Richard D.; Greenberg, David E.; Olivier, Kenneth N.; Holland, Steven M.] NIH, Bethesda, MD 20892 USA. RP Kim, RD (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2009 VL 179 IS 12 BP 1165 EP 1165 PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 455TB UT WOS:000266787500017 ER PT J AU Athar, M Back, JH Kopelovich, L Bickers, DR Kim, AL AF Athar, Mohammad Back, Jung Ho Kopelovich, Levy Bickers, David R. Kim, Arianna L. TI Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE Resveratrol; Human cancer; Cell cycle regulation; Apoptosis; Transcription factors; Pro-oxidant; Lysosome; Growth signals ID BREAST-CANCER CELLS; NF-KAPPA-B; CARCINOMA A431 CELLS; S-PHASE ARREST; CHEMOPREVENTIVE AGENT RESVERATROL; HUMAN MEDULLOBLASTOMA CELLS; MAMMARY EPITHELIAL-CELLS; ACTIVATED PROTEIN-KINASE; TNF-INDUCED ACTIVATION; INDUCED APOPTOSIS AB Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3,4',5-trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ATR; transcription factors NF-kappa B, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl2 and Bcl-X(L). In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the antiproliferative mechanisms of resveratrol. (C) 2009 Elsevier Inc. All rights reserved. C1 [Back, Jung Ho; Bickers, David R.; Kim, Arianna L.] Columbia Univ, Dept Dermatol, Med Ctr, Irving Canc Res Ctr, New York, NY 10032 USA. [Athar, Mohammad] Univ Alabama, Dept Dermatol, Birmingham, AL 35294 USA. [Kopelovich, Levy] NCI, Dept Dermatol, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kim, AL (reprint author), Columbia Univ, Dept Dermatol, Med Ctr, Irving Canc Res Ctr, 1130 St Nicholas Ave 321B, New York, NY 10032 USA. EM ak309@columbia.edu FU NIH [R01 ES-015323, R01 CA-097249-01]; [K01-AR048582-04]; [R03 CA1 25855-01] FX This work was partially supported by the NIH Grants to R01 ES-015323 to M.A., R01 CA-097249-01 to D.R.B., and K01-AR048582-04 and R03 CA1 25855-01 to A.L.K. NR 141 TC 226 Z9 239 U1 3 U2 39 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JUN 15 PY 2009 VL 486 IS 2 BP 95 EP 102 DI 10.1016/j.abb.2009.01.018 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 457OD UT WOS:000266940300001 PM 19514131 ER PT J AU Huang, Y Wuchty, S Ferdig, MT Przytycka, TM AF Huang, Yang Wuchty, Stefan Ferdig, Michael T. Przytycka, Teresa M. TI Graph theoretical approach to study eQTL: a case study of Plasmodium falciparum SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT Joint Conference of Intelligent Systems for Molecular Biology and the European Conference on Computational Biology CY JUN 27-JUL 02, 2009 CL Stockholm, SWEDEN ID HUMAN GENE-EXPRESSION; GENOMICS; GENOMEWIDE; SEQUENCE; YEAST AB Motivation: Analysis of expression quantitative trait loci (eQTL) significantly contributes to the determination of gene regulation programs. However, the discovery and analysis of associations of gene expression levels and their underlying sequence polymorphisms continue to pose many challenges. Methods are limited in their ability to illuminate the full structure of the eQTL data. Most rely on an exhaustive, genome scale search that considers all possible locus-gene pairs and tests the linkage between each locus and gene. Result: To analyze eQTLs in a more comprehensive and efficient way, we developed the Graph based eQTL Decomposition method (GeD) that allows us to model genotype and expression data using an eQTL association graph. Through graph-based heuristics, GeD identifies dense subgraphs in the eQTL association graph. By identifying eQTL association cliques that expose the hidden structure of genotype and expression data, GeD effectively filters out most locus-gene pairs that are unlikely to have significant linkage. We apply GeD on eQTL data from Plasmodium falciparum, the human malaria parasite, and show that GeD reveals the structure of the relationship between all loci and all genes on a whole genome level. Furthermore, GeD allows us to uncover additional eQTLs with lower FDR, providing an important complement to traditional eQTL analysis methods. C1 [Huang, Yang; Przytycka, Teresa M.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Wuchty, Stefan] Northwestern Univ, NW Inst Complex, Evanston, IL 60201 USA. [Ferdig, Michael T.] Univ Notre Dame, Dept Biol Sci, Eck Inst Global Hlth, Notre Dame, IN 46556 USA. RP Przytycka, TM (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov RI Ferdig, Michael/C-6627-2016 FU NIAID NIH HHS [AI071121, AI055035, R01 AI055035, R01 AI071121] NR 25 TC 5 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2009 VL 25 IS 12 BP I15 EP I20 DI 10.1093/bioinformatics/btp189 PG 6 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 451VF UT WOS:000266498300003 PM 19477981 ER PT J AU Schulz, S Beisswanger, E van den Hoek, L Bodenreider, O van Mulligen, EM AF Schulz, Stefan Beisswanger, Elena van den Hoek, Laszlo Bodenreider, Olivier van Mulligen, Erik M. TI Alignment of the UMLS semantic network with BioTop: methodology and assessment SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT Joint Conference of Intelligent Systems for Molecular Biology and the European Conference on Computational Biology CY JUN 27-JUL 02, 2009 CL Stockholm, SWEDEN ID FORMAL REPRESENTATION; ONTOLOGIES; WEB; TERMINOLOGY; EXPERIENCE AB Motivation: For many years, the Unified Medical Language System (UMLS) semantic network (SN) has been used as an upper-level semantic framework for the categorization of terms from terminological resources in biomedicine. BioTop has recently been developed as an upper-level ontology for the biomedical domain. In contrast to the SN, it is founded upon strict ontological principles, using OWL DL as a formal representation language, which has become standard in the semantic Web. In order to make logic-based reasoning available for the resources annotated or categorized with the SN, a mapping ontology was developed aligning the SN with BioTop. Methods: The theoretical foundations and the practical realization of the alignment are being described, with a focus on the design decisions taken, the problems encountered and the adaptations of BioTop that became necessary. For evaluation purposes, UMLS concept pairs obtained from MEDLINE abstracts by a named entity recognition system were tested for possible semantic relationships. Furthermore, all semantic-type combinations that occur in the UMLS Metathesaurus were checked for satisfiability. Results: The effort-intensive alignment process required major design changes and enhancements of BioTop and brought up several design errors that could be fixed. A comparison between a human curator and the ontology yielded only a low agreement. Ontology reasoning was also used to successfully identify 133 inconsistent semantic-type combinations. C1 [Schulz, Stefan] Univ Med Ctr Freiburg, Inst Med Biometry & Med Informat, D-79104 Freiburg, Germany. [Beisswanger, Elena] Jena Univ Language & Informat Engn Lab, Jena, Germany. [van den Hoek, Laszlo; van Mulligen, Erik M.] Erasmus MC, Rotterdam, Netherlands. [Bodenreider, Olivier] Natl Lib Med, Bethesda, MD USA. RP Schulz, S (reprint author), Univ Med Ctr Freiburg, Inst Med Biometry & Med Informat, Stefan Meier Str 26, D-79104 Freiburg, Germany. EM stschulz@uni-freiburg.de OI van Mulligen, Erik/0000-0003-1377-9386 FU Intramural NIH HHS [Z99 LM999999] NR 50 TC 8 Z9 8 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUN 15 PY 2009 VL 25 IS 12 BP I69 EP I76 DI 10.1093/bioinformatics/btp194 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 451VF UT WOS:000266498300010 PM 19478019 ER PT J AU Gadgeel, SM Harlan, LC Zeruto, CA Osswald, M Schwartz, AG AF Gadgeel, Shirish M. Harlan, Linda C. Zeruto, Christopher A. Osswald, Michael Schwartz, Ann G. TI Patterns of Care in a Population-based Sample of Soft Tissue Sarcoma Patients in the United States SO CANCER LA English DT Article DE soft tissue sarcomas; SEER; patterns of care ID PROGNOSTIC-FACTORS; RADIATION-THERAPY; ADJUVANT CHEMOTHERAPY; UTERINE SARCOMA; RETROPERITONEAL; TRIAL; BRACHYTHERAPY; RADIOTHERAPY; EXTREMITIES; GUIDELINES AB BACKGROUND: Soft tissue sarcomas (STS) are relatively uncommon tumors. Data regarding the patterns of care of patients with STS and its consistency with available guidelines are relatively sparse. The authors conducted a detailed analysis of STS patients diagnosed in 2002 and sampled from the Surveillance, Epidemiology, and End Results registries. METHODS: The authors sampled 1369 patients with invasive sarcomas. Hospital records were reabstracted, and treating physicians were contacted to verify the therapy provided to each patient. RESULTS: The median age of patients was 60 years. There was a slight male predominance among the patients with nongynecologic sarcomas. Fifty percent of the patients had localized stage sarcoma. Most patients received surgery, but negative margins were obtained in only 50% of patients. Complete resection was less frequent in patients >= 50 years old. Radiation therapy was used in 53% of patients with extremity sarcomas but in only 20% to 30% of the patients with sarcomas at other sites. About 27% of all patients received chemotherapy. Tumor grade was significantly associated With the use of radiation and chemotherapy. Surgical resection, tumor grade, tumor size, use of radiation therapy, and age significantly influenced survival. CONCLUSIONS: Patterns of care of STS differ based on the site of the tumor. The patterns of care for extremity sarcomas are fairly consistent with the available recommendations, but the patterns of care for other sites are less consistent. In addition to certain tumor characteristics, age of the patient was significantly associated with therapy and patient outcome. Cancer 2009;115:2744-54. (C) 2009 American Cancer Society. C1 [Gadgeel, Shirish M.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Harlan, Linda C.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Rockville, MD USA. [Zeruto, Christopher A.] Informat Management Serv Inc, Silver Spring, MD USA. [Osswald, Michael] San Antonio Mil Med Canc, San Antonio, TX USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Populat Studies & Prevent Program, Detroit, MI USA. RP Gadgeel, SM (reprint author), 4100 John R,4 HWCRC, Detroit, MI 48201 USA. EM gadgeels@karmanos.org FU [N01-PC-35,133]; [N01-PC-35,135]; [N01-PC-35,141]; [N01-PC-35,136]; [N01-PC-35,137]; [N01-PC35,138]; [N01-PC-35,139]; [N01-PC-35,142]; [N01-PC-35,143]; [N01-PC-35,145]; [N01-PC-54,402]; [N01-PC-54,404]; [N01-PC-54,405] FX Supported in part by, grants N01-PC-35,133, N01-PC-35,135, N01-PC-35,141, N01-PC-35,136, N01-PC-35,137, N01-PC35,138, N01-PC-35,139, N01-PC-35,142, N01-PC-35,143, N01-PC-35,145, N01-PC-54,402, N01-PC-54,404, and N01-PC-54,405. NR 27 TC 8 Z9 9 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2009 VL 115 IS 12 BP 2744 EP 2754 DI 10.1002/cncr.24307 PG 11 WC Oncology SC Oncology GA 455UD UT WOS:000266790900020 PM 19396819 ER PT J AU Brennan, SE Kuwano, Y Alkharouf, N Blackshear, PJ Gorospe, M Wilson, GM AF Brennan, Sarah E. Kuwano, Yuki Alkharouf, Nadim Blackshear, Perry J. Gorospe, Myriam Wilson, Gerald M. TI The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ZINC-FINGER PROTEINS; AU-RICH ELEMENTS; GENE-EXPRESSION; DNA FRAGMENTATION; BREAST-CANCER; CELL LINES; BINDING; DEGRADATION; APOPTOSIS AB AU-rich element-binding proteins (ARE-BP) regulate the stability and/or translational efficiency of mRNAs containing cognate binding sites. Many targeted transcripts encode factors that control processes such as cell division, apoptosis, and angiogenesis, suggesting that dysregulated ARE-BP expression could dramatically influence oncogenic phenotypes. Using several approaches, we evaluated the expression of four well-characterized ARE-BPs across a variety of human neoplastic syndromes. AUF1, TIA-1, and HuR mRNAs were not systematically dysregulated in cancers; however, tristetraprolin mRNA levels were significantly decreased across many tumor types, including advanced cancers of the breast and prostate. Restoring tristetraprolin expression in an aggressive tumor cell line suppressed three key tumorgenic phenotypes: cell proliferation, resistance to proapoptotic stimuli, and expression of vascular endothelial growth factor mRNA. However, the cellular consequences of tristetraprolin expression varied across different cell models. Analyses of gene array data sets revealed that suppression of tristetraprolin expression is a negative prognostic indicator in breast cancer, because patients with low tumor tristetraprolin mRNA levels were more likely to present increased pathologic tumor grade, vascular endothelial growth factor expression, and mortality from recurrent disease. Collectively, these data establish that tristetraprolin expression is frequently suppressed in human cancers, which in turn can alter tumorigenic phenotypes that influence patient outcomes. [Cancer Res 2009;69(12):5168-76] C1 [Brennan, Sarah E.; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Brennan, Sarah E.; Wilson, Gerald M.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Kuwano, Yuki; Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Alkharouf, Nadim] Towson Univ, Dept Comp & Informat Sci, Baltimore, MD USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, GM (reprint author), Univ Maryland, Sch Med, Dept Biochem & Mol Biol, 108 N Greene St, Baltimore, MD 21201 USA. EM gwils001@umaryland.edu FU American Cancer Society [RSG-07-293-01-GMC]; NIH [R01 CA102428]; Intramural Research program of the National Institute on Aging-NIH FX American Cancer Society grant RSG-07-293-01-GMC and NIH grant R01 CA102428 (G.M. Wilson) and the Intramural Research program of the National Institute on Aging-NIH (M. Gorospe and Y. Kuwano). NR 40 TC 102 Z9 104 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2009 VL 69 IS 12 BP 5168 EP 5176 DI 10.1158/0008-5472.CAN-08-4238 PG 9 WC Oncology SC Oncology GA 464LM UT WOS:000267506400032 PM 19491267 ER PT J AU Solier, S Pommier, Y AF Solier, Stephanie Pommier, Yves TI The apoptotic ring A novel entity with phosphorylated histones H2AX and H2B and activated DNA damage response kinases SO CELL CYCLE LA English DT Article DE apoptosis; H2AX; histone; DNA repair; TRAIL; Chk2; DNA-PK; ATM; H2B ID DOUBLE-STRAND BREAKS; I CLEAVAGE COMPLEXES; TOPOISOMERASE-I; REPLICATION STRESS; CELL-CYCLE; FRAGMENTATION; GAMMA-H2AX; PATHWAY; CANCER; REPAIR AB We recently showed that histone H2AX phosphorylated on serine 139 (gamma-H2AX), a hallmark of DNA damage response (DDR), also forms early during apoptosis induced by death receptor activation. Here, we extend and discuss our findings on apoptotic gamma-H2AX, which differs from the well-established DDR with nuclear foci. During apoptosis induced by death receptors agonists (TRAIL and FasL) and staurosporine, gamma- H2AX is initiated in the nuclear periphery immediately inside the nuclear envelope while total H2AX remains distributed throughout the nucleus. This process is readily detectable by immunofluorescence microscopy and we refer to it as the "gamma-H2AX ring". It is conserved both in cancer and normal cells. The gamma-H2AX ring contains the activated checkpoints kinases, ATM, Chk2 and DNA-PK; the latter being the main effector for the apoptotic gamma-H2AX phosphorylation. Notably, we show here that the gamma- H2AX ring coincides with phosphorylated H2B on serine 14 (P(S14)-H2B), another histone modification associated with apoptosis. The coordinated phosphorylations of H2AX and H2B suggest a previously unrecognized histone phosphorylation signature for apoptosis consisting of gamma-H2AX together with P(S14)-H2B and possibly P(Y142)-H2AX. This signature ("phospho-histone 2 code") together with the gamma-H2AX ring provides a new feature to monitor and study apoptosis. C1 [Solier, Stephanie; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Center for Cancer Research; National Cancer Institute; National Institutes of Health FX This work was supported by the Center for Cancer Research, National Cancer Institute, National Institutes of Health. We wish to thank all members of the Laboratory of Molecular Pharmacology for stimulating discussions and suggestions during the course of these studies; special thanks to Dr. Christophe Redon and Dr. Kurt W. Kohn. NR 36 TC 50 Z9 50 U1 0 U2 6 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUN 15 PY 2009 VL 8 IS 12 BP 1853 EP 1859 DI 10.4161/cc.8.12.8865 PG 7 WC Cell Biology SC Cell Biology GA 457SZ UT WOS:000266955000015 PM 19448405 ER PT J AU Yan, P Wang, T Newton, GJ Knyushko, TV Xiong, YJ Bigelow, DJ Squier, TC Mayer, MU AF Yan, Ping Wang, Ting Newton, Gregory J. Knyushko, Tatyana V. Xiong, Yijia Bigelow, Diana J. Squier, Thomas C. Mayer, M. Uljana TI A Targeted Releasable Affinity Probe (TRAP) for In Vivo Photocrosslinking SO CHEMBIOCHEM LA English DT Article DE arsenic; bioorganic chemistry; fluorescent probes; mass spectrometry; photoaffinity labeling ID PROTEIN-PROTEIN INTERACTIONS; ESCHERICHIA-COLI HYDROGENASE; TETRACYSTEINE-TAGGED PROTEINS; RNA-POLYMERASE HOLOENZYME; MASS-SPECTROMETRY; TRANSCRIPTION INITIATION; SARCOPLASMIC-RETICULUM; CALMODULIN-BINDING; STRUCTURAL BASIS; LINKED PEPTIDES AB Protein crosslinking, especially coupled to mass-spectrometric identification, is increasingly used to determine protein binding partners and protein-protein interfaces for isolated protein complexes. The modification of crosslinkers to permit their targeted use in living cells is of considerable importance for studying protein-interaction networks, which are commonly modulated through weak interactions that are formed transiently to permit rapid cellular response to environmental changes. We have therefore synthesized a targeted and releasable affinity probe (TRAP) consisting of a biarsenical fluorescein linked to benzophenone that binds to a tetracysteine sequence in a protein engineered for specific labeling. Here, the utility of TRAP for capturing protein binding partners upon photoactivation of the benzophenone moiety has been demonstrated in living bacteria and mammalian cells. In addition, ligand exchange of the arsenic-sulfur bonds between TRAP and the tetracysteine sequence to added dithiols results in fluorophore transfer to the crosslinked binding partner. In isolated protein complexes, this release from the original binding site permits the identification of the proximal binding interface through mass spectrometric fragmentation and computational sequence identification. C1 [Wang, Ting; Xiong, Yijia; Bigelow, Diana J.; Squier, Thomas C.; Mayer, M. Uljana] Pacific NW Natl Lab, Cell Biol & Biochem Grp, Richland, WA 99354 USA. [Yan, Ping] Novozymes Inc, Davis, CA 95618 USA. [Newton, Gregory J.] Univ Tokyo, Komaba Open Lab, Meguro Ku, Tokyo 1538904, Japan. [Knyushko, Tatyana V.] NCI, Harris IT Serv, NIH, Bethesda, MD 20814 USA. RP Mayer, MU (reprint author), Pacific NW Natl Lab, Cell Biol & Biochem Grp, 999 Battelle Blvd,Stop P7-54, Richland, WA 99354 USA. EM uljana.mayer@pnl.gov NR 66 TC 12 Z9 12 U1 2 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD JUN 15 PY 2009 VL 10 IS 9 BP 1507 EP 1518 DI 10.1002/cbic.200900029 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 464JE UT WOS:000267500400015 PM 19441027 ER PT J AU Piekarz, RL Bates, SE AF Piekarz, Richard L. Bates, Susan E. TI Epigenetic Modifiers: Basic Understanding and Clinical Development SO CLINICAL CANCER RESEARCH LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; HUMAN LEUKEMIA-CELLS; ESOPHAGEAL CANCER-CELLS; DNA TOPOISOMERASE-II; XIAP DOWN-REGULATION; SODIUM-BUTYRATE; DEPSIPEPTIDE FR901228; MYELOGENOUS LEUKEMIA; HUMAN BREAST; ANTILEUKEMIC INTERACTIONS AB More than 60 years after the first description of differentiation in cell culture and 40 years after the synthesis of 5-azacytidine, epigenetic therapies have been added to the anticancer armamentarium. DNA methyltransferase (DNMT) inhibitors such as 5-aza-2'-deoxycytidine or 5-azacytidine have been approved in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), whereas the histone deacetylase inhibitors (HDIs) including vorinostat, romidepsin, panobinostat, belinostat, and entinostat have been shown to be active in cutaneous and peripheral T-cell lymphoma. Although the range of malignancies in which monotherapy with DNMT inhibitors or HDIs are effective has been limited to date, the possibility remains that a broader spectrum of activity will be identified as combination studies are completed. Meanwhile, basic science has provided a steadily increasing understanding of the complexity of the epigenome, including the histone code and triggers for aberrant methylation, and their contribution to oncogenesis. As our basic understanding of the epigenetics of cancer increases, the number of potential therapeutic targets will also increase, offering more hope in the quest to treat cancer by normalizing the epigenome. This issue of CCR Focus is dedicated to understanding the clinical and translational aspects of epigenetics research. C1 [Piekarz, Richard L.; Bates, Susan E.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 85 TC 86 Z9 89 U1 3 U2 15 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 3918 EP 3926 DI 10.1158/1078-0432.CCR-08-2788 PG 9 WC Oncology SC Oncology GA 459DP UT WOS:000267080800006 PM 19509169 ER PT J AU Schrump, DS AF Schrump, David S. TI Cytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical Implications SO CLINICAL CANCER RESEARCH LA English DT Review ID MESSENGER-RNA EXPRESSION; MYELOID-LEUKEMIA CELLS; HUMAN BREAST-CANCER; NF-KAPPA-B; TRICHOSTATIN-A; GENE-EXPRESSION; LUNG-CANCER; PROSTATE-CANCER; HDAC INHIBITORS; VALPROIC ACID AB Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacologic agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clinical implications of HDAC inhibition as a strategy for cancer therapy. C1 NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Rm 4-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM david_schrump@nih.gov NR 136 TC 96 Z9 99 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 3947 EP 3957 DI 10.1158/1078-0432.CCR-08-2787 PG 11 WC Oncology SC Oncology GA 459DP UT WOS:000267080800009 PM 19509170 ER PT J AU Schwartz, AL Malgor, R Dickerson, E Weeraratna, AT Slominski, A Wortsman, J Harii, N Kohn, AD Moon, RT Schwartz, FL Goetz, DJ Kohn, LD McCall, KD AF Schwartz, Anthony L. Malgor, Ramiro Dickerson, Eric Weeraratna, Ashani T. Slominski, Andrzej Wortsman, Jacobo Harii, Norikazu Kohn, Aimee D. Moon, Randall T. Schwartz, Frank L. Goetz, Douglas J. Kohn, Leonard D. McCall, Kelly D. TI Phenylmethimazole Decreases Toll-Like Receptor 3 and Noncanonical Wnt5a Expression in Pancreatic Cancer and Melanoma Together with Tumor Cell Growth and Migration SO CLINICAL CANCER RESEARCH LA English DT Article ID STAT3 SER727 PHOSPHORYLATION; VISCERAL FAT ACCUMULATION; IP-10 GENE-TRANSCRIPTION; KAPPA-B SITE; VASCULAR INFLAMMATION; PROSTATE-CANCER; TNF-ALPHA; ACTIVATION; PROLIFERATION; DISEASE AB Purpose: To evaluate whether (a) Wnt5a expression in pancreatic cancer and malignant melanoma cells might be associated with constitutive levels of Toll-like receptor 3 (TLR3) and/or TLR3 signaling; (b) phenylmethimazole (C10), a novel TLR signaling inhibitor, could decrease constitutive Wnt5a and TLR3 levels together with cell growth and migration; and (c) the efficacy of C10 as a potential inhibitor of pancreatic cancer and malignant melanoma cell growth in vivo. Experimental Design: We used a variety of molecular biology techniques including but not limited to PCR, Western blotting, and ELISA to evaluate the presence of constitutively activated TLR3/Wnt5a expression and signaling. 3-(4,5-Dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide-based technology and scratch assays were used to evaluate inhibition of cell growth and migration, respectively. TLR3 regulation of cell growth was confirmed using small interfering RNA technology. Nude and severe combined immunodeficient mice were implanted with human pancreatic cancer and/or melanoma cells and the effects of C10 on tumor growth were evaluated. Results: We show that constitutive TLR3 expression is associated with constitutive Wnt5a in human pancreatic cancer and malignant melanoma cell lines, that C10 can decrease constitutive TLR3/Wnt5a expression and signaling, suggesting that they are interrelated signal systems, and that C10 inhibits growth and migration in both of these cancer cell lines. We also report that C10 is effective at inhibiting human pancreatic cancer and malignant melanoma tumor growth in vivo in nude or severe combined immunodeficient mice and associate this with inhibition of signal transducers and activators of transcription 3 activation. Conclusions: C10 may have potential therapeutic applicability in pancreatic cancer and malignant melanoma. C1 [Schwartz, Anthony L.; Goetz, Douglas J.; McCall, Kelly D.] Ohio Univ, Russ Coll Engn & Technol, Biomed Engn Program, Athens, OH 45701 USA. [Dickerson, Eric; Harii, Norikazu; Kohn, Leonard D.] Ohio Univ, Edison Biotechnol Inst, Athens, OH 45701 USA. [Malgor, Ramiro] Ohio Univ, Dept Biomed Sci, Athens, OH 45701 USA. [Schwartz, Frank L.; McCall, Kelly D.] Ohio Univ, Dept Specialty Med, Coll Osteopath Med, Diabet Res Ctr,Appalachian Rural Hlth Inst, Athens, OH 45701 USA. [Goetz, Douglas J.] Ohio Univ, Dept Chem & Biomol Engn, Athens, OH 45701 USA. [Weeraratna, Ashani T.] NIA, Immunol Lab, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Slominski, Andrzej] Univ Tennessee, Ctr Hlth Sci, Dept Pathol & Lab Med, Memphis, TN 38163 USA. [Wortsman, Jacobo] So Illinois Univ, Dept Med, Springfield, IL USA. [Kohn, Aimee D.] Cascade Canc Ctr, Kirkland, WA USA. [Moon, Randall T.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP McCall, KD (reprint author), Ohio Univ, Russ Coll Engn & Technol, Biomed Engn Program, Konneker Res Bldg,Room 077,Bldg 25, Athens, OH 45701 USA. EM mccallk@ohiou.edu RI Moon, Randall/B-1743-2014 OI Moon, Randall/0000-0002-9352-1408 FU National Institute on Aging; National Institutes of Allergy and Infectious Diseases, NIH FX Intramural Research Program of the National Institute on Aging and an STTR grant from the National Institutes of Allergy and Infectious Diseases, NIH to Interthyr and Ohio University. NR 50 TC 31 Z9 31 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 4114 EP 4122 DI 10.1158/1078-0432.CCR-09-0005 PG 9 WC Oncology SC Oncology GA 459DP UT WOS:000267080800026 PM 19470740 ER PT J AU Matthews, K Noker, PE Tian, BH Grimes, SD Fulton, R Schweikart, K Harris, R Aurigemma, R Wang, MH Barnes, MN Siegal, GP Hemminki, A Zinn, K Curiel, DT Alvarez, RD AF Matthews, Kellie Noker, Patricia E. Tian, Baohong Grimes, Sheila D. Fulton, Ronna Schweikart, Karen Harris, Raymond Aurigemma, Rose Wang, Minghui Barnes, Mack N. Siegal, Gene P. Hemminki, Akseli Zinn, Kurt Curiel, David T. Alvarez, Ronald D. TI Identifying the Safety Profile of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Anticipation of a Phase I Clinical Trial in Patients with Recurrent Ovarian Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID KINASE GENE-THERAPY; HUMAN-MALIGNANT GLIOMA; MEDIATED DELIVERY; MOLECULAR CHEMOTHERAPY; GYNECOLOGICAL DISEASES; ADVANCED GENERATION; EXPRESSION; CARCINOMA; VECTORS; GANCICLOVIR AB Purpose: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. Experimental Design: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4,19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. Results: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time. Conclusions: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity. C1 [Matthews, Kellie; Barnes, Mack N.; Alvarez, Ronald D.] Univ Alabama, Div Gynecol Oncol, Birmingham, AL USA. [Zinn, Kurt] Univ Alabama, Dept Radiol, Birmingham, AL USA. [Wang, Minghui; Curiel, David T.] Univ Alabama, Div Human Gene Therapy, Birmingham, AL USA. [Siegal, Gene P.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Noker, Patricia E.; Tian, Baohong; Grimes, Sheila D.; Fulton, Ronna] So Res Inst, Birmingham, AL 35255 USA. [Schweikart, Karen] Toxicol & Pharmacol Branch, Bethesda, MD USA. [Aurigemma, Rose] NCI, Biol Resources Branch, Frederick, MD 21701 USA. [Harris, Raymond] Sci Applicat Int Corp, Biopharmaceut Dev Program, Frederick, MD USA. [Hemminki, Akseli] Univ Helsinki, Canc Gene Therapy Grp, Mol Canc Biol Program, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Transplantat Lab, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Haartman Inst, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, HUSLAB, Helsinki, Finland. [Hemminki, Akseli] Univ Helsinki, Cent Hosp, Helsinki, Finland. RP Matthews, K (reprint author), 618 19th St S,OHB 549, Birmingham, AL 35294 USA. EM ksmatthews13@gmail.com OI Zinn, Kurt/0000-0001-7463-4741 FU NCI NIH HHS [T32 CA075930, R01 CA108585, R01 CA121187] NR 31 TC 19 Z9 20 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 4131 EP 4137 DI 10.1158/1078-0432.CCR-08-3354 PG 7 WC Oncology SC Oncology GA 459DP UT WOS:000267080800028 PM 19509153 ER PT J AU Glynn, SA Boersma, BJ Howe, TM Edvardsen, H Geisler, SB Goodman, JE Ridnour, LA Lonning, PE Borresen-Dale, AL Naume, B Kristensen, VN Chanock, SJ Wink, DA Ambs, S AF Glynn, Sharon A. Boersma, Brenda J. Howe, Tiffany M. Edvardsen, Hege Geisler, Stephanie B. Goodman, Julie E. Ridnour, Lisa A. Lonning, Per E. Borresen-Dale, Anne-Lise Naume, Bjorn Kristensen, Vessela N. Chanock, Stephen J. Wink, David A. Ambs, Stefan TI A Mitochondrial Target Sequence Polymorphism in Manganese Superoxide Dismutase Predicts Inferior Survival in Breast Cancer Patients Treated with Cyclophosphamide SO CLINICAL CANCER RESEARCH LA English DT Article ID MNSOD GENE POLYMORPHISM; CELL CARCINOMA-CELLS; OXIDATIVE STRESS; PROSTATE-CANCER; ALA-9VAL POLYMORPHISM; GAMMA-RAYS; RISK; APOPTOSIS; OVEREXPRESSION; DOXORUBICIN AB Purpose: Manganese superoxide dismutase protects against oxidative damage and modulates the efficacy of chemotherapeutic drugs. A functional single-nucleotide polymorphism in codon 16 of SOD2 (rs4880), which encodes manganese superoxide dismutase, results in a substitution of valine by alanine (Val16Ala). We hypothesized that this single-nucleotide polymorphism affects breast cancer survival of patients receiving chemotherapy. Experimental Design: Two patient populations from the United States (n = 248) and Norway (n = 340) were genotyped for Val16Ala. Kaplan-Meier survival and Cox proportional hazards regression analyses were used to examine the relationship between Val16Ala and disease-specific survival. Results: Val16Ala was significantly associated with breast cancer outcome in both patient populations. Carriers of the Ala allele had inferior survival rates in the multivariate analysis [hazard ratio (HR), 2.44 and 95% confidence interval (95% CI), 1.11-5.37 in U.S. cohort; HR, 1.91 and 95% CI, 1.06-3.45 in Norway cohort for Ala/Ala versus Val/Val]. In an analysis of the combined cohorts, this association was significant for patients receiving adjuvant therapy (HR, 2.47; 95% CI, 1,464.19), but not for patients without it (HR, 1.47; 95% Cl, 0.57-3.74). After further stratification by type of chemotherapy, the effect of the Ala allele was mostly restricted to cyclophosphamide-containing chemotherapy regimens (HR, 22.0; 95% Cl, 5.22-92.9; Ala/Ala versus Val/Val). Conclusion: The Val16Ala polymorphism affects survival of patients receiving cyclophosphamide-containing chemotherapy. The findings provide the first evidence pointing toward a mechanism for cyclophosphamide resistance in breast cancer patients. C1 [Glynn, Sharon A.; Boersma, Brenda J.; Howe, Tiffany M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Glynn, Sharon A.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20892 USA. [Kristensen, Vessela N.] Univ Oslo, Fac Med, Inst Clin Epidemiol & Mol Biol EpiGen, Oslo, Norway. [Naume, Bjorn] Rikshosp Univ Hosp, Norwegian Radium Hosp, Dept Oncol, Oslo, Norway. [Borresen-Dale, Anne-Lise] Rikshosp Univ Hosp, Norwegian Radium Hosp, Fac Med, Oslo, Norway. [Edvardsen, Hege; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Rikshosp Univ Hosp, Norwegian Radium Hosp, Dept Genet, Inst Canc Res, Oslo, Norway. [Geisler, Stephanie B.; Lonning, Per E.] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. [Geisler, Stephanie B.; Lonning, Per E.] Univ Bergen, Inst Med, Sect Oncol, Bergen, Norway. [Goodman, Julie E.] Gradient Corp, Cambridge, MA 02138 USA. [Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Glynn, Sharon/D-7136-2013; Boersma, Brenda/A-9270-2009 OI Glynn, Sharon/0000-0003-1459-2580; Boersma, Brenda/0000-0002-8992-2735 FU NIH; National Cancer Institute; Center for Cancer Research; Research Council of Norway; Norwegian Cancer Society; All-Ireland Cancer Consortium National Cancer Institute Cancer Prevention Fellowship; Health Research Board of Ireland FX Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research; Research Council of Norway; and Norwegian Cancer Society. Sharon A. Glynn is a recipient of an All-Ireland Cancer Consortium National Cancer Institute Cancer Prevention Fellowship, sponsored in part by the Health Research Board of Ireland. NR 50 TC 20 Z9 21 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN 15 PY 2009 VL 15 IS 12 BP 4165 EP 4173 DI 10.1158/1078-0432.CCR-09-0119 PG 9 WC Oncology SC Oncology GA 459DP UT WOS:000267080800032 PM 19509150 ER EF