FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Satpute-Krishnan, P DeGiorgis, JA Bearer, EL AF Satpute-Krishnan, P DeGiorgis, JA Bearer, EL TI Fast anterograde transport of Herpes Simplex Virus: Role for the amyloid precursor protein of Alzheimer's disease SO AGING CELL LA English DT Review DE Herpes Simplex Virus; HSV; amyloid precursor; protein; APP; kinesin; fast axonal transport; anterograde transport ID SQUID GIANT-AXON; RECEPTOR-RELATED PROTEIN; NONMUSCLE MYOSIN-II; KINESIN LIGHT-CHAIN; AXOPLASMIC ORGANELLES; ACTIN-FILAMENTS; GOLGI-APPARATUS; ENDOPLASMIC-RETICULUM; CYTOPLASMIC DOMAIN; ALPHA-HERPESVIRUS AB Anterograde transport of herpes simplex virus (HSV) from its site of synthesis in the neuronal cell body out the neuronal process to the mucosal membrane is crucial for transmission of the virus from one person to another, yet the molecular mechanism is not known. By injecting GFP-labeled HSV into the giant axon of the squid, we reconstitute fast anterograde transport of human HSV and use this as an assay to uncover the underlying molecular mechanism. HSV travels by fast axonal transport at velocities four-fold faster (0.9 mum/sec average, 1.2 mum/sec maximal) than that of mitochondria moving in the same axon (0.2 mum/sec) and ten-fold faster than negatively charged beads (0.08 mum/sec). Transport of HSV utilizes cellular transport mechanisms because it appears to be driven from inside cellular membranes as revealed by negative stain electron microscopy and by the association of TGN46, a component of the cellular secretory pathway, with GFP-labeled viral particles. Finally, we show that amyloid precursor protein (APP), a putative receptor for the microtubule motor, kinesin, is a major component of viral particles, at least as abundant as any viral encoded protein, while another putative motor receptor, JlP 1/2, is not detected. Conventional kinesin is also associated with viral particles. This work links fast anterograde transport of the common pathogen, HSV, with the neurodegenerative Alzheimer's disease. This novel connection should prompt new ideas for treatment and prevention strategies. Key words: Herpes Simplex Virus; HSV; amyloid precursor; protein; APP; kinesin; fast axonal transport; anterograde transport. C1 Brown Univ, Sch Med, Dept Pathol & Lab Med, Providence, RI 02912 USA. NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP Bearer, EL (reprint author), Brown Univ, Sch Med, Dept Pathol & Lab Med, Biomed Ctr Rm 518, Providence, RI 02912 USA. FU NIGMS NIH HHS [GMS 47562, R01 GM047368] NR 105 TC 57 Z9 60 U1 0 U2 5 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1474-9718 J9 AGING CELL JI Aging Cell PD DEC PY 2003 VL 2 IS 6 BP 305 EP 318 DI 10.1046/j.1474-9728.2003.00069.x PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 753GW UT WOS:000187224500003 PM 14677633 ER PT J AU Semba, RD Blaum, C Guralnik, JM Moncrief, DT Ricks, MO Fried, LP AF Semba, RD Blaum, C Guralnik, JM Moncrief, DT Ricks, MO Fried, LP TI Carotenoid and vitamin E status are associated with indicators of sarcopenia among older women living in the community SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE aging; alpha-carotene; beta-carotene; carotenoids; lutein; lycopene; sarcopenia; women; zeaxanthin ID NUTRITION EXAMINATION SURVEY; HUMAN SKELETAL-MUSCLE; 3RD NATIONAL-HEALTH; ALPHA-TOCOPHEROL; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; OXIDATIVE DAMAGE; SERUM; AGE; ANTIOXIDANTS AB Background and aims: Oxidative stress may play a role in the pathogenesis of sarcopenia, and the relationship between dietary antioxidants and sarcopenia needs further elucidation. The aim was to determine whether dietary carotenoids and alpha-tocopherol are associated with sarcopenia, as indicated by low grip, hip, and knee strength. Methods: Cross-sectional analyses were conducted on 669 non-disabled to severely disabled community-dwelling women aged 70 to 79 who participated in the Women's Health and Aging Studies. Plasma carotenoids and a-tocopherol were measured. Grip, hip, and knee strength were measured, and low strength was defined as the lowest tertile of each strength measure. Results: Higher plasma concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin were associated with reduced risk of low grip, hip, and knee strength. After adjusting for potential confounding factors such as age, race, smoking, cardiovascular disease, arthritis, and plasma interleukin-6 concentrations, there was an independent association for women in the highest compared with the lowest quartile of total caratenoids with low grip strength [Odds Ratios (OR) 0.34, 95% Confidence Interval (CI) 0.20-0.59], low hip strength (OR 0.28, 95% CI 0.16-0.48), and low knee strength (OR 0.45, 95% CI 0.27-0.75), and there was an independent association for women in the highest compared with the lowest quartile of alpha-tocopherol with low grip strength (OR 0.44, 95% CI 0.24-0.78) and low knee strength (OR 0.52, 95% CI 0.29-0.95). Conclusions: Higher carotenoid and alpha-tocopherol status were independently associated with higher strength measures. These data support the hypothesis that oxidative stress is associated with sarcopenia in older adults, but further longitudinal and interventional studies are needed to establish causality. (C) 2003, Editrice Kurtis. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Semba, RD (reprint author), 550 N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU NCRR NIH HHS [RR00722]; NIA NIH HHS [N01-AG12112, R01 AG11703, R37 AG019905]; NIAID NIH HHS [R01 AI41956] NR 39 TC 59 Z9 62 U1 1 U2 7 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD DEC PY 2003 VL 15 IS 6 BP 482 EP 487 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 769MC UT WOS:000188653000007 PM 14959951 ER PT J AU Akinshola, BE Yasuda, RP Peoples, RW Taylor, RE AF Akinshola, BE Yasuda, RP Peoples, RW Taylor, RE TI Ethanol sensitivity of recombinant homomeric and heteromeric AMPA receptor subunits expressed in Xenopus oocytes SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE ethanol; glutamate; AMPA; receptor; Xenopus oocytes ID AMINO-ACID RECEPTORS; D-ASPARTATE RECEPTORS; CENTRAL-NERVOUS-SYSTEM; GLUTAMATE RECEPTORS; RAT-BRAIN; KAINATE RECEPTORS; HIPPOCAMPAL-NEURONS; NMDA RECEPTORS; INHIBITION; CHANNELS AB Background: Ethanol is known to acutely inhibit AMPA receptor function, and sensitivity of AMPA receptors to ethanol is dependent on subunit composition in vivo and in vitro. A commonly used in vitro expression system for studying recombinant receptor subunits is the Xenopus laevis oocyte and two-electrode voltage-clamp electrophysiological recording. To date, ethanol sensitivity of injected receptor subunit complementary RNA (cRNA) has not been shown to be correlated with the actual expression of receptor subunits in oocytes. In this study, we compared ethanol sensitivity of homomeric and heteromeric AMPA receptor subunits microinjected into Xenopus oocytes and confirmed subunit expression in oocytes by immunoblot. Methods: cRNAs coding for the "flop" type AMPA GluR1 or GluR3 (homomeric), GluR2/GluR3 (heteromeric combination), and GluR1/2/3 (heteromeric combination) were microinjected in equimolar amounts of 16 to 20 ng into oocytes, which were studied for their sensitivity to ethanol. Oocytes injected with cRNA for homomeric or heteromeric subunit combinations were homogenized and the expressed subunits quantified with anti-GluR1, anti-GluR2, and anti-GluR2/3 antibodies. Results: Ethanol concentrations of 10 to 500 mM consistently inhibited currents activated in oocytes by 200 muM kainic acid. The expressed homomeric GluR1 receptor and heteromeric GluR1/2/3 receptor combination currents showed similar sensitivity to ethanol inhibition with half-maximal inhibition values of 170 +/- 12 mM and 176 +/- 8 mM, respectively. The expressed homomeric GluR3 receptor and heteromeric GluR2/3 receptor combination currents were differentially sensitive to ethanol inhibition with respective IC50 values of 238 +/- 9 mM and 338 +/- 16 mM. Conclusion: The expressed homomeric, and heteromeric "flop" type AMPA receptors were differentially sensitive to ethanol, which may in part explain differential ethanol sensitivity in native neurons. C1 Howard Univ, Coll Med, Mol Pharmacol Lab, Dept Pharmacol, Washington, DC 20059 USA. Georgetown Univ, Dept Pharmacol, Washington, DC USA. Natl Inst Alcohol Abuse & Alcoholism, Unit Cellular Neuropharmacol, Cellular & Mol Neurobiol Lab, NIH, Bethesda, MD USA. RP Akinshola, BE (reprint author), Howard Univ, Coll Med, Mol Pharmacol Lab, Dept Pharmacol, 520 W St, Washington, DC 20059 USA. FU NIAAA NIH HHS [R29AA11284, R21AA13415]; PHS HHS [U2411898] NR 51 TC 8 Z9 8 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD DEC PY 2003 VL 27 IS 12 BP 1876 EP 1883 DI 10.1097/01.ALC.0000098874.65490.52 PG 8 WC Substance Abuse SC Substance Abuse GA 758WF UT WOS:000187674000004 PM 14691374 ER PT J AU Lindquist, R Dupuis, G Terrin, ML Hoogwerf, B Czajkowski, S Herd, JA Barton, FB Tracy, MF Hunninghake, DB Treat-Jacobson, D Shumaker, S Zyzanski, S Goldenberg, I Knatterud, GL AF Lindquist, R Dupuis, G Terrin, ML Hoogwerf, B Czajkowski, S Herd, JA Barton, FB Tracy, MF Hunninghake, DB Treat-Jacobson, D Shumaker, S Zyzanski, S Goldenberg, I Knatterud, GL CA POST CABG Biobehavioral Study Inve TI Comparison of health-related quality-of-life outcomes of men and women after coronary artery bypass surgery through 1 year: Findings from the POST CABG Biobehavioral Study SO AMERICAN HEART JOURNAL LA English DT Article; Proceedings Paper CT Outcomes 1999 Meeting CY MAY 27-30, 1999 CL KEY WEST, FLORIDA ID LONGITUDINAL DATA; CLINICAL-TRIALS; RECOVERY; DISEASE; IMPACT; MODELS AB Background Women undergoing coronary artery bypass graft (CABG) surgery have a worse medical condition and fewer social and financial resources than men. Some studies have found that women recover less well than men after CABG, whereas others have found women's outcomes comparable to those of men. Past studies of health-related quality of life after CABG have too few women for adequate comparison with men and have not included patients whose data are not available at baseline (eg, emergency CABG), limiting generalizability. Methods A longitudinal study of symptoms and health-related quality of life was conducted among patients from four clinical centers enrolling both men (n = 405) and women (n = 269) in the Post CABG Biobehavioral Study in the United States and Canada. Results After 6 weeks from CABG (average 81 days), both men and women had less anxiety and symptoms related to depression than before surgery (P < .001). After 6 months (average 294 days), both men and women improved in. physical and social functioning (P < .001). Although changes in scale scores were similar for men and women at each time point, women scored lower than men on these domains (P < .001, adjusted for baseline medical and sociodemographic differences) and had more symptoms related to depression through I year after CABG (P = .003). Conclusions Both male and female patients improve in physical, social, and emotional functioning after CABG, and recovery over time is similar in men and women. However, women's health-related quality-of-life scale scores remained less favorable than men's through 1 year after surgery. C1 Maryland Med Res Inst, Baltimore, MD 21210 USA. Univ Minnesota, Minneapolis, MN USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Univ Quebec, Montreal, PQ H3C 3P8, Canada. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Minneapolis Heart Inst Fdn, Minneapolis, MN USA. RP Terrin, ML (reprint author), Maryland Med Res Inst, 600 Wyndhurst Ave, Baltimore, MD 21210 USA. FU NHLBI NIH HHS [N01-HC-7501-7506] NR 31 TC 53 Z9 57 U1 2 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2003 VL 146 IS 6 BP 1038 EP 1044 DI 10.1016/S0002-8703(03)00451-4 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 751RF UT WOS:000187080200020 PM 14660996 ER PT J AU Carney, RM Blumenthal, JA Catellier, D Freedland, KE Berkman, LF Watkins, LL Czajkowski, SM Hayano, J Jaffe, AS AF Carney, RM Blumenthal, JA Catellier, D Freedland, KE Berkman, LF Watkins, LL Czajkowski, SM Hayano, J Jaffe, AS TI Depression as a risk factor for mortality after acute myocardial infarction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PREDICTORS; TRIAL; THROMBOLYSIS; ANXIETY; DEATH AB The ENRICHD clinical trial, which compared an intervention for depression and social isolation to usual care, failed to decrease the rate of mortality and recurrent acute myocardial infarction (AMI) in post-AMI patients. One explanation for this is that depression was not associated with increased mortality in these patients. The purpose of this study was to determine if depression was associated with an increased risk of mortality in a subsample of the ENRICHD trial's depressed patients compared with a group of nondepressed patients recruited for an ancillary study. Three hundred fifty-eight depressed patients with an acute AMI from the ENRICHD clinical trial and 408 nondepressed patients who met the ENRICHD medical inclusion criteria were followed for up to 30 months. There-were 47 deaths (6.1%) and 57 nonfatal AMIs (7.4%). After adjusting for other risk factors, depressed patients were at higher risk for all-cause mortality (hazard ratio 2.4, 95% confidence interval 1.2 to 4.7) but not for nonfatal recurrent infarction (hazard ratio 1.2, 95% confidence interval 0.7 to 2.0) compared with nondepressed patients. In conclusion, depression was an independent risk factor for death after AMI, but it did not have a significant effect on mortality until nearly 12 months after the acute event, nor did it predict nonfatal recurrent infarction. (C) 2003 by Excerpta Medica, Inc. C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Epidemiol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Biostat, St Louis, MO 63110 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Harvard Univ, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. Nagoya City Univ, Grad Sch Med, Nagoya, Aichi, Japan. Mayo Clin, Rochester, MN USA. RP Carney, RM (reprint author), Behav Med Ctr, 4625 Lindell Blvd,Suite 420, St Louis, MO 63108 USA. FU NHLBI NIH HHS [N01-HC-55146, 1UO-1HL58946, N01-HC-55140, N01-HC-55142, N01-HC-55148] NR 17 TC 127 Z9 131 U1 0 U2 6 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2003 VL 92 IS 11 BP 1277 EP 1281 DI 10.1016/j.amjcard.2003.08.007 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 747FL UT WOS:000186794500005 PM 14636903 ER PT J AU Chang, M Havlik, RJ Corti, MC Chaves, PHM Fried, LP Guralnik, JM AF Chang, M Havlik, RJ Corti, MC Chaves, PHM Fried, LP Guralnik, JM TI Relation of heart rate at rest and mortality in the women's health and aging study SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CARDIOVASCULAR RISK; PHYSICAL-ACTIVITY; BLOOD-PRESSURE; ELDERLY MEN; POPULATION; DISEASE; ATHEROSCLEROSIS; ASSOCIATION; SURVIVAL; SEVERITY AB Increased heart rate (HR) has been shown to be associated with increased risk of all-cause and heart disease mortality. However, HR as a health indicator in disabled older women has not been closely examined. The purpose of this study is to assess the association between HR and 3-year mortality in disabled older women. HR at rest was measured using the electrocardiogram. Three groups were categorized by baseline HR (beats per minute): (1) <60, (2) 60 to 89, and (3) greater than or equal to90. The survival rate over 3 years was examined. For the total population, age-adjusted 3-year mortality was nearly 40% for the HR greater than or equal to90 group, compared with <20% mortality in the HR 60 to 89 group. Women with a HR <60 beats/min had similar mortality to those with HRs 60 to 89 beats/min. Among women with no heart disease and normal electrocardiograms, mortality was slightly lower in all groups, but the association of elevated HR with increased mortality remained. In Cox proportional hazard models, after adjustment for age, number of diseases, medications, blood pressure, smoking status, body mass index, ankle-brachial index, activity status, physical performance score, and forced expiratory volume in the first second, there remained a twofold increase in the,risk of death for the HR :90 group. Subclinical conditions not measured in this study, such as mild heart failure, may be associated with both increased HR and mortality; this may explain the relation. In patients with and without heart disease, further investigation, of cardiovascular status may be warranted if their HR is 2:90 beats/min. (C) 2003 by Excerpta Medica, Inc. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Osped camposampiero, Dept Geriatr, Local Hlth Unit 15, Padua, Italy. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Ctr Aging & Hlth, Baltimore, MD USA. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-1-2112] NR 29 TC 24 Z9 24 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 1 PY 2003 VL 92 IS 11 BP 1294 EP 1299 DI 10.1016/j.amjcard.2003.08.010 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 747FL UT WOS:000186794500008 PM 14636906 ER PT J AU Weinberg, C AF Weinberg, C TI Invited commentary: Making the most of genotype asymmetries SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID CASE-PARENT TRIADS; LINKAGE DISEQUILIBRIUM; ASSOCIATION; DISEASE; DESIGNS; GENES C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Weinberg, C (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. OI Lee, Wen-Chung/0000-0003-3171-7672 NR 13 TC 5 Z9 5 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 DEC 1 PY 2003 VL 158 IS 11 BP 1033 EP 1035 DI 10.1093/aja/kwg267 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 749AQ UT WOS:000186896800002 PM 14630597 ER PT J AU Toren, A Rozenfeld-Granot, G Heath, KE Amariglio, N Rocca, B Crosson, J Epstein, CJ Laghi, F Landolfi, R Carlsson, LE Argraves, S Bizzaro, N Moxey-Mims, M Brok-Simoni, F Martignetti, JA Greinacher, A Rechavi, G AF Toren, A Rozenfeld-Granot, G Heath, KE Amariglio, N Rocca, B Crosson, J Epstein, CJ Laghi, F Landolfi, R Carlsson, LE Argraves, S Bizzaro, N Moxey-Mims, M Brok-Simoni, F Martignetti, JA Greinacher, A Rechavi, G TI MYH9 spectrum of autosomal-dominant giant platelet syndromes: Unexpected association with fibulin-1 variant-D inactivation SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE giant platelet syndrome; myosin heavy chain 9; fibulin; antisense ID FECHTNER-SYNDROME; LEUKOCYTE INCLUSIONS; CHROMOSOME 22Q11-13; ALPORTS-SYNDROME; GENETIC-LINKAGE; MACROTHROMBOCYTOPENIA; RNA; MUTATIONS; REGION AB The autosomal-dominant giant platelet syndromes (Fechtner, Epstein, and Sebastian platelet syndromes and May-Hegglin anomaly) represent a group of disorders characterized by variable degrees of macrothrombocytopenia with further combinations of neutrophil inclusion bodies and Alport-like syndrome manifestations, namely, deafness, renal disease, and eye abnormalities. The disease-causing gene of these giant platelet syndromes was previously mapped by us to chromosome 22. Following their successful mapping; these syndromes were shown to represent a broad phenotypic spectrum of disorders caused by different mutations in the nonmuscle myosin heavy chain 9 gene (MYH9). In this study, we examined the potential role of another gene, fibulin-1, encoding an extracellular matrix protein as a disease modifier. Eight unrelated families with autosomal-dominant giant platelet syndromes were studied for DNA sequence mutations and expression of the four fibulin-1 splice variants (A-D). A mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family, whereas no MYH9 mutations were identified. Unexpectedly, fibulin-1 variant D expression was absent in affected individuals from all eight families and coupled with expression of a putative antisense RNA. Transfection of the putative antisense RNA into H1299 cells abolished variant D expression. Based on the observation that only affected individuals lack variant D expression and demonstrate antisense RNA overexpression, we suggest that these autosomal-dominant giant platelet syndromes are associated, and may be modified, by aberrant antisense gene regulation of the fibulin-1 gene. (C) 2003 Wiley-Liss, Inc. C1 Chaim Sheba Med Ctr, Pediat Hemato Oncol Dept, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Inst Hematol, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. Mt Sinai Sch Med, Dept Human Genet, New York, NY USA. Mt Sinai Sch Med, Dept Pediat, New York, NY USA. Catholic Univ Med, Res Ctr Pathophysiol Haemostasis, Rome, Italy. Univ Minnesota, Hennepin Cty Med Ctr, Inst Pathol, Minneapolis, MN 55415 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Castrovillari Hosp, Dept Med, Castrovillari, Italy. Univ Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. Med Univ S Carolina, Dept Cell Biol, Charleston, SC 29425 USA. Civ Hosp, Clin Pathol Lab, Venice, Italy. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Toren, A (reprint author), Chaim Sheba Med Ctr, Pediat Hemato Oncol Dept, IL-52621 Tel Hashomer, Israel. RI Heath, Karen/K-7760-2014 OI Heath, Karen/0000-0002-5816-7044 FU NICHD NIH HHS [5 P30 HD28822] NR 28 TC 13 Z9 17 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2003 VL 74 IS 4 BP 254 EP 262 DI 10.1002/ajh.10425 PG 9 WC Hematology SC Hematology GA 749LJ UT WOS:000186921800006 PM 14635206 ER PT J AU Licht, CL Stevnsner, T Bohr, VA AF Licht, CL Stevnsner, T Bohr, VA TI Cockayne syndrome group B cellular and biochemical functions SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Review ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; NUCLEOTIDE EXCISION-REPAIR; LIGHT-INDUCED APOPTOSIS; PCNA COMPLEX-FORMATION; PROTEIN FAMILY-MEMBER; INDUCED DNA-DAMAGE; CSB GENE-PRODUCT; XERODERMA-PIGMENTOSUM; HUMAN-FIBROBLASTS AB The devastating genetic disorder Cockayne syndrome (CS) arises from mutations in the CSA and CSB genes. CS is characterized by progressive multisystem degeneration and is classified as a segmental premature-aging syndrome. The CS complementation group B (CSB) protein is at the interface of transcription and DNA repair and is involved in transcription-coupled and global genome-DNA repair, as well as in general transcription. Recent structure-function studies indicate a process-dependent variation in the molecular mechanism employed by CSB and provide a starting ground for a description of the mechanisms and their interplay. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Aarhus Univ, Dept Mol Biol, Lab DNA Repair, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 109 TC 90 Z9 93 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC PY 2003 VL 73 IS 6 BP 1217 EP 1239 DI 10.1086/380399 PG 23 WC Genetics & Heredity SC Genetics & Heredity GA 756PW UT WOS:000187491100001 PM 14639525 ER PT J AU Kogevinas, M Zahm, SH AF Kogevinas, M Zahm, SH TI Introduction: Epidemiologic research on occupational health in women SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Editorial Material C1 Municipal Inst Med Res, Resp & Environm Hlth Res Unit, Barcelona 08003, Spain. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. RP Kogevinas, M (reprint author), Municipal Inst Med Res, Resp & Environm Hlth Res Unit, 80 Dr Aiguader Rd, Barcelona 08003, Spain. RI Kogevinas, Manolis/C-3918-2017 NR 16 TC 3 Z9 4 U1 4 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD DEC PY 2003 VL 44 IS 6 BP 563 EP 564 DI 10.1002/ajim.10317 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 745LP UT WOS:000186690400001 PM 14635232 ER PT J AU Zahm, SH Blair, A AF Zahm, SH Blair, A TI Occupational cancer among women: Where have we been and where are we going? SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT 3rd International Congress on Womens Health - Occupation, Cancer and Reproduction CY SEP 13, 2002 CL BARCELONA, SPAIN SP NIH, Off Res Womens Hlth, Minist Health, Spain DE occupation; industry; cancer; women ID ASBESTOS TEXTILE WORKERS; MULTICENTER CASE-CONTROL; RADIUM DIAL WORKERS; LUNG-CANCER; BLADDER-CANCER; GENDER DIFFERENCES; RISK-FACTORS; UNITED-STATES; FOLLOW-UP; LYMPHOPROLIFERATIVE DISORDERS AB Studies of occupational exposures have been a fruitful area of research for identifying carcinogens. Some of the early observations, such as increased risk of breast cancer among nuns and bone cancer among radium dial workers, were made among women. Recent research on cancer among women has shown increased risks of cancer in many industries and occupations. Estimates that 1% of cancer among women is attributable to occupation are based on research conducted mainly in the 1970s among men in developed countries. These studies do not reflect the dramatic changes in the participation of women in the workplace or the patterns of employment of women in developing countries. The proportion of women in the paid workforce, the amounts and types of unpaid labor, the distribution of women by economy sector, the scale of the workplaces, the allowable exposure levels in the workplace, and implementation of controls have changed over time and vary internationally. Occupational cancer researchers need to expand their focus on women, increase activities in developing countries, include newly created industries, use sophisticated exposure assessment methods, and, where appropriate, incorporate molecular epidemiologic techniques to discover new occupational carcinogens and to identify where better control measures are needed. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Zahm, SH (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS 8074, Bethesda, MD 20892 USA. RI Zahm, Shelia/B-5025-2015 NR 129 TC 31 Z9 34 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD DEC PY 2003 VL 44 IS 6 BP 565 EP 575 DI 10.1002/ajim.10270 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 745LP UT WOS:000186690400002 PM 14635233 ER PT J AU Wyszynski, DF Albacha-Hejazi, H Aldirani, M Hammod, M Shkair, H Karam, A Alashkar, J Holmes, TN Pugh, EW Doheny, KF McIntosh, I Beaty, TH Bailey-Wilson, JE AF Wyszynski, DF Albacha-Hejazi, H Aldirani, M Hammod, M Shkair, H Karam, A Alashkar, J Holmes, TN Pugh, EW Doheny, KF McIntosh, I Beaty, TH Bailey-Wilson, JE TI A genome-wide scan for loci predisposing to non-syndromic cleft lip with or without cleft palate in two large Syrian families SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE linkage; oral clefts; CL/P; gene; genetics; susceptibility ID NONSYNDROMIC ORAL CLEFTS; PERICONCEPTIONAL VITAMIN USE; INFANT C677T MUTATION; ALPHA-GENE VARIANTS; LINKAGE DISEQUILIBRIUM; COMPLEX TRAITS; CANDIDATE GENES; SAUDI-ARABIA; OROFACIAL CLEFTS; MULTIPLEX FAMILIES AB Non-syndromic cleft lip with/without cleft palate (CL/P) is a common, usually non-fatal birth defect of complex etiology. Several segregation analyses have demonstrated that genetic factors are important in the pathogenesis of CL/P, most likely through the interaction of several genes of modest effects. The aim of this study was to perform a genome-wide linkage analysis to identify/search for candidate gene loci for CL/P. We conducted a genome-wide search in two large, relatively isolated Syrian families, each one with a large number of cases with CL/P (18 in family 1 and 4 in family 2). A locus with a multipoint LOD score of 2.80 and a 2-point non-parametric MLS LOD of 3.0 was detected on 17p13.1. Other chromosomal regions with multipoint LOD scores greater than or equal to1.2 (P less than or equal to 0.01) included 3p21.2, 4q32.1, and 7q34. These data indicate the possible presence of several susceptibility loci for CL/P and identify a strong candidate locus for this common birth defect on chromosome 17p13. Published 2003 Wiley-Liss, Inc(dagger). C1 NHGRI, NIH, Triad Technol Ctr, Inherited Dis Res Branch, Baltimore, MD 21224 USA. Boston Univ, Sch Med, Dept Med, Genet Program, Boston, MA 02118 USA. Ibn Al Nafees Hosp, Damascus, Syria. Johns Hopkins Sch Med, Ctr Inherited Dis Res, Baltimore, MD USA. Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Bailey-Wilson, JE (reprint author), NHGRI, NIH, Triad Technol Ctr, Inherited Dis Res Branch, Suite 2000,333 Cassell Dr, Baltimore, MD 21224 USA. EM jebw@nhgri.nih.gov OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NHGRI NIH HHS [N01 HG 65403]; NIDCR NIH HHS [R01 DE 10293] NR 91 TC 29 Z9 31 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC 1 PY 2003 VL 123A IS 2 BP 140 EP 147 DI 10.1002/ajmg.a.20283 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 744DK UT WOS:000186612500003 PM 14598337 ER PT J AU Zabetian, CP Romero, R Robertson, D Sharma, S Padbury, JF Kuivaniemi, H Kim, KS Kim, CH Kohnke, MD Kranzler, HR Gelernter, J Cubells, JF AF Zabetian, CP Romero, R Robertson, D Sharma, S Padbury, JF Kuivaniemi, H Kim, KS Kim, CH Kohnke, MD Kranzler, HR Gelernter, J Cubells, JF TI A revised allele frequency estimate and haplotype analysis of the DBH deficiency mutation IVS1+2T -> C in African- and European-Americans SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID DOPAMINE-BETA-HYDROXYLASE; NORADRENALINE; FAILURE C1 VA Puget Sound Hlth Care Syst, Dept Neurol, Seattle, WA 98108 USA. Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. Wayne State Univ, NICHHD, Perinatol Res Branch, Detroit, MI USA. Vanderbilt Univ, Autonom Dysfunct Ctr, Dept Med, Nashville, TN USA. Vanderbilt Univ, Autonom Dysfunct Ctr, Dept Pharmacol, Nashville, TN USA. Vanderbilt Univ, Autonom Dysfunct Ctr, Dept Neurol, Nashville, TN USA. Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. Womens & Childrens Hosp, Providence, RI USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. Harvard Univ, McLean Hosp, Sch Med, Mol Neurobiol Lab, Belmont, MA 02178 USA. Tuebingen Univ Hosp, Univ Hosp Psychiat & Psychotherapy, Tubingen, Germany. Univ Connecticut, Sch Med, Alcohol Res Ctr, Dept Psychiat, Farmington, CT USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. VA Connecticut Healthcare Syst, Dept Psychiat, West Haven, CT USA. RP Zabetian, CP (reprint author), VA Puget Sound Hlth Care Syst, Dept Neurol, 1660 S Columbian Way, Seattle, WA 98108 USA. EM zabetian@u.washington.edu OI Zabetian, Cyrus/0000-0002-7739-4306 NR 10 TC 6 Z9 6 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC 1 PY 2003 VL 123A IS 2 BP 190 EP 192 DI 10.1002/ajmg.a.20300 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 744DK UT WOS:000186612500012 PM 14598346 ER PT J AU Goncalves, LF Lee, W Chaiworapongsa, T Espinoza, J Schoen, ML Falkensammer, P Treadwell, M Romero, R AF Goncalves, LF Lee, W Chaiworapongsa, T Espinoza, J Schoen, ML Falkensammer, P Treadwell, M Romero, R TI Four-dimensional ultrasonography of the fetal heart with spatiotemporal image correlation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE prenatal diagnosis; ultrasonography; four-dimensional ultrasonography; three-dimensional ultrasonography; spatiotemporal image correlation; fetal echocardiography; congenital heart disease ID LOW-RISK PREGNANCIES; PRENATAL-DIAGNOSIS; 3-DIMENSIONAL ULTRASONOGRAPHY; 4-CHAMBER VIEW; HUMAN-FETUS; ECHOCARDIOGRAPHY; DISEASE; ACCURACY; ULTRASOUND; POPULATION AB OBJECTIVE: This study was undertaken to describe a new technique for the examination of the fetal heart using four-dimensional ultrasonography with spatiotemporal image correlation (STIC). STUDY DESIGN: Volume data sets of the fetal heart were acquired with a new cardiac gating technique (STIC), which uses automated transverse and longitudinal sweeps of the anterior chest wall. These volumes were obtained from 69 fetuses: 35 normal, 16 with congenital anomalies not affecting the cardiovascular system, and 18 with cardiac abnormalities. Dynamic multiplanar slicing and surface rendering of cardiac structures were performed. To illustrate the STIC technique, two representative volumes from a normal fetus were compared with volumes obtained from fetuses with the following congenital heart anomalies: atrioventricular septal defect, tricuspid stenosis, tricuspid atresia, and interrupted inferior vena cava with abnormal venous drainage. RESULTS: Volume datasets obtained with a transverse sweep were utilized to demonstrate the cardiac chambers, moderator band, interatrial and interventricular septae, atrioventricular valves, pulmonary veins, and outflow tracts. With the use of a reference dot to navigate the four-chamber view, intracardiac structures could be simultaneously studied in three orthogonal planes. The same volume dataset was used for surface rendering of the atrioventricular valves. The aortic and ductal arches were best visualized when the original plane of acquisition was sagittal. Volumes could be interactively manipulated to simultaneously visualize both outflow tracts, in addition to the aortic and ductal arches. Novel views of specific structures were generated. For example, the location and extent of a ventricular septal defect was imaged in a sagittal view of the interventricular septum. Furthermore, surface-rendered images of the atrioventricular valves were employed to distinguish between normal and pathologic conditions. Representative video clips were posted on the Journal's Web site to demonstrate the diagnostic capabilities of this new technique. CONCLUSION: Dynamic multiplanar slicing and surface rendering of the fetal heart are feasible with STIC technology. One good quality volume dataset, obtained from a transverse sweep, can be used to examine the four-chamber view and the outflow tracts. This novel method may assist in the evaluation of fetal cardiac anatomy. C1 Wayne State Univ, Hutzel Hosp, Perinatal Res Branch,NICHD, NIH,DHHS,Dept Obstet & Gynecol, Detroit, MI 48201 USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. GE Co, Med Syst Kretztech, Zipf, Austria. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, Perinatal Res Branch,NICHD, NIH,DHHS,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov NR 59 TC 127 Z9 151 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 BP 1792 EP 1802 DI 10.1016/S0002-9378(03)00913-X PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 760UP UT WOS:000187853900064 PM 14710117 ER PT J AU Abrahams, VM Straszewski, SL Romero, R Mor, G AF Abrahams, VM Straszewski, SL Romero, R Mor, G TI Toll-like receptor 2 induces apoptosis in trophoblast cells: A novel mechanism for first-trimester pregnancy failure SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Yale Univ, New Haven, CT USA. NICHHD, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 314 BP S147 EP S147 DI 10.1016/j.ajog.2003.10.315 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500312 ER PT J AU Andres, R AF Andres, R CA NICHD MFMU TI The impact of tobacco and cocaine use on preterm premature rupture of the membranes (pPROM) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 251 BP S131 EP S131 DI 10.1016/j.ajog.2003.10.252 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500250 ER PT J AU Beckerman, K Covington, D Watts, H Tilson, H Chavers, S Sacks, S AF Beckerman, K Covington, D Watts, H Tilson, H Chavers, S Sacks, S TI Risk of birth defects associated with antiretroviral exposure during pregnancy SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NYU, Sch Med, Dept Ob Gyn, New York, NY USA. PharmaRes Corp, Wilmington, NC USA. NICHHD, Pediat Adolescent Maternal AIDS Branch, Rockville, MD USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. GlaxoSmithKline, Epidemiol, Res Triangle Pk, NC USA. F Hoffmann La Roche & Co Ltd, Epidemiol, Nutley, NJ USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 13 BP S60 EP S60 DI 10.1016/j.ajog.2003.10.012 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500014 ER PT J AU Bujold, E Chaiworapongsa, T Hammoud, A Berman, S Hendler, I Blackwell, S Romero, R AF Bujold, E Chaiworapongsa, T Hammoud, A Berman, S Hendler, I Blackwell, S Romero, R TI Lactate dehydrogenase in amniotic fluid: A rapid, sensitive, and widely available test for the detection of intraamniotic inflammation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Wayne State Univ, Detroit, MI USA. NIH, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 368 BP S162 EP S162 DI 10.1016/j.ajog.2003.10.371 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500365 ER PT J AU Chaiworapongsa, T Espinoza, J Kim, YM Gomez, R Yoon, B Bujold, E Romero, R AF Chaiworapongsa, T Espinoza, J Kim, YM Gomez, R Yoon, B Bujold, E Romero, R TI A role for heat shock protein 70 in spontaneous parturition at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Detroit, MI USA. Seoul Natl Univ, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 501 BP S196 EP S196 DI 10.1016/j.ajog.2003.10.505 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500495 ER PT J AU Chaiworapongsa, T Espinoza, J Kim, YM Bujold, E Camacho, N Edwin, S Gomez, R Romero, R AF Chaiworapongsa, T Espinoza, J Kim, YM Bujold, E Camacho, N Edwin, S Gomez, R Romero, R TI Heat-shock proteins are elevated in intra-amniotic infection SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 428 BP S177 EP S177 DI 10.1016/j.ajog.2003.10.431 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500424 ER PT J AU Chaiworapongsa, T Gomez, R Edwin, S Mor, G Barder, T Romero, R AF Chaiworapongsa, T Gomez, R Edwin, S Mor, G Barder, T Romero, R TI A proteomic approach for the identification of biological markers of preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatal Res Branch, NIH, DHHS, Detroit, MI USA. Yale Univ, New Haven, CT USA. Epogen Inc, Darien, IL USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 112 BP S95 EP S95 DI 10.1016/j.ajog.2003.10.110 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500113 ER PT J AU Ecker, J Karumanchi, A Roberts, J Taylor, R Levine, R Thadhani, R AF Ecker, J Karumanchi, A Roberts, J Taylor, R Levine, R Thadhani, R TI First-trimester placental growth factor, SFLT-1, and risk for preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Harvard Univ, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 14 BP S60 EP S60 DI 10.1016/j.ajog.2003.10.013 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500015 ER PT J AU Hauth, J AF Hauth, J CA NICHD MFMU Network TI MFMU Cesarean Registry: Thromboembolism-occurrence and risk factors in 39,285 cesarean births SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 207 BP S120 EP S120 DI 10.1016/j.ajog.2003.10.208 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500206 ER PT J AU Hoffman, M Sciscione, A Vahratian, A Troendle, J Zhang, J AF Hoffman, M Sciscione, A Vahratian, A Troendle, J Zhang, J TI A comparison of labor curves between induced and noninduced multiparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Christiana Hosp, Newark, DE USA. Univ N Carolina Chapel Hill, Bethesda, MD USA. NIH, Epidemiol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 507 BP S198 EP S198 DI 10.1016/j.ajog.2003.10.511 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500501 ER PT J AU Kim, YM Tromp, G Kuivaniemi, SH Espinoza, J Bujold, E Kim, MR Kim, GJ Romero, R AF Kim, YM Tromp, G Kuivaniemi, SH Espinoza, J Bujold, E Kim, MR Kim, GJ Romero, R TI Spontaneous labor at term and histologic chorioamnionitis are characterized by up-regulation of the pattern recognition receptor toll-like receptor-2 SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 142 BP S103 EP S103 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500142 ER PT J AU Kim, YM Kim, MR Kim, GJ Chaiworapongsa, T Gomez, R Camacho, N Yoon, B Romero, R AF Kim, YM Kim, MR Kim, GJ Chaiworapongsa, T Gomez, R Camacho, N Yoon, B Romero, R TI The uterine cervix expresses the pattern-recognition receptors: Toll-like receptors-2 and-4 SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Seoul Natl Univ, Seoul, South Korea. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 141 BP S103 EP S103 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500141 ER PT J AU Kim, YM Kim, GJ Kim, MR Chaiworapongsa, T Espinoza, J Yoon, B Bujold, E Romero, R AF Kim, YM Kim, GJ Kim, MR Chaiworapongsa, T Espinoza, J Yoon, B Bujold, E Romero, R TI Skin: An active component of the fetal innate immune system SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Seoul Natl Univ, Seoul, South Korea. Wayne State Univ, Detroit, MI USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 47 BP S74 EP S74 DI 10.1016/j.ajog.2003.10.045 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500048 ER PT J AU Levine, R Maynard, S Qian, C Lim, KH England, L Yu, K Schisterman, E Thadhani, R Sachs, B Epstein, F Sibai, B Sukhatme, V Karumanchi, A AF Levine, R Maynard, S Qian, C Lim, KH England, L Yu, K Schisterman, E Thadhani, R Sachs, B Epstein, F Sibai, B Sukhatme, V Karumanchi, A TI Acute rise in circulating SFLT-1 may herald preeclampsia SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, DHHS, Bethesda, MD USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Allied Technol Grp, Rockville, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Cincinnati, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 6 BP S57 EP S57 DI 10.1016/j.ajog.2003.10.006 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500007 ER PT J AU Meis, P AF Meis, P TI More than one previous preterm delivery and the risk of preterm birth in women treated with 17 alpha-hydroxyprogesterone (17P) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, MFMU Network, CRMC, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 394 BP S168 EP S168 DI 10.1016/j.ajog.2003.10.396 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500391 ER PT J AU Ramsey, P Parker, R AF Ramsey, P Parker, R TI Elevated midtrimester maternal serum human chorionic gonadotropin (HCG) levels, but not progesterone or estriol, are associated with the subsequent development of preeclampsia (PRE) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NIH, Bethesda, MD 20892 USA. Univ Alabama, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 123 BP S98 EP S98 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500124 ER PT J AU Romero, R Chaiworapongsa, T Gomez, R Kim, YM Edwin, S Bujold, E Yoon, B AF Romero, R Chaiworapongsa, T Gomez, R Kim, YM Edwin, S Bujold, E Yoon, B TI Proteomic profiling of premature labor: A method to identify clinical biomarkers and mechanisms of disease SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. Wayne State Univ, Detroit, MI USA. Seoul Natl Univ, Seoul, South Korea. NR 0 TC 3 Z9 3 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 20 BP S63 EP S63 DI 10.1016/j.ajog.2003.10.019 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500021 ER PT J AU Simhan, H AF Simhan, H CA NICHD MFMU Network TI The MFMU PROM study: The relationship of maternal plasma cytokine concentrations and antibiotics with latency and histologic amnionitis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 403 BP S170 EP S170 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500400 ER PT J AU Simhan, H AF Simhan, H CA NICHD MFMU Network TI The MFMU prom study: Maternal & neonatal cytokines, histologic findings, & neonatal morbidity SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 128 BP S99 EP S99 DI 10.1016/j.ajog.2003.10.126 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500129 ER PT J AU Spong, C Wood, L Poggi, S Abebe, D AF Spong, C Wood, L Poggi, S Abebe, D TI Postnatal therapy to prevent alcohol-induced learning abnormalities in fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, SDMP, LDN, NIH, Bethesda, MD USA. Georgetown Univ, Washington, DC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 21 BP S63 EP S63 DI 10.1016/j.ajog.2003.10.020 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500022 ER PT J AU Straszewski, S Mor, G Romero, R Neale, D AF Straszewski, S Mor, G Romero, R Neale, D TI Serum from preeclamptic women induces caspase-3 activation in first-trimester trophoblast cells SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Yale Univ, Div Maternal Fetal Med, New Haven, CT USA. NICHHD, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 111 BP S95 EP S95 DI 10.1016/j.ajog.2003.10.109 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500112 ER PT J AU Tromp, G Kuivaniemi, H Chaiworapongsa, T Kim, YM Edwin, S Romero, R AF Tromp, G Kuivaniemi, H Chaiworapongsa, T Kim, YM Edwin, S Romero, R TI Genome-wide expression profiling of fetal membranes reveals deficient expression of proteinase inhibitor 3 in premature rupture of membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. NICHHD, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 54 BP S78 EP S78 DI 10.1016/j.ajog.2003.10.052 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500055 ER PT J AU Vahratian, A Zhang, J Troendle, JN Siega-Riz, AM Savitz, D Thorp, J AF Vahratian, A Zhang, J Troendle, JN Siega-Riz, AM Savitz, D Thorp, J TI Maternal obesity and labor progression in nulliparous women SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NIH, US Dept HHS, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RI Vahratian, Anjel/A-1182-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 526 BP S202 EP S202 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500520 ER PT J AU Vahratian, A Zhang, J Hasling, J Troendle, J Klebanoff, M Thorp, J AF Vahratian, A Zhang, J Hasling, J Troendle, J Klebanoff, M Thorp, J TI Effects of early epidural analgesia vs IV analgesia on labor progression: A natural experiment SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NIH, US Dept HHS, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Tripler Army Med Ctr, Tripler, HI USA. Univ N Carolina, Chapel Hill, NC USA. RI Vahratian, Anjel/A-1182-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 525 BP S202 EP S202 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500519 ER PT J AU Varner, M AF Varner, M CA NICHD MFMU Network TI Is there a seasonal variation in the diagnosis of oligohydramnios? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NICHD, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 437 BP S180 EP S180 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500433 ER PT J AU Zhang, J Troendle, J Vahratian, A Sciscione, A Hoffman, M AF Zhang, J Troendle, J Vahratian, A Sciscione, A Hoffman, M TI Elective labor induction and labor progression in nulliparas SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NIH, Epidemiol Branch, Bethesda, MD 20892 USA. NIH, Biostat Branch, Bethesda, MD 20892 USA. Christiana Hosp, Newark, DE USA. RI Vahratian, Anjel/A-1182-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 539 BP S206 EP S206 DI 10.1016/j.ajog.2003.10.543 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500533 ER PT J AU Zhang, J Hamilton, B Martin, J Trumble, A AF Zhang, J Hamilton, B Martin, J Trumble, A TI Delayed interval delivery improves infant survival: A population-based study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 24th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 02-07, 2004 CL NEW ORLEANS, LOUISIANA SP Soc Maternal Fetal Med C1 NIH, Epidemiol Branch, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2003 VL 189 IS 6 SU S MA 268 BP S136 EP S136 DI 10.1016/j.ajog.2003.10.269 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 761LP UT WOS:000187910500267 ER PT J AU Moroi, SE Lark, KK Sieving, PA Nouri-Mahdavi, K Schlotzer-Schrehardt, U Katz, GJ Ritch, R AF Moroi, SE Lark, KK Sieving, PA Nouri-Mahdavi, K Schlotzer-Schrehardt, U Katz, GJ Ritch, R TI Long anterior zonules and pigment dispersion SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT 13th Annual Meeting of the American-Glaucoma-Society CY MAR 06-09, 2003 CL SAN FRANCISCO, CALIFORNIA SP Amer Glaucoma Soc ID AGE; LENS AB PURPOSE: To describe pigment dispersion associated with long anterior zonules. DESIGN: Multicenter observational case series. METHODS: Fifteen patients, seven of whom were treated for glaucoma or ocular hypertension, were identified with long anterior zonules and pigment dispersion. Transmission electron microscopy was performed on one anterior capsule specimen. RESULTS: All patients had anterior zonules that inserted centrally on the lens capsule. Signs of pigment dispersion included corneal endothelial pigmentation, loss of the pupillary ruff, and variable trabecular meshwork pigmentation. Ultrasound biomicroscopy verified the lack of posterior iris insertion and concavity. There was no exfoliation material. Transmission electron microscopy showed zonular lamellae with adherent pigment granules, and no exfoliation material. CONCLUSIONS: Long anterior zonules inserted onto the central lens capsule may cause mechanical disruption of the pigment epithelium at the pupillary ruff and central iris leading to pigment dispersion. (C) 2003 by Elsevier Inc. All rights reserved. C1 Univ Michigan, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. New York Med Coll, Valhalla, NY 10595 USA. New York Eye & Ear Infirm, New York, NY 10003 USA. St Joseph Mercy Hosp, Ypsilanti, MI USA. Univ Erlangen Nurnberg, Dept Ophthalmol, D-8520 Erlangen, Germany. Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90024 USA. Iran Univ Med Sci, Dept Ophthalmol, Tehran, Iran. NEI, NIH, Bethesda, MD 20892 USA. Cabarrus Eye Ctr, Concord, NC USA. RP Moroi, SE (reprint author), Univ Michigan, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. RI Nouri-Mahdavi, Kouros/H-8922-2013 OI Nouri-Mahdavi, Kouros/0000-0001-9403-8904 NR 8 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD DEC PY 2003 VL 136 IS 6 BP 1176 EP 1178 DI 10.1016/S0002-9394(03)00657-3 PG 3 WC Ophthalmology SC Ophthalmology GA 749MF UT WOS:000186924000036 PM 14644241 ER PT J AU Flanders, KC Major, CD Arabshahi, A Aburime, EE Okada, MH Fujii, M Blalock, TD Schultz, GS Sowers, A Anzano, MA Mitchell, JB Russo, A Roberts, AB AF Flanders, KC Major, CD Arabshahi, A Aburime, EE Okada, MH Fujii, M Blalock, TD Schultz, GS Sowers, A Anzano, MA Mitchell, JB Russo, A Roberts, AB TI Interference with transforming growth factor-beta/Smad3 signaling results in accelerated healing of wounds in previously irradiated skin SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RADIATION-IMPAIRED WOUNDS; MICE LACKING SMAD3; FACTOR-BETA; IONIZING-RADIATION; MOUSE SKIN; GENE-EXPRESSION; TGF-BETA; FIBROBLASTS; TISSUE; TGF-BETA-1 AB Transforming growth factor (TGF)-beta regulates many aspects of wound repair including inflammation, chemotaxis, and deposition of extracellular matrix. We previously showed that epithelialization of incisional wounds is accelerated in mice null for Smad3, a key cytoplasmic mediator of TGF-beta signaling. Here, we investigated the effects of loss of Smad3 on healing of wounds in skin previously exposed to ionizing radiation, in which scarring fibrosis complicates healing. Cutaneous wounds made in Smad3-null mice 6 weeks after irradiation showed decreased wound widths, enhanced epithelialization, and reduced numbers of neutrophils and myofibroblasts; compared to wounds in irradiated wild-type littermates. Differences in breaking strength of wild-type and Smad3-null wounds were not significant. As shown previously for neutrophils, chemotaxis of primary dermal fibroblasts to TGF-beta required Smad3, but differentiation of fibroblasts to myofibroblasts by TGF-beta was independent of Smad3. Previous irradiation-enhanced induction of connective tissue growth factor mRNA in wildtype, but not Smad3-null fibroblasts, suggested that this may contribute to the heightened scarring in irradiated wild-type skin as demonstrated by Picrosirius red staining. Overall, the data suggest that attenuation of Smad3 signaling might improve the healing of wounds in previously irradiated skin commensurate with an inhibition of fibrosis. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. Univ Florida, Inst Wound Healing, Dept Obstet Gynecol, Gainesville, FL USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 42 TC 101 Z9 110 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2003 VL 163 IS 6 BP 2247 EP 2257 DI 10.1016/S0002-9440(10)63582-1 PG 11 WC Pathology SC Pathology GA 746WC UT WOS:000186769800013 PM 14633599 ER PT J AU Geisbert, TW Hensley, LE Larsen, T Young, HA Reed, DS Geisbert, JB Scott, DP Kagan, E Jahrling, PB Davis, KJ AF Geisbert, TW Hensley, LE Larsen, T Young, HA Reed, DS Geisbert, JB Scott, DP Kagan, E Jahrling, PB Davis, KJ TI Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques - Evidence that dendritic cells are early and sustained targets of infection SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; APOPTOSIS-INDUCING LIGAND; HUMAN T-CELLS; VIRUS-INFECTION; MEASLES-VIRUS; CYTOKINE PRODUCTION; GUINEA-PIGS; HUMAN MONOCYTES; IN-VITRO; NONHUMAN-PRIMATES AB Ebola virus (EBOV) infection causes a severe and fatal hemorrhagic disease that in many ways appears to be similar in humans and nonhuman primates; however, little is known about the development of EBOV hemorrhagic fever. in the present study, 21 cynomolgus monkeys were experimentally infected with EBOV and examined sequentially over a 6-day period to investigate the pathological events of EBOV infection that lead to death. importantly, dendritic cells in lymphoid tissues were identified as early and sustained targets of EBOV, implicating their important role in the immunosuppression characteristic of EBOV infections. Bystander lymphocyte apoptosis, previously described in end-stage tissues, occurred early in the disease-course in intravascular and extravascular locations. Of note, apoptosis and loss of NK cells was a prominent finding, suggesting the importance of innate immunity in determining the fate of the host. Analysis of peripheral blood mononuclear cell gene expression showed temporal increases in tumor necrosis factor-related apoptosis-inducing ligand and Fas transcripts, revealing a possible mechanism for the observed bystander apoptosis, while up-regulation of NAIP and cIAP2 mRNA suggest that EBOV has evolved additional mechanisms to resist host defenses by inducing protective transcripts in cells that it infects. The sequence of pathogenetic events identified in this study should provide new targets for rational prophylactic and chemotherapeutic interventions. C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21701 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Geisbert, TW (reprint author), USA, Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. OI Reed, Douglas/0000-0003-0076-9023 NR 82 TC 292 Z9 312 U1 7 U2 56 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2003 VL 163 IS 6 BP 2347 EP 2370 DI 10.1016/S0002-9440(10)63591-2 PG 24 WC Pathology SC Pathology GA 746WC UT WOS:000186769800022 PM 14633608 ER PT J AU Geisbert, TW Young, HA Jahrling, PB Davis, KJ Larsen, T Kagan, E Hensley, LE AF Geisbert, TW Young, HA Jahrling, PB Davis, KJ Larsen, T Kagan, E Hensley, LE TI Pathogenesis of Ebola hemorrhagic fever in primate models - Evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR; INFECTION; APOPTOSIS; PATHOLOGY; MONKEYS; MONOCYTES/MACROPHAGES; GLYCOPROTEINS; INVOLVEMENT; MACROPHAGES; ACTIVATION AB Ebola virus (EBOV) infection causes a severe and often fatal hemorrhagic disease in humans and nonhuman primates. Whether infection of endothelial cells is central to the pathogenesis of EBOV hemorrhagic fever (HF) remains unknown. To clarify the role of endothelial cells In EBOV HF, we examined tissues of 21 EBOV-infected cynomolgus monkeys throughout time, and also evaluated EBOV infection of primary human umbilical vein endothelial cells and primary human lung-derived microvascular endothelial cells in vitro. Results showed that endothelial cells were not early cellular targets of EBOV in vivo, as viral replication was not consistently observed until day 5 after infection, a full day after the onset of disseminated intravascular coagulation. Moreover, the endothelium remained relatively intact even at terminal stages of disease. Although human umbilical vein endothelial cells and human lung-derived microvascular endothelial cells were highly permissive to EBOV replication, significant cytopathic effects were not observed. Analysis of host cell gene response at 24 to 144 hours after infection showed some evidence of endothelial cell activation, but changes were unremarkable considering the extent of viral replication. Together, these data suggest that coagulation abnormalities associated with EBOV HF are not the direct result of EBOV-induced cytolysis of endothelial cells, and are likely triggered by immune-mediated mechanisms. C1 Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21701 USA. RP Geisbert, TW (reprint author), USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NR 38 TC 174 Z9 193 U1 0 U2 21 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2003 VL 163 IS 6 BP 2371 EP 2382 DI 10.1016/S0002-9440(10)63592-4 PG 12 WC Pathology SC Pathology GA 746WC UT WOS:000186769800023 PM 14633609 ER PT J AU Shan, L Yu, MS Qiu, CP Snyderwine, EG AF Shan, L Yu, MS Qiu, CP Snyderwine, EG TI Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LOOP-HELIX PROTEINS; SPRAGUE-DAWLEY RATS; MOLECULAR-CLONING; EXPRESSION; ID-1; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; CANCER; GENE; TUMORIGENESIS; 7,12-DIMETHYLBENZANTHRACENE AB Id4 belongs to a family of helix-loop-helix (HLH) proteins that impact cellular growth and differentiation via regulation of basic HLH transcription factors. Herein the rat Id4 gene was cloned (GenBank Accession No. AF468681). The expression of rat Id4 was examined in rat mammary gland tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a carcinogen found in the human diet. By real-time polymerase chain reaction analysis, relative expression of Id4 mRNA in carcinomas, adenomas, and normal tissue was 27, 6, and 1, respectively. Immunohistochemical analysis indicated statistically elevated nuclear expression for 1d4 protein in carcinomas in comparison to adenomas and normal mammary gland. in carcinomas, Id4 nuclear expression was positively correlated with proliferation, invasiveness, and tumor weight (Fisher Exact Test or Spearman Correlation, P < 0.05). The consequence of enforced expression of Id4 on mammary epithelial cell proliferation, differentiation, and growth In soft agar was examined in HC11 cells, a well-characterized model for studying various aspects of mammary epithelial cell biology. After transient and stable transfection of HC11 cells, Id4 overexpression increased cell proliferation and inhibited lactogenic hormone-mediated differentiation as revealed by inhibition of beta-casein promoter activity and beta-casein expression. in addition, enforced expression of Id4 in HC11 cells induced a statistically significant increase in colony growth in soft agar. The results implicate Id4 in rat mammary gland carcinogenesis and suggest that Id4 may contribute to carcinogenesis by inhibiting mammary epithelial cell differentiation and stimulating mammary epithelial cell growth. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Canc Res Ctr, Bldg 37,Room 4146,37 Convent Dr, Bethesda, MD 20892 USA. NR 42 TC 28 Z9 30 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2003 VL 163 IS 6 BP 2495 EP 2502 DI 10.1016/S0002-9440(10)63604-8 PG 8 WC Pathology SC Pathology GA 746WC UT WOS:000186769800035 PM 14633621 ER PT J AU Fanelli, A Grollman, EF Wang, D Philp, NJ AF Fanelli, A Grollman, EF Wang, D Philp, NJ TI MCT1 and its accessory protein CD147 are differentially regulated by TSH in rat thyroid cells SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE monocarboxylate transporter 1; monocarboxylate transporter 4; thyroid gland; thyroid-stimulating hormone; FRTL-5 cells; glycolysis; lactate ID RETINAL-PIGMENT EPITHELIUM; MONOCARBOXYLATE TRANSPORTER; IODIDE TRANSPORT; SKELETAL-MUSCLE; EXPRESSION; GLUCOSE; THYROTROPIN; METABOLISM; TOPOLOGY; TISSUE AB In thyroid cells, basal and TSH-stimulated glycolysis is associated with lactic acid efflux. In this report, we address whether monocarboxylate transporters (MCTs) are present in thyroid tissue for exporting excess lactic acid generated by aerobic glycolysis. Using immunostaining techniques, we show that MCT4 localizes with its accessory protein CD147 in the basolateral membrane of rat thyroid follicular cells. In cultured rat thyroid (FRTL-5) cells, MCT1 rather than MCT4 is expressed. CD147 colocalizes and coimmunoprecipitates with MCT1. TSH upregulates MCT1/CD147 expression as a function of time through a cAMP-dependent mechanism as forskolin reproduces the effect of TSH. TSH enhances protein expression of both MCT1 and CD147 in FRTL-5 cells. Whereas MCT1 protein expression is controlled at the level of transcription, CD147 protein expression is regulated by a posttranscriptional mechanism. Results of these studies suggest that hormone stimulation of transport is mediated by regulating MCT1 transcription. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. NIDDKD, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Philp, NJ (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, 1021 Locust St,Rm 534, Philadelphia, PA 19107 USA. FU NEI NIH HHS [EY-12042] NR 31 TC 31 Z9 31 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD DEC 1 PY 2003 VL 285 IS 6 BP E1223 EP E1229 DI 10.1152/ajpendo.00172.2003 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 741TC UT WOS:000186474500009 PM 14607782 ER PT J AU Chen, J Petranka, J Yamamura, K London, RE Steenbergen, C Murphy, E AF Chen, J Petranka, J Yamamura, K London, RE Steenbergen, C Murphy, E TI Gender differences in sarcoplasmic reticulum calcium loading after isoproterenol SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE neuronal nitric oxide synthase; ischemia ID NITRIC-OXIDE SYNTHASE; PERFUSED RABBIT HEART; RAT CARDIAC MYOCYTES; ADRENERGIC-STIMULATION; VENTRICULAR MYOCYTES; RELEASE CHANNEL; TRANSGENIC MICE; CA2+; INJURY; CARDIOPROTECTION AB Males exhibit enhanced myocardial ischemia-reperfusion injury versus females under hypercontractile conditions associated with increased sarcoplasmic reticulum (SR) Ca2+. We therefore examined whether there were gender differences in SR Ca2+. We used NMR Ca2+ indicator 1,2-bis(2-amino-5,6-difluorophenoxy)-ethane-N, N,N',N'-tetraacetic acid to measure SR Ca2+ in perfused rabbit hearts. Isoproterenol increased SR Ca2+ in males from a baseline of 1.13 +/- 0.07 to 1.52 +/- 0.24 mM (P < 0.05). Female hearts had basal SR Ca2+ that was not significantly different from males (1.04 +/- 0.03 mM), and addition of isoproterenol to females resulted in a time-averaged SR Ca2+ (0.97 +/- 0.07 mM) that was significantly less than in males. To confirm this difference, we measured caffeine-induced release of SR Ca2+ with fura-2 in isolated ventricular myocytes. Ca2+ release after caffeine in untreated male myocytes was 377 +/- 41 nM and increased to 650 +/- 55 nM in isoproterenol-treated myocytes (P < 0.05). Ca2+ release after caffeine addition in untreated females was 376 +/- 27 nM and increased to 503 +/- 49 nM with isoproterenol, significantly less than in male myocytes treated with isoproterenol (P < 0.05). Treatment of female myocytes with N-G-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase (NOS), resulted in higher SR Ca2+ release than that measured in females treated only with isoproterenol and was not significantly different from that measured in males with isoproterenol. Female myocytes also have significantly higher levels of neuronal NOS. This gender difference in SR Ca2+ handling may contribute to reduced ischemia-reperfusion injury observed in females. C1 NIEHS, Labs Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Murphy, E (reprint author), NIEHS, Labs Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01 HL039752] NR 31 TC 43 Z9 43 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC 1 PY 2003 VL 285 IS 6 BP H2657 EP H2662 DI 10.1152/ajpheart.00557.2003 PG 6 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 742MN UT WOS:000186521700048 PM 12946930 ER PT J AU Wink, DA Miranda, KM Katori, T Mancardi, D Thomas, DD Ridnour, L Espey, MG Feelisch, M Colton, CA Fukuto, JM Pagliaro, P Kass, DA Paolocci, N AF Wink, DA Miranda, KM Katori, T Mancardi, D Thomas, DD Ridnour, L Espey, MG Feelisch, M Colton, CA Fukuto, JM Pagliaro, P Kass, DA Paolocci, N TI Orthogonal properties of the redox siblings nitroxyl and nitric oxide in the cardiovascular system: a novel redox paradigm SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Review DE guanosine 3 ',5 '-cyclic monophosphate; calcitonin gene-related peptide; Angeli's salt ID HYDROXY-L-ARGININE; MYOCARDIAL ISCHEMIA-REPERFUSION; SOLUBLE GUANYLATE-CYCLASE; LOW-DENSITY-LIPOPROTEIN; INDUCED HEART-FAILURE; GENE-RELATED PEPTIDE; NO-CENTER-DOT; SUPEROXIDE-DISMUTASE; ENDOTHELIAL-CELLS; RELAXING FACTOR AB Endogenous formation of nitric oxide (NO) and related nitrogen oxides in the vascular system is critical to regulation of multiple physiological functions. An imbalance in the production or availability of these species can result in progression of disease. Nitrogen oxide research in the cardiovascular system has primarily focused on the effects of NO and higher oxidation products. However, nitroxyl (HNO), the one-electron-reduction product of NO, has recently been shown to have unique and potentially beneficial pharmacological properties. HNO and NO often induce discrete biological responses, providing an interesting redox system. This article discusses the emerging aspects of HNO chemistry and attempts to provide a framework for the distinct effects of NO and HNO in vivo. C1 NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21287 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. Univ Calif Los Angeles, Ctr Hlth Sci, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Turin, Dipartimento Sci Clin & Biol, I-10041 Orbassano, Italy. RP Wink, DA (reprint author), NCI, Tumor Biol Sect, Radiat Biol Branch, NIH, Bldg 10,Rm B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009; Pagliaro, Pasquale/E-5239-2010; Feelisch, Martin/C-3042-2008 OI Feelisch, Martin/0000-0003-2320-1158 NR 145 TC 60 Z9 61 U1 2 U2 7 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC 1 PY 2003 VL 285 IS 6 BP H2264 EP H2276 DI 10.1152/ajpheart.00531.2003 PG 13 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 742MN UT WOS:000186521700003 PM 12855429 ER PT J AU Hoe, KL Armando, I Baiardi, G Sreenath, T Kulkarni, A Martinez, A Saavedra, JM AF Hoe, KL Armando, I Baiardi, G Sreenath, T Kulkarni, A Martinez, A Saavedra, JM TI Molecular cloning, characterization, and distribution of the gerbil angiotensin II AT(2) receptor SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE adrenal gland; brain; CGP-42112; dental papilla ID TYPE-2 RECEPTOR; LIGAND-BINDING; AT2 RECEPTOR; PHOSPHOINOSITIDE HYDROLYSIS; TRANSMEMBRANE DOMAIN; SUBTYPE AT2; RAT-BRAIN; EXPRESSION; AUTORADIOGRAPHY; AFFINITY AB We isolated a cDNA clone encoding the gerbil AT(2) receptor (gAT(2)) gene from a gerbil adrenal gland cDNA library. The full-length cDNA contains a 1,089-bp open reading frame encoding 363 amino acid residues with 90.9, 96.1, and 95.6% identity with the human (hAT(2)), rat (rAT(2)), and mouse AT(2) (mAT(2)) receptors, respectively. There are at least seven non-conserved amino acids in the NH2-terminal domain and in positions Val(196), Val(217), and Met(293), important for angiotensin (ANG) II but not for CGP-42112 binding. Displacement studies in adrenal sections revealed that affinity of the gAT(2) receptor was 10-20 times lower for ANG II, ANG III, and PD-123319 than was affinity of the rAT(2) receptor. The affinity of each receptor remained the same for CGP-42112. When transfected into COS-7 cells, the gAT(2) receptor shows affinity for ANG II that is three times lower than that shown by the hAT(2) receptor, whereas affinities for ANG III and the AT(2) receptor ligands CGP-42112 and PD-123319 were similar. Autoradiography in sections of the gerbil head showed higher binding in muscles, retina, skin, and molars at embryonic day 19 than at 1 wk of age. In situ hybridization and emulsion autoradiography revealed that at embryonic day 19 the gAT(2) receptor mRNA was highly localized to the base of the dental papilla of maxillary and mandibular molars. Our results suggest selective growth-related functions in late gestation and early postnatal periods for the gAT(2) receptor and provide an essential basis for future mutagenesis studies to further define structural requirements for agonist binding. C1 NIMH, Pharmacol Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Gene Targeting Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Armando, I (reprint author), NIMH, Pharmacol Sect, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Rm 2D-57, Bethesda, MD 20892 USA. NR 40 TC 5 Z9 6 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC 1 PY 2003 VL 285 IS 6 BP R1373 EP R1383 DI 10.1152/ajpregu.00008.2003 PG 11 WC Physiology SC Physiology GA 742ZE UT WOS:000186547300013 PM 14615403 ER PT J AU Pritchard, JB AF Pritchard, JB TI The gill and homeostasis: transport under stress SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Editorial Material ID MITOCHONDRIA-RICH CELLS; FRESH-WATER; FISH GILLS; EXPRESSION; PHYSIOLOGY; TELEOST; ELASMOBRANCH; MECHANISMS; EPITHELIA; NA+ C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 110 Alexander Dr,MD F1-03, Res Triangle Pk, NC 27709 USA. NR 24 TC 4 Z9 4 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD DEC 1 PY 2003 VL 285 IS 6 BP R1269 EP R1271 DI 10.1152/ajpregu.00516.2003 PG 3 WC Physiology SC Physiology GA 742ZE UT WOS:000186547300001 PM 14615396 ER PT J AU Jung, JY Madsen, KM Han, KH Yang, CW Knepper, MA Sands, JM Kim, J AF Jung, JY Madsen, KM Han, KH Yang, CW Knepper, MA Sands, JM Kim, J TI Expression of urea transporters in potassium-depleted mouse kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE immunogold labeling; descending thin limb of loop of Henle; urine concentration ID URINARY CONCENTRATING ABILITY; LONG-TERM REGULATION; RAT-KIDNEY; ANTIDIURETIC-HORMONE; BRATTLEBORO RATS; DOWN-REGULATION; VASA-RECTA; UT-B; LOCALIZATION; UT-A1 AB Urea transport in the kidney is mediated by a family of transporter proteins that include the renal urea transporter (UT-A) and the erythrocyte urea transporter (UT-B). The purpose of this study was to determine the location of the urea transporter isoforms in the mouse kidney and to examine the effects of prolonged potassium depletion on the expression and distribution of these transporters by ultrastructural immunocytochemistry. C57BL6 mice were fed a low-potassium diet for 2 wk, and control animals received normal chow. After 2 wk on a low-potassium diet, urinary volume increased and urinary osmolality decreased (833 +/- 30 vs. 1,919 +/- 174 mosmol/ kgH(2)O), as previously demonstrated. Kidneys were processed for immunocytochemistry with antibodies against UT-A1 (L446), UT-A1 and UT-A2 (L194), UT-A3 (Q2), and UT-B. In normal mice, UT-A1 and UT-A3 were expressed mainly in the cytoplasm of the terminal inner medullary collecting duct (IMCD). UT-A2 immunoreactivity was observed mainly on the basolateral membrane of the type 1 epithelium of the descending thin limb (DTL) of short-looped nephrons. The intensity of UT-A1 and UT-A3 immunoreactivity in the IMCD was markedly reduced in potassium-depleted mice. In contrast, there was a significant increase in UT-A2 immunoreactivity in the DTL. The intensity of UT-B immunoreactivity in the descending vasa recta (DVR) was reduced in potassium-depleted animals compared with controls. In control animals, UT-B immunoreactivity was predominantly observed in the plasma membrane, whereas in potassium-depleted mice, it was mainly observed in cytoplasmic granules in endothelial cells of the DVR. In summary, potassium depletion is associated with reduced expression of UT-A1, UT-A3, and UT-B but increased expression of UT-A2. We conclude that reduced expression of urea transporters may play a role in the impaired urine-concentrating ability associated with potassium deprivation. C1 Catholic Univ Korea, Dept Internal Med, Coll Med, Seoul 137701, South Korea. Univ Florida, Coll Med, Dept Med, Gainesville, FL 32610 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Dept Med, Div Renal, Atlanta, GA 30322 USA. RP Kim, J (reprint author), Catholic Univ Korea, Dept Anat, Coll Med, 505 Banpo Dong, Seoul 137701, South Korea. EM jinkim@catholic.ac.kr FU NIDDK NIH HHS [R01 DK063657, R01 DK041707] NR 50 TC 26 Z9 26 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2003 VL 285 IS 6 BP F1210 EP F1224 DI 10.1152/ajprenal.00111.2003 PG 15 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 739VH UT WOS:000186366800020 PM 12952854 ER PT J AU Nielsen, J Kwon, TH Praetorius, J Kim, YH Frokiaer, J Knepper, MA Nielsen, S AF Nielsen, J Kwon, TH Praetorius, J Kim, YH Frokiaer, J Knepper, MA Nielsen, S TI Segment-specific ENaC downregulation in kidney of rats with lithium-induced NDI SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aldosterone; collecting duct; epithelial sodium channel; hypertension; nephrogenic diabetes insipidus; sodium reabsorption; sodium wasting ID EPITHELIAL SODIUM-CHANNEL; CORTICAL COLLECTING TUBULE; LUNG LIQUID CLEARANCE; NA+ CHANNEL; DIABETES-INSIPIDUS; ANGIOTENSIN-II; BETA-SUBUNIT; GAMMA-ENAC; ALPHA-ENAC; LOCALIZATION AB Lithium-induced nephrogenic diabetes insipidus is associated with increased renal sodium excretion in addition to severe urinary concentrating defects. However, the molecular basis for this altered renal sodium excretion remains undefined. The amiloride-sensitive sodium channel ( ENaC) is expressed in the renal connecting tubule and collecting duct and is essential in renal regulation of body sodium balance and blood pressure. We hypothesized that dysregulation of ENaC subunits may be responsible for the increased sodium excretion associated with lithium treatment. Lithium treatment for 28 days resulted in severe polyuria, increased fractional excretion of sodium, and increased plasma aldosterone concentration. Immunoblotting revealed that lithium treatment induced a marked decrease in the protein abundance of beta-ENaC and gamma-ENaC in the cortex and outer medulla. Moreover, immunohistochemistry and laser confocal microscopy demonstrated an almost complete absence of beta-ENaC and gamma-ENaC labeling in cortical and outer medullary collecting duct, which was not affected by dietary sodium intake. In contrast, immunohistochemistry showed increased apical labeling of all ENaC subunits in the connecting tubule and inner medullary collecting duct in rats on a fixed sodium intake but not in rats with free access to sodium. Except for a modest downregulation of the thiazide-sensitive Na-Cl cotransporter, the key renal sodium transporters upstream from the connecting tubule ( including the alpha(1)-subunit of Na-K-ATPase, type 3 Na/H exchanger, and Na-K-2Cl cotransporter) were unchanged. These results identify a marked and highly segment-specific downregulation of beta-ENaC and gamma-ENaC in the cortical and outer medullary collecting duct, chief sites for collecting duct sodium reabsorption, in rats with a lithium-induced increase in fractional excretion of sodium. C1 Aarhus Univ, Water & Salt Res Ctr, Inst Anat, DK-8000 Aarhus C, Denmark. Dongguk Univ, Dept Physiol, Sch Med, Kyungju 780714, South Korea. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Water & Salt Res Ctr, Inst Anat, Bldg 233, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 51 TC 40 Z9 40 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2003 VL 285 IS 6 BP F1198 EP F1209 DI 10.1152/ajprenal.00118.2003 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 739VH UT WOS:000186366800019 PM 12928314 ER PT J AU Song, J Knepper, MA Verbalis, JG Ecelbarger, CA AF Song, J Knepper, MA Verbalis, JG Ecelbarger, CA TI Increased renal ENaC subunit and sodium transporter abundances in streptozotocin-induced type 1 diabetes SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE kidney; epithelial sodium channel; natriuresis; diuresis; type 2 sodium-phosphate cotransporter; type 3 sodium/hydrogen exchanger; bumetanide-sensitive sodium-potassium-2chloride; cotransporter; aquaporin; sodium-chloride cotransporter; hyperglycemia; proteomics ID RAT-KIDNEY; WATER CHANNEL; VASOPRESSIN; EXPRESSION; AQUAPORINS; MECHANISMS; PROTEINS; MELLITUS; COTRANSPORTER; ALDOSTERONE AB Uncontrolled diabetes mellitus (DM) is associated with copious water and sodium losses. We hypothesized that the kidney compensates for these losses by increasing the abundances of key sodium and water transporters and channels. Using targeted proteomic analysis via immunoblotting of kidney homogenates, we examined comprehensive regulation of transport proteins. In three studies, streptozotocin (STZ; 65 mg/kg) or vehicle was administered intraperitoneally to male Sprague-Dawley rats. In study 2, to control for potential renal toxicity of STZ, one group of STZ-treated rats was intensively treated with insulin to control diabetes. In another group, the reversibility of DM and related changes was assessed by treating animals with insulin for the final 4 days. In study 3, we correlated blood glucose to transporter changes by treating animals with different doses of insulin. In study 1, STZ treatment resulted in significantly increased band densities for the type 3 sodium/hydrogen exchanger (NHE3), the thiazide-sensitive Na-Cl cotransporter (NCC), and epithelial sodium channel ( ENaC) subunits alpha, beta, and gamma (85- and 70-kDa bands) to 204, 125, 176, 132, 147, and 241% of vehicle mean, respectively. In study 2, aquaporin-2 (AQP2) and AQP3 were increased with DM, but not AQP1 or AQP4. Neither these changes, nor blood glucose itself, could be returned to normal by short-term intensive insulin treatment. Whole kidney abundance of AQP3, the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2), and gamma-ENaC (85-kDa band) correlated most strongly with blood glucose in study 3. These comprehensive changes would be expected to decrease volume contraction accompanying large-solute and water losses associated with DM. C1 Georgetown Univ, Dept Med, Div Endocrinol & Metab, Washington, DC 20057 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Ecelbarger, CA (reprint author), Georgetown Univ, Dept Med, Div Endocrinol & Metab, Box 571412, Washington, DC 20057 USA. EM ecelbarc@georgetown.edu FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [R01 HL074142]; NIDDK NIH HHS [K01 DK 02672, R01 DK 38094] NR 32 TC 30 Z9 31 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2003 VL 285 IS 6 BP F1125 EP F1137 DI 10.1152/ajprenal.00143.2003 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 739VH UT WOS:000186366800012 PM 12904328 ER PT J AU Sporn, AL Greenstein, DK Gogtay, N Jeffries, NO Lenane, M Gochman, P Clasen, LS Blumenthal, J Giedd, JN Rapoport, JL AF Sporn, AL Greenstein, DK Gogtay, N Jeffries, NO Lenane, M Gochman, P Clasen, LS Blumenthal, J Giedd, JN Rapoport, JL TI Progressive brain volume loss during adolescence in childhood-onset schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GRAY-MATTER; 1ST-EPISODE PSYCHOSIS; AFFECTIVE-DISORDERS; K-SADS; DEFICITS; AGE; ASSOCIATION; MRI; ABNORMALITIES; IMPAIRMENTS AB Objective: Previous reports have documented a striking progressive reduction in cortical gray matter volume during adolescence in patients with childhood-onset schizophrenia. This study examined the rate of loss in cortical gray matter volume in relation to age and clinical status in adolescent patients over a follow-up period of 2-6 years. Method: A total of 131 brain magnetic resonance imaging scans were acquired for 60 subjects with childhood-onset schizophrenia (mean age=14.5 years, SD=2.5), and 140 scans were acquired for 64 matched healthy comparison subjects. One or more follow-up scans were acquired at approximately 2-year intervals for 39 subjects with childhood-onset schizophrenia and 43 healthy subjects. Developmental trajectories for total and regional brain volumes were examined in relation to age by using polynomial growth models and data from all available scans. The rate of gray matter reduction in patients with childhood-onset schizophrenia was examined in relation to developmental and clinical measures by using stepwise regression. Results: Rates of brain volume reduction were significantly higher for patients with childhood-onset schizophrenia than for healthy comparison subjects. In childhood-onset schizophrenia, the rate of gray matter reduction was related to premorbid impairment and baseline severity of clinical symptoms but not to gender, ethnicity, or age at onset of the disorder. Unexpectedly, greater clinical improvement was significantly related to a higher rate of gray matter reduction. Longitudinal trajectories suggested that the rate of cortical loss plateaus during adolescence. Conclusions: Striking loss of cerebral gray matter is seen through adolescence in patients with childhood-onset schizophrenia. The rate of reduction was related to premorbid impairment and baseline symptom severity, but it may also be in part a plastic response to illness. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Biostat Branch, Bethesda, MD USA. RP Sporn, AL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Rm 3N202, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008; Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 51 TC 112 Z9 119 U1 2 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2003 VL 160 IS 12 BP 2181 EP 2189 DI 10.1176/appi.ajp.160.12.2181 PG 9 WC Psychiatry SC Psychiatry GA 748VN UT WOS:000186881900017 PM 14638588 ER PT J AU Callicott, JH Mattay, VS Verchinski, BA Marenco, S Egan, MF Weinberger, DR AF Callicott, JH Mattay, VS Verchinski, BA Marenco, S Egan, MF Weinberger, DR TI Complexity of prefrontal cortical dysfunction in schizophrenia: More than up or down SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID WORKING-MEMORY; FRONTAL ACTIVATION; CORTEX; PERFORMANCE; DEFICITS; FMRI; TASK AB Objective: Numerous neuroimaging studies have examined the function of the dorsolateral prefrontal cortex in schizophrenia; although abnormalities usually are identified, it is unclear why some studies find too little activation and others too much. The authors' goal was to explore this phenomenon. Method: They used the N-back working memory task and functional magnetic resonance imaging at 3 T to examine a group of 14 patients with schizophrenia and a matched comparison group of 14 healthy subjects. Results: Patients' performance was significantly worse on the two-back working memory task than that of healthy subjects. However, there were areas within the dorsolateral prefrontal cortex of the patients that were more active and areas that were less active than those of the healthy subjects. When the groups were subdivided on the basis of performance on the working memory task into healthy subjects and patients with high or low performance, locales of greater prefrontal activation and locales of less activation were found in the high-performing patients but only locales of underactivation were found in the low-performing patients. Conclusions: These findings suggest that patients with schizophrenia whose performance on the N-back working memory task is similar to that of healthy comparison subjects use greater prefrontal resources but achieve lower accuracy (i.e., inefficiency) and that other patients with schizophrenia fail to sustain the prefrontal network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in schizophrenia are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the dorsolateral prefrontal cortex. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Callicott, JH (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Rm 4D-20,MSC 1389, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008; Callicott, Joseph/C-9102-2009 OI Marenco, Stefano/0000-0002-2488-2365; Callicott, Joseph/0000-0003-1298-3334 NR 16 TC 441 Z9 456 U1 0 U2 12 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2003 VL 160 IS 12 BP 2209 EP 2215 DI 10.1176/appi.ajp.160.12.2209 PG 7 WC Psychiatry SC Psychiatry GA 748VN UT WOS:000186881900021 PM 14638592 ER PT J AU Noaghiul, S Hibbeln, JR AF Noaghiul, S Hibbeln, JR TI Cross-national comparisons of seafood consumption and rates of bipolar disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; PLACEBO-CONTROLLED TRIAL; MENTAL-HEALTH SURVEY; MAJOR DEPRESSION; CEREBROSPINAL-FLUID; GENERAL-POPULATION; FISH CONSUMPTION; YOUNG-ADULTS; EPIDEMIOLOGY; COMMUNITY AB Objective: The authors sought to determine if greater seafood consumption, a measure of omega-3 fatty acid intake, is associated with lower prevalence rates of bipolar disorder in community samples. Method: Lifetime prevalence rates in various countries for bipolar I disorder, bipolar II disorder, bipolar spectrum disorder, and schizophrenia were identified from population-based epidemiological studies that used similar methods. These epidemiological studies used structured diagnostic interviews with similar diagnostic criteria and were population based with large sample sizes. Simple linear and nonlinear regression analyses were used to compare these prevalence data to differences in apparent seafood consumption, an economic measure of disappearance of seafood from the economy. Results: Simple exponential decay regressions showed that greater seafood consumption predicted lower lifetime prevalence rates of bipolar I disorder, bipolar II disorder, and bipolar spectrum disorder. Bipolar II disorder and bipolar spectrum disorder had an apparent vulnerability threshold below 50 Ib of seafood/person/year. The absence of a correlation between lifetime prevalence rates of schizophrenia and seafood consumption suggests a specificity to affective disorders. Conclusions: These data describe a robust correlational relationship between greater seafood consumption and lower prevalence rates of bipolar disorders. These data provide a cross-national context for understanding ongoing clinical intervention trials of omega-3 fatty acids in bipolar disorders. C1 NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, New York, NY USA. RP Hibbeln, JR (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 12420 Parklawn Dr,Room 1-14, Bethesda, MD 20892 USA. NR 45 TC 164 Z9 177 U1 4 U2 18 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 2003 VL 160 IS 12 BP 2222 EP 2227 DI 10.1176/appi.ajp.160.12.2222 PG 6 WC Psychiatry SC Psychiatry GA 748VN UT WOS:000186881900023 PM 14638594 ER PT J AU Fee, E Cueto, M Beatty, R AF Fee, E Cueto, M Beatty, R TI Public health in Central America SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. Univ Peruana Cayetano Heredia, Lima, Peru. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2003 VL 93 IS 12 BP 2011 EP 2011 DI 10.2105/AJPH.93.12.2011 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 748WH UT WOS:000186848400012 PM 14652322 ER PT J AU Tedeschi, SK Brown, TM Fee, E AF Tedeschi, SK Brown, TM Fee, E TI Considerations on human capital SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. Brown Univ, Providence, RI 02912 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, Rochester, NY 14627 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2003 VL 93 IS 12 BP 2012 EP 2015 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 748WH UT WOS:000186848400013 ER PT J AU Tedeschi, SK Brown, TM Fee, E AF Tedeschi, SK Brown, TM Fee, E TI Salvador Allende - Physician, socialist, populist, and president SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. Brown Univ, Providence, RI 02912 USA. NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, 601 Elmwood Ave, Rochester, NY 14627 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2003 VL 93 IS 12 BP 2014 EP 2015 DI 10.2105/AJPH.93.12.2014 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 748WH UT WOS:000186848400014 PM 14652324 ER PT J AU Barry, TS Jaffe, ES Sorbara, L Raffeld, M Pittaluga, S AF Barry, TS Jaffe, ES Sorbara, L Raffeld, M Pittaluga, S TI Peripheral T-cell lymphomas expressing CD30 and CD15 SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE peripheral T-cell lymphoma; Hodgkin's lymphoma; CD15; CD30; TCR-gamma chain gene rearrangement; immunohistochemistry ID REED-STERNBERG CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; CLASSICAL HODGKINS-DISEASE; EPSTEIN-BARR-VIRUS; IMMUNOGLOBULIN GENE REARRANGEMENTS; ANTIGEN RECEPTOR GENES; LEU-M1 ANTIGEN; CHAIN GENE; IMMUNOPHENOTYPE; CLASSIFICATION AB Coexpression of CD30 and CD15 is typically associated with classic Hodgkin's lymphoma (HL). Peripheral T-cell lymphomas (PTCLs) can often display histologic features that simulate classic HL. However, reports of PTCLs coexpressing both CD30 and CD 15 have been infrequently described. We report 11 cases of PTCL in which at least a subset of the neoplastic cells coexpressed CD30 and CD15. The patients included 4 women and 7 men and age ranged from 43 to 83 years (median, 62 years). Nine of 10 patients had advanced stage III or IV disease at presentation. Nodal involvement predominated in 8 of 11 patients, whereas 2 patients presented primarily with skin involvement. Two distinct groups were identified based on morphologic and immunophenotypic features. The first group of 5 cases had histologic features mimicking classic HL with CD30+. CD15+ Reed-Stemberg (RS)-like cells in an inflammatory background of varied extent and composition. The background lymphoid cells showed minimal cytologic atypia. The RS-like cells were negative for CD20 and CD79a in all cases, and CD45 expression was absent in 4 of 5 cases. The RS-like cells expressed CD25 and at least one T-cell-associated marker in all cases. The background T-cell population showed convincing subset predominance in 4 of 5 cases and loss of T-cell-associated antigens in 3 of 5 cases and coexpression of CD30 and CD15 in one case. The second group of 6 cases had morphologic features more in keeping with PTCL than classic HL. The proportion of neoplastic cells coexpressing CD30 and CD 15 varied. Loss of T-cell antigens was noted in all cases and CD4 predominated in 4 of 5 cases. Three of the 6 cases expressed CD45. PCR analysis revealed clonal T-cell receptor gamma (TCR-gamma) chain gene rearrangements in 9 of 11 cases, but no immunoglobulin heavy (IgH) chain gene rearrangements. In situ hybridization studies for Epstein-Barr virus were negative in all cases. In some PTCL cases, the overlap with classic HL can be striking, and combined immunophenotypic and molecular studies are often necessary to confirm the diagnosis. C1 NCI, Hematopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Pittaluga, S (reprint author), NCI, Hematopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2N202,10 Canc Dr, Bethesda, MD 20892 USA. NR 48 TC 58 Z9 62 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2003 VL 27 IS 12 BP 1513 EP 1522 DI 10.1097/00000478-200312000-00003 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 747TH UT WOS:000186820600003 PM 14657710 ER PT J AU Stadtman, ER Levine, RL AF Stadtman, ER Levine, RL TI Free radical-mediated oxidation of free amino acids and amino acid residues in proteins SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 7th International Congress on Amino Acids and Proteins CY AUG 06-10, 2001 CL VIENNA, AUSTRIA DE protein carbonyls; oxygen free radicals; methionine oxidation/reduction; oxidized protein proteolysis ID METAL-CATALYZED OXIDATION; NITROGEN-CENTERED RADICALS; NITRIC-OXIDE; HYDROGEN-PEROXIDE; HYPOCHLOROUS ACID; GLUTAMINE-SYNTHETASE; METHIONINE RESIDUES; OXIDIZED PROTEINS; CARBONYL GROUPS; CELLULAR-REGULATION AB We summarize here results of studies designed to elucidate basic mechanisms of reactive oxygen (ROS)-mediated oxidation of proteins and free amino acids. These studies have shown that oxidation of proteins can lead to hydroxylation of aromatic groups and aliphatic amino acid side chains, nitration of aromatic amino acid residues, nitrosylation of sulfhydryl groups, sulfoxidation of methionine residues, chlorination of aromatic groups and primary amino groups, and to conversion of some amino acid residues to carbonyl derivatives. Oxidation can lead also to cleavage of the polypeptide chain and to formation of cross-linked protein aggregates. Furthermore, functional groups of proteins can react with oxidation products of polyunsaturated fatty acids and with carbohydrate derivatives (glycation/glycoxidation) to produce inactive derivatives. Highly specific methods have been developed for the detection and assay of the various kinds of protein modifications. Because the generation of carbonyl derivatives occurs by many different mechanisms, the level of carbonyl groups in proteins is widely used as a marker of oxidative protein damage. The level of oxidized proteins increases with aging and in a number of age-related diseases. However, the accumulation of oxidized protein is a complex function of the rates of ROS formation, antioxidant levels, and the ability to proteolytically eliminate oxidized forms of proteins. Thus, the accumulation of oxidized proteins is also dependent upon genetic factors and individual life styles. It is noteworthy that surface-exposed methionine and cysteine residues of proteins are particularly sensitive to oxidation by almost all forms of ROS; however, unlike other kinds of oxidation the oxidation of these sulfur-containing amino acid residues is reversible. It is thus evident that the cyclic oxidation and reduction of the sulfur-containing amino acids may serve as an important antioxidant mechanism, and also that these reversible oxidations may provide an important mechanism for the regulation of some enzyme functions. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2140,50 South Dr,MSC 8012, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 117 TC 755 Z9 799 U1 19 U2 179 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD DEC PY 2003 VL 25 IS 3-4 BP 207 EP 218 DI 10.1007/s00726-003-0011-2 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 751ZA UT WOS:000187119900002 PM 14661084 ER PT J AU Requena, JR Levine, RL Stadtman, ER AF Requena, JR Levine, RL Stadtman, ER TI Recent advances in the analysis of oxidized proteins SO AMINO ACIDS LA English DT Article; Proceedings Paper CT 7th International Congress on Amino Acids and Proteins CY AUG 06-10, 2001 CL VIENNA, AUSTRIA DE glutamic semialdehyde; aminoadipic semialdehyde; hydroxyaminovaleric acid; hydroxyaminocaproic acid; protein carbonyls; metal catalyzed oxidation ID METAL-CATALYZED OXIDATION; LOW-DENSITY LIPOPROTEINS; APOLIPOPROTEIN B-100; VALERIC ACID; LIFE-SPAN; RESIDUES; DAMAGE; ARGININE; PROLINE; DISEASE AB Glutamic semialdehyde is a product of oxidation of arginine and proline, and aminoadipic semialdehyde, of oxidation of lysine. These two carbonyl-containing compounds are the main carbonyl products of metal-catalyzed oxidation of proteins, accounting for 55-100% of the total carbonyl value. Accordingly, they are quantitatively very important contributors to the total value of protein carbonyls in tissues as measured by the classic spectophotometric assay. Sensitive gas chromatography-mass spectrometry based analytical methods allow their quantitation in a variety of biological samples, including tissue protein, cell cultures and lipoproteins. These measurements provide specific information on the oxidative status of proteins that is complementary to that afforded by protein carbonyls, and will be useful tools in the ongoing effort to define and assess the role of protein oxidation in pathology and aging. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Requena, JR (reprint author), Univ Santiago, Sch Med, Dept Microbiol, Prion Res Unit, Rua San Francisco S-N, Santiago, Spain. RI Levine, Rodney/D-9885-2011 NR 30 TC 144 Z9 149 U1 12 U2 32 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD DEC PY 2003 VL 25 IS 3-4 BP 221 EP 226 DI 10.1007/s00726-003-0012-1 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 751ZA UT WOS:000187119900003 PM 14661085 ER PT J AU Maxson, L Wong, C Herrmann, LM Caughey, B Baron, GS AF Maxson, L Wong, C Herrmann, LM Caughey, B Baron, GS TI A solid-phase assay for identification of modulators of prion protein interactions SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE prion; PrP; cell-free conversion; solid-phase assay; biotin; anti-TSE ID CELL-FREE FORMATION; CONGO RED; RESISTANT STATE; SCRAPIE; CONVERSION; INHIBITION; PRP; FORM; MEMBRANES; BINDING AB The progression of the transmissible spongiform encephalopathies (TSEs) is characterized in part by accumulation of a proteinase K-resistant form of the prion protein, which has been converted from the endogenous, proteinase K-sensitive form. This conversion reaction provides a target for possible anti-TSE strategies. We have adapted a cell-free conversion reaction to a high-throughput, solid-phase format that can be used to screen possible therapeutic compounds for inhibitory activity or to illuminate inhibition and conversion mechanisms. The solid-phase assay was compatible with reactions performed under a variety of conditions. Using this assay, we report that phthalocyanine tetrasulfonate, a known modulator of conversion, inhibited conversion by interfering with binding between the protease-sensitive and the protease-resistant forms of the prion protein. A biotinylated form of the protease-sensitive prion protein was successfully converted to the protease-resistant isoform in the solid-phase assay, indicating that biotinylation provides a nonisotopic labeling strategy for large-scale screens. Published by Elsevier Inc. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Baron, GS (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 32 TC 15 Z9 17 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 1 PY 2003 VL 323 IS 1 BP 54 EP 64 DI 10.1016/j.ab.2003.07.028 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 747UF UT WOS:000186822700009 PM 14622959 ER PT J AU Li, W Backlund, PS Boykins, RA Wang, GY Chen, HC AF Li, W Backlund, PS Boykins, RA Wang, GY Chen, HC TI Susceptibility of the hydroxyl groups in serine and threonine to beta-elimination/Michael addition under commonly used moderately high-temperature conditions SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE beta-elimination/Michael addition reaction; phosphoserine; phosphothreonine; phosphopeptide; MALDI-TOF; LC-MS/MS ID PHOSPHORYLATION SITES; MASS-SPECTROMETRY; CHEMICAL MODIFICATION; SUBSTITUTED SERYL; SEQUENCE-ANALYSIS; PROTEINS; PEPTIDES; PHOSPHOPEPTIDES; IDENTIFICATION; RESIDUES AB The beta-elimination/Michael addition reaction has been employed for the modification of O-acylated and phosphorylated Ser and Thr residues in a variety of derivatives. The modified Ser and Thr can be analyzed by amino acid composition analysis, N-terminal Edman degradation sequence analysis, and tandem mass spectrometric sequencing which generally allows the identification and localization of the phosphorylation or glycosylation sites. However, the reactivity of the free hydroxyl group on serine and threonine by sodium hydroxide-induced beta-elimination has not been critically examined. In this study, two analogous phosphopeptides, KMpSTLSYR and KMSpTLSYR, were subjected to beta-elimination under the widely used conditions previously reported, followed by sulfite or ethanethiol addition. After treatment of the phosphopeptides in 0.1 N NaOH/0.6 M Na2SO3 at 37 degreesC for 24 h, matrix-assisted laser desorption ionization-time of flight mass spectrometric analyses of the products revealed an appreciable mass peak with an additional observed mass of 64 compared to the expected mass from the conversion of phosphate to sulfite. Similarly, treatment of the phosphopeptides in 0.52 N NaOH/1.36 M ethanethiol at 50degreesC for 18 h or for even as short as I h also yielded additional 44 mass of ethylthiogroup in excess of the expected mass for the modified phosphopeptide. Electrospray ionization tandem mass spectrometric analysis confirms that the modification occurred on the hydroxyl group of Ser and Thr in addition to P-Ser and P-Thr. On the other hand, modification on the free hydroxyl group of Ser or Thr was not detected under the mild condition of 0.1 N NaOH/0.6 M Na2SO3 at 25 degreesC for 24 h as previously reported (Li et al., Anal. Chem. 74:5701-5710, 2002). This finding suggests that temperatures above 25 degreesC and excessive alkalinity should be avoided to prevent the O-elimination of the hydroxyl group of Ser and Thr in peptides. This is of particular concern when employing highly sensitive tandem mass spectrometric methods for the identification and localization of Ser and Thr as modification sites by the P-elimination/Michael addition reaction. The additional modification site(s) may complicate the interpretation of data and lead to an erroneous conclusion. Published by Elsevier Inc. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Bacterial Parasit & Allegen Prod, Biophys Lab, Bethesda, MD 20892 USA. RP Chen, HC (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NR 27 TC 31 Z9 32 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 1 PY 2003 VL 323 IS 1 BP 94 EP 102 DI 10.1016/j.ab.2003.08.015 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 747UF UT WOS:000186822700013 PM 14622963 ER PT J AU Fox, SD Lempicki, RA Hosack, DA Baseler, MW Kovacs, JA Lane, HC Veenstra, TD Issaq, HJ AF Fox, SD Lempicki, RA Hosack, DA Baseler, MW Kovacs, JA Lane, HC Veenstra, TD Issaq, HJ TI A comparison of mu LC/electrospray ionization-MS and GC/MS for the measurement of stable isotope enrichment from a [H-2(2)]-glucose metabolic probe in T-cell genomic DNA SO ANALYTICAL CHEMISTRY LA English DT Article ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MODIFIED NUCLEOSIDES; MASS-SPECTROMETRY; LYMPHOCYTES; TURNOVER; KINETICS; HUMANS AB Measurement of the proliferation of lymphocytes and other high-turnover cell populations in vivo can be accomplished through the incorporation of an isotopically labeled DNA precursor into actively dividing cells and the subsequent determination of the isotope enrichment in the isolated genomic DNA from selected cell populations. Two published gas chromatography/mass spectrometry (GC/MS) methods were successfully modified by our laboratory whereby a postinjection methylation reaction, rather than silylation or acetylation, was used to form a volatile derivative of deoxyadenosine (dA). We also developed a second robust microcapillary liquid chromatography-electrospray ionization (muLC-ESI)/MS method that is faster and more sensitive than the GUMS method and does not require sample derivatization. Following administration of [6,6-H-2(2)]-glucose to human immunodeficiency virus-infected patients , peripheral blood was drawn; cells were obtained by lymphapheresis and fractionated. DNA was isolated from the desired cell subtypes and enzymatically hydrolyzed to the free deoxyribonucleosides. The digest was analyzed using both capillary GC/ MS and muLC/ESI-MS to measure the levels of the dA and [H-2(2)]-dA or their reaction products. Sample enrichments were calculated by comparison to standard curves prepared from dA and [H-2(2)]-dA. The muLC/ESl-MS, method required fewer cells, less sample preparation, shorter analysis times, and a single calibration curve. Overall, the muLC/EST-MS method is superior to the GC/MS method m terms of precision and accuracy, while providing a 4-fold increase in sensitivity (from 20 pmol at 0.2% [H-2(2)]-dA enrichment to 5 pmol at 0.1% [H-2(2)]-dA enrichment). C1 SAIC Frederick Inc, Natl Canc Inst Frederick, Analyt Chem Lab, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Natl Canc Inst Frederick, Lab Immunopathogenesis & Bioinformat, Ft Detrick, MD 21702 USA. NIAID, Crit Care Med Dept, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIAID, Crit Care Med Dept, Clin Mol Retrovirol Sect, NIH, Bethesda, MD 20892 USA. RP Issaq, HJ (reprint author), SAIC Frederick Inc, Natl Canc Inst Frederick, Analyt Chem Lab, POB B, Ft Detrick, MD 21702 USA. RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU NCI NIH HHS [N01-CO-12400] NR 15 TC 5 Z9 5 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD DEC 1 PY 2003 VL 75 IS 23 BP 6517 EP 6522 DI 10.1021/ac030186v PG 6 WC Chemistry, Analytical SC Chemistry GA 750HV UT WOS:000186986000024 PM 14640722 ER PT J AU Chelius, D Zhang, T Wang, GH Shen, RF AF Chelius, D Zhang, T Wang, GH Shen, RF TI Global protein identification and quantification technology using two-dimensional liquid chromatography nanospray mass spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; MIXTURES; YEAST; DATABASE; PEPTIDES; GENOME AB A simple and reliable method is described here for the identification and relative quantification of proteins in complex mixtures using two-dimensional liquid chromatography/tandem. mass spectrometry. The method is based on the classical proteomic analysis where proteins are digested with trypsin and the resulting peptides are separated by multidimensional liquid chromatography. The separated peptides are analyzed by tandem mass spectrometry and identified via a database search algorithm such as SEQUEST. The peak areas (integrated ion counts over the peptide elution time) of all identified peptides are calculated, and the relative concentration of each protein is determined by comparing the peak areas of all peptides from that protein in one sample versus those from the other. Using this strategy, we compared the relative level of protein expression of A431 cells (an epidermal cell line) grown in the presence or absence of epidermal growth factor (EGF). Our results are consistent with the published observations of the transient effects of EGF. In addition, the difference in the concentrations of several phosphopeptides determined in our studies suggests the possibility of several new targets involved in the EGF cell-signaling pathway. This global protein identification and quantification technology should prove to be a valuable means for comparing proteomes in biological samples subjected to differential treatments. C1 Thermo Finnigan Corp, Proteom Div, San Jose, CA 95134 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Chelius, D (reprint author), Thermo Finnigan Corp, Proteom Div, 355 River Oaks Pkwy, San Jose, CA 95134 USA. NR 18 TC 92 Z9 95 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD DEC 1 PY 2003 VL 75 IS 23 BP 6658 EP 6665 DI 10.1021/ac034607k PG 8 WC Chemistry, Analytical SC Chemistry GA 750HV UT WOS:000186986000044 PM 14640742 ER PT J AU Coleman, CM Loredo, GA Lo, CW Tuan, RS AF Coleman, CM Loredo, GA Lo, CW Tuan, RS TI Correlation of GDF5 and connexin 43 mRNA expression during embryonic development SO ANATOMICAL RECORD PART A-DISCOVERIES IN MOLECULAR CELLULAR AND EVOLUTIONARY BIOLOGY LA English DT Article DE growth/differentiation factor 5; connexin 43; chondrogenesis; heart development; spine development; tendon development ID GAP-JUNCTIONAL COMMUNICATION; CHICK LIMB BUD; MOUSE LIMB; INVITRO CHONDROGENESIS; OSTEOBLASTIC CELLS; MESENCHYMAL CELLS; BETA-SUPERFAMILY; JOINT FORMATION; DIFFERENTIATION; DEFICIENCY AB Growth/differentiation factor 5 (GDF5) regulates connexin expression and enhances embryonic chondrogenesis in a gap junction-dependent manner, suggesting that GDF5 action on developmental skeletogenesis is coordinated with gap junction activities. The results shown here demonstrate concordance between the mRNA expression profiles of GDF5 and the gap junction gene, Cx43, in the mouse embryonic limb, spine, and heart, consistent with coordinated functions for these gene products during developmental organogenesis. (C) 2003 Wiley-Liss, Inc. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1503,MSC 8022, Bethesda, MD 20892 USA. FU NCI NIH HHS [R01 CA71602]; NIAMS NIH HHS [Z01 AR041131]; NIEHS NIH HHS [R01 ES07005] NR 31 TC 17 Z9 24 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0003-276X J9 ANAT REC PART A JI Anat. Rec. Part A PD DEC PY 2003 VL 275A IS 2 BP 1117 EP 1121 DI 10.1002/ar.a.10125 PG 5 WC Anatomy & Morphology SC Anatomy & Morphology GA 748WQ UT WOS:000186884300007 PM 14613311 ER PT J AU Davidson, KW Goldstein, M Kaplan, RM Kaufmann, PG Knatterud, GL Orleans, CT Spring, B Trudeau, KJ Whitlock, EP AF Davidson, KW Goldstein, M Kaplan, RM Kaufmann, PG Knatterud, GL Orleans, CT Spring, B Trudeau, KJ Whitlock, EP TI Evidence-based behavioral medicine: What is it and how do we achieve it? SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID SERVICES-TASK-FORCE; RANDOMIZED CONTROLLED-TRIALS; CONSORT STATEMENT; CLINICAL-TRIALS; PRACTICE GUIDELINES; SYSTEMATIC REVIEWS; PRIMARY-CARE; RECOMMENDATIONS; PREVENTION; DEPRESSION AB The goal of evidence-based medicine is ultimately to improve patient outcomes and quality of care. Systematic reviews of the available published evidence are required to identify interventions that lead to improvements in behavior, health, and wellbeing. Authoritative literature reviews depend on the quality of published research and re search reports. The Consolidated Standards for Reporting Trials (CONSORT) Statement (www.consort-statement.org) was developed to improve the design and reporting of interventions involving randomized clinical trials (RCTs) in medical journals. We describe the 22 CONSORT guidelines and explain their application to behavioral medicine research and to evidence-based practice. Additional behavioral medicine-specific guidelines (e. g., treatment adherence) are also presented. Use of these guidelines by clinicians, educators, policymakers, and researchers who design, report, and evaluate or review RCTs will strengthen the research itself and accelerate efforts to apply behavioral medicine research to improve the processes and outcomes of behavioral medicine practice. C1 Mt Sinai Sch Med, New York, NY 10029 USA. Univ Calif San Diego, San Diego, CA 92103 USA. NHLBI, Bethesda, MD 20892 USA. Maryland Med Res Inst, Baltimore, MD USA. Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. Univ Illinois, Chicago, IL 60637 USA. CUNY, Grad Ctr, New York, NY USA. RP Davidson, KW (reprint author), Columbia Univ, Coll Phys & Surg, Behav Cardiovasc Hlth & Hypertens Program, 622 W 168 St,PH9 Ctr,Room 948, New York, NY 10032 USA. NR 39 TC 211 Z9 211 U1 0 U2 19 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2003 VL 26 IS 3 BP 161 EP 171 DI 10.1207/S15324796ABM2603_01 PG 11 WC Psychology, Multidisciplinary SC Psychology GA 755AY UT WOS:000187366700001 PM 14644692 ER PT J AU Vaurs-Barriere, C Wong, K Weibel, TD Abu-Asab, M Weiss, MD Kaneski, CR Mixon, TH Bonavita, S Creveaux, I Heiss, JD Tsokos, M Goldin, E Quarles, RH Boespflug-Tanguy, O Schiffmann, R AF Vaurs-Barriere, C Wong, K Weibel, TD Abu-Asab, M Weiss, MD Kaneski, CR Mixon, TH Bonavita, S Creveaux, I Heiss, JD Tsokos, M Goldin, E Quarles, RH Boespflug-Tanguy, O Schiffmann, R TI Insertion of mutant proteolipid protein results in missorting of myelin proteins SO ANNALS OF NEUROLOGY LA English DT Article ID PELIZAEUS-MERZBACHER-DISEASE; LINKED SPASTIC PARAPLEGIA; GENE-MUTATIONS; MONOCLONAL-ANTIBODIES; NONSENSE MUTATION; GLYCOPROTEIN MAG; MICE DEFICIENT; BASIC-PROTEIN; CNS MYELIN; PLP AB Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Dex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and PO. Myelin-associated glycoprotein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations. C1 NIH, Bethesda, MD 20892 USA. Med Res, U384, Clermont Ferrand, France. Armed Forces Inst Pathol, Dept Neuropathol & Ophthalm Pathol, Div Neuromusc Pathol, Washington, DC 20306 USA. NINDS, Dev & Metab Neurol Branch, Bethesda, MD USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NINDS, Lab Mol & Cellular Neurobiol, Myelin & Brain Dev Sect, NIH, Bethesda, MD USA. Univ Naples 2, Div Neurol 2, Naples, Italy. RP Schiffmann, R (reprint author), NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Abu-Asab, Mones/0000-0002-4047-1232; Kaneski, Christine/0000-0003-1453-2502; Heiss, John/0000-0002-3890-0165 FU Intramural NIH HHS [Z99 NS999999]; NINDS NIH HHS [NS 002984-05, Z01 NS002984] NR 49 TC 17 Z9 17 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2003 VL 54 IS 6 BP 769 EP 780 DI 10.1002/ana.10762 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 749LZ UT WOS:000186923400008 PM 14681886 ER PT J AU Groll, AH Mickiene, D Petraitis, V Petraitiene, R Alfaro, RM King, C Piscitelli, SC Walsh, TJ AF Groll, AH Mickiene, D Petraitis, V Petraitiene, R Alfaro, RM King, C Piscitelli, SC Walsh, TJ TI Comparative drug disposition, urinary pharmacokinetics, and renal effects of multilamellar liposomal nystatin and amphotericin B deoxycholate in rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PERSISTENTLY NEUTROPENIC RABBITS; IN-VITRO ACTIVITY; ENCAPSULATED NYSTATIN; POLYENE ANTIBIOTICS; ANTIFUNGAL ACTIVITY; LIPID COMPLEX; COMPARTMENTAL PHARMACOKINETICS; ASPERGILLUS-FUMIGATUS; TISSUE DISTRIBUTION; NEPHROTOXICITY AB The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C-max) (17 to 56 mug/ml for LNYS versus 3.36 mug/ml for DAMB; P < 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) (17 to 77 μg . h/ml for LNYS versus 12 μg . h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P = 0.013) and a less than or equal to 8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a greater than or equal to 10-fold-higher C-max (16 to 10 mug/ml for LNYS versus 0.96 mug/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC(0-24) (63 to 35 mug . h/ml for LNYS versus 8.9 mug . h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized AUC(0-24) in urine (P = 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P, <0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Pharmacokinet Res Lab, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Pathol, Bethesda, MD 20892 USA. Univ Munster, Childrens Hosp, Dept Pediat Hematol Oncol, D-4400 Munster, Germany. Univ Munster, Childrens Hosp, Ctr Bone Marrow Transplantat, Infect Dis Res Program, D-4400 Munster, Germany. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Rm 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 42 TC 12 Z9 12 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 2003 VL 47 IS 12 BP 3917 EP 3925 DI 10.1128/AAC.47.12.3917-3925.2003 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 749LG UT WOS:000186921500039 PM 14638502 ER PT J AU Thierry, KL Lamb, ME Orbach, Y AF Thierry, KL Lamb, ME Orbach, Y TI Awareness of the origin of knowledge predicts child witnesses' recall of alleged sexual and physical abuse SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article ID AUTOBIOGRAPHICAL MEMORY; FORENSIC INTERVIEWS/; EYEWITNESS TESTIMONY; EVENTS; PRESCHOOLERS; CONTRADICTIONS; SUGGESTIBILITY; EXPERIENCES; QUESTION; RECOUNT AB Children who understand that knowledge may have different origins produce more information in their free-recall accounts than children who are less aware of source. We examined whether the tendency to make knowledge attributions was related to the number and proportion of details elicited from child witnesses using open-ended invitations and whether this relationship varied depending on the number of incidents of abuse reported. The tendency to make knowledge attributions was measured in the presubstantive portion of protocol-guided interviews with 3- to I I-year-old alleged victims of abuse. Hierarchical regression analyses revealed that the production of knowledge attribution details was positively related to the proportion of substantive episodic details produced by 3- to 6-year-olds recalling a single incident and by 3- to 11-year-olds recalling multiple incidents of abuse. Presubstantive source details were also positively correlated with the amount of source information recalled about incidents of abuse. These findings remained significant after controlling for the children's verbosity, the relative prominence of open-ended invitations, and the children's ages. (C) 2003 US Government work. C1 NICHHD, Rockledge Ctr 1, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), NICHHD, Rockledge Ctr 1, 6705 Rockledge Dr,Suite 8048, Bethesda, MD 20892 USA. EM Michael_Lamb@nih.gov NR 48 TC 4 Z9 4 U1 1 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD DEC PY 2003 VL 17 IS 8 BP 953 EP 967 DI 10.1002/acp.933 PG 15 WC Psychology, Experimental SC Psychology GA 760UV UT WOS:000187854400005 ER PT J AU Pfister, SL Spitzbarth, N Zeldin, DC Lafite, P Mansuy, D Campbell, WB AF Pfister, SL Spitzbarth, N Zeldin, DC Lafite, P Mansuy, D Campbell, WB TI Rabbit aorta converts 15-HPETE to trihydroxyeicosatrienoic acids: potential role of cytochrome P450 SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE cytochrome P450; lipoxygenase; arachidonic acid; rabbit aorta; endothelium ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; ARACHIDONIC-ACID; MOLECULAR-CLONING; SULFAPHENAZOLE DERIVATIVES; EPOXYEICOSATRIENOIC ACIDS; DEPENDENT RELAXATIONS; CORONARY-ARTERIES; ACTIVE-SITES; FATTY-ACIDS; METABOLISM AB Previous work showed that rabbit aorta metabolizes arachidonic acid via 15-lipoxygenase to 15-hydroperoxyeicosatetraenoic acid (15-HPETE), which undergoes an enzymatic rearrangement to 11-hydroxy-14,15-epoxyeicosatrienoic acid (11-H-14,15-EETA) and 15-hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA). Hydrolysis of the epoxy group results in the formation of 11, 14,15- and 11,12,15-trihydroxyeicosatrienoic acids (THETAs). Endothelial cells have several heme-containing enzymes including cytochromes P450 (CYP), nitric oxide synthase (eNOS), and prostacyclin (PGI(2)) synthase that catalyze the rearrangement of 15-HPETE to HEETAs. Incubation of arachidonic acid and 15-lipoxygenase, or 15-HPETE with rabbit aortic microsomes or rat liver microsomes, a rich source of CYP, resulted in the formation of a product that comigrated with THETAs and HEETAs on HPLC. Immunoblot analysis showed the presence of CYP2C8 and CYP2J2 in aortic tissue and when CYP2J2 or CYP2C8 was incubated with arachidonic acid and 15-lipoxygenase, the major products were 11,12,15- and 11,14,15-THETAs. Incubation of purified hematin, CYP2C11, eNOS or PG12 synthase enzymes with arachidonic acid and 15-lipoxygenase produced a different pattern of metabolites from rabbit aortic microsomes. Clotrimazole, a non-specific CYP inhibitor, and ebastine and terfenadone, specific CYP2J2 inhibitors, blocked the ability of aortic microsomes to produce THETAs while specific inhibitors of PG12 synthase, eNOS or CYP2C8/2C9 had no effect on THETA production. We suggest that a CYP, possibly CYP2J2, may function as the hydroperoxide isomerase converting 15-HPETE to HEETAs in rabbit vascular tissue. Further hydrolysis of the epoxy group of the HEETAs results in the formation of 11, 12,15- and 11, 14,15-THETAs. The HEETAs and THETAs are both vasodilators and may function as important regulators of vascular tone. (C) 2003 Elsevier Inc. All rights reserved. C1 Med Coll Wisconsin, Dept Pharmacol & Toxicol, Milwaukee, WI 53226 USA. Natl Inst Environm Hlth Sci, Pulm Pathobiol Lab, Res Triangle Pk, NC 27709 USA. Univ Paris 05, CNRS, UMR 8601, Chim & Biochim Pharmacol & Toxicol Lab, F-75270 Paris 06, France. RP Med Coll Wisconsin, Dept Pharmacol & Toxicol, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM wbcamp@mcw.edu RI Lafite, Pierre/F-6806-2011 OI Lafite, Pierre/0000-0003-1637-4966 FU NHLBI NIH HHS [HL-37981] NR 46 TC 21 Z9 22 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 EI 1096-0384 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD DEC 1 PY 2003 VL 420 IS 1 BP 142 EP 152 DI 10.1016/j.abb.2003.09.026 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 748EL UT WOS:000186849500016 PM 14622984 ER PT J AU Blumberg, HP Kaufman, J Martin, A Whiteman, R Zhang, JHY Gore, JC Charney, DS Krystal, JH Peterson, BS AF Blumberg, HP Kaufman, J Martin, A Whiteman, R Zhang, JHY Gore, JC Charney, DS Krystal, JH Peterson, BS TI Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; MONOZYGOTIC TWINS DISCORDANT; MAJOR DEPRESSION; MOOD DISORDERS; MESSENGER-RNA; NEUROPSYCHOLOGICAL PERFORMANCE; NEUROANATOMICAL STRUCTURES; STRUCTURAL ABNORMALITIES; EMISSION TOMOGRAPHY; GLUCOSE-METABOLISM AB Background: The purported functions of medial temporal lobe structures suggest their involvement in the pathophysiology of bipolar disorder (BD). Previous reports of abnormalities in the volume of the amygdala and hippocampus in patients with BD have been inconsistent in their findings and limited to adult samples. Appreciation of whether volumetric abnormalities are early features of BD or whether the abnormalities represent neurodegenerative changes associated with illness duration is limited by the paucity of data in juvenile samples. Objective: To investigate amygdala and hippocampal volume in adults and adolescents with BD. Setting and Participants: Subjects included 36 individuals (14 adolescents and 22 adults) in outpatient treatment for BD type I at a university hospital or Veterans Affairs medical center or in the surrounding community, and 56 healthy comparison subjects (23 adolescents and 33 adults). Design and Main Outcome Measures: Amygdala and hippocampal volumes were defined and measured on high-resolution anatomic magnetic resonance imaging scans. We used a mixed-model, repeated-measures statistical analysis to compare amygdala and hippocampal volumes across groups while covarying for total brain volume, age, and sex. Potential effects of illness features were explored, including rapid cycling, medication, alcohol or other substance dependence, duration, and mood state. Results: For both the amygdala and hippocampal regions, we found an overall significant volume reduction in the BD compared with the control group (P<.0001). Amygdala volume reductions (15.6%) were highly significant (P<.0001). We observed a nonsignificant trend (P=.054) toward reductions in hippocampal volumes of lesser magnitude (5.3%). Effects of illness features were not detected. Conclusions: These results suggest that BD is associated with decreased volumes of medial temporal lobe structures, with greater effect sizes in the amygdala than in the hippocampus. These abnormalities are likely manifested early in the course of illness, as they affected adolescent and adult subjects similarly in this sample. C1 Vet Affairs Connecticut Healthcare Syst, Dept Psychiat 116A, West Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT USA. Yale Univ, Sch Med, Yale Child Study Ctr, New Haven, CT USA. Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, West Haven, CT USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NIMH, Mood & Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Vanderbilt Univ, Ctr Med, Dept Radiol, Nashville, TN 37232 USA. RP Blumberg, HP (reprint author), Vet Affairs Connecticut Healthcare Syst, Dept Psychiat 116A, 950 Campbell Ave, West Haven, CT 06516 USA. FU NIAAA NIH HHS [KO2AA 00261]; NIMH NIH HHS [MH01232, MH01792, MH59139] NR 94 TC 256 Z9 259 U1 2 U2 12 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 2003 VL 60 IS 12 BP 1201 EP 1208 DI 10.1001/archpsyc.60.12.1201 PG 8 WC Psychiatry SC Psychiatry GA 750WV UT WOS:000187022200004 PM 14662552 ER PT J AU Blindauer, K Shoulson, I Kieburtz, K McDermott, M Gardiner, I Kamp, C Marshall, F Zhang, L Shinaman, MA Fahn, S Suchowersky, O Wooten, FG Frei, K Pathak, M Luong, N Tuite, P Schacherer, R Jennings, D Stavris, K Wojcieszek, J Elmer, L Aiken, L Rajput, A Rajput, A Ewanishin, M Shirley, T Golbe, L Caputo, D Dewey, R Estes, B DeMarcaida, T Counihan, T Deeley, C Jankovic, J Hunter, C Fernandez, HH Lannon, MC Hubble, J La Fontaine, AL Pantella, C Derwent, L Calabrese, V Roberge, P Lou, JS Andrews, P Nieves, A Sime, E Shults, C Fontaine, D Racette, B Cooper, P Welsh, M Kawai, C Waters, C Hauser, R Gauger, L Panisset, M Hall, J O'Brien, C Judd, D Dalvi, A Schwieteren, D Mahant, P Williamson, K Christine, C Hevezi, J Kang, UJ Richman, J Kompoliti, K Jaglin, J Trugman, J Rost-Ruffner, E Grimes, D Colcher, A Reichwein, S Tarsy, D Ryan, P Bertoni, J Peterson, C Atchison, P Allen, C Curran, T Bailey, S Brocht, A Hodgeman, K Josephson, L Lenio, E O'Connell, C Rothenburgh, K Rumfola, L Watts, A Weaver, C Tariot, P Raubertas, R Chase, T Goodin, T Bianchine, J Woltering, F Mendzelevski, B AF Blindauer, K Shoulson, I Kieburtz, K McDermott, M Gardiner, I Kamp, C Marshall, F Zhang, L Shinaman, MA Fahn, S Suchowersky, O Wooten, FG Frei, K Pathak, M Luong, N Tuite, P Schacherer, R Jennings, D Stavris, K Wojcieszek, J Elmer, L Aiken, L Rajput, A Rajput, A Ewanishin, M Shirley, T Golbe, L Caputo, D Dewey, R Estes, B DeMarcaida, T Counihan, T Deeley, C Jankovic, J Hunter, C Fernandez, HH Lannon, MC Hubble, J La Fontaine, AL Pantella, C Derwent, L Calabrese, V Roberge, P Lou, JS Andrews, P Nieves, A Sime, E Shults, C Fontaine, D Racette, B Cooper, P Welsh, M Kawai, C Waters, C Hauser, R Gauger, L Panisset, M Hall, J O'Brien, C Judd, D Dalvi, A Schwieteren, D Mahant, P Williamson, K Christine, C Hevezi, J Kang, UJ Richman, J Kompoliti, K Jaglin, J Trugman, J Rost-Ruffner, E Grimes, D Colcher, A Reichwein, S Tarsy, D Ryan, P Bertoni, J Peterson, C Atchison, P Allen, C Curran, T Bailey, S Brocht, A Hodgeman, K Josephson, L Lenio, E O'Connell, C Rothenburgh, K Rumfola, L Watts, A Weaver, C Tariot, P Raubertas, R Chase, T Goodin, T Bianchine, J Woltering, F Mendzelevski, B CA Parkinson Study Grp Steering Comm Safety Monitoring Comm TI A controlled trial of rotigotine monotherapy in early Parkinson's disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID PRAMIPEXOLE; ROPINIROLE; LEVODOPA AB Background: Oral dopamine agonists are effective for treating early Parkinson's disease (PD). Rotigotine is a dopamine agonist delivered through a silicone-based transdermal patch that is replaced every 24 hours. Objectives: To assess the efficacy and safety of rotigotine in patients with PD not receiving dopaminergic medications. Design: Randomized, double-blind, placebo-controlled study. Patients: Two hundred forty-two patients with early PD. Intervention: Treatment with patches containing either 4.5, 9.0, 13.5, or 18.0 mg of rotigotine or placebo for 11 weeks. Main Outcome Measure; The change in the sum of the scores of the activities of daily living and motor components of the Unified Parkinson's Disease Rating Scale from baseline to the end of treatment. Results: There was a significant dose-related improvement in the motor and activities of daily living Unified Parkinson's Disease Rating Scale score between baseline and week 11 for the 13.5- and 18.0-mg groups compared with placebo (placebo, 0.3 +/- 7.7; 13.5-mg group, 5.1 +/- 7.0, P = .001; 18.0-mg group, 5.3 +/- 7.0, P < .001). Adverse experiences that occurred more commonly among subjects randomized to active treatment vs placebo included nausea, application site reactions, dizziness, insomnia, somnolence, vomiting, and fatigue. Conclusions: Rotigotine can be safely administered once daily transdermally and improves parkinsonian signs in patients with early PD. C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Rochester, Rochester, NY 14627 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Univ Calgary, Calgary, AB T2N 1N4, Canada. Univ Virginia, Hlth Sci Ctr, Charlottesville, VA 22903 USA. Parkinsons & Movement Disorder Inst, Fountain Valley, CA USA. Univ Minnesota, Minneapolis, MN 55455 USA. Yale Univ, New Haven, CT 06520 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Med Coll Ohio, Toledo, OH 43699 USA. Royal Univ Hosp, Saskatoon Dist Hlth Board, Saskatoon, SK, Canada. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Rochester, Rochester, NY 14627 USA. Baylor Coll Med, Houston, TX 77030 USA. Brown Univ, Mem Hosp Rhode Isl, Pawtucket, RI 02860 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Calgary, Calgary, AB T2N 1N4, Canada. Hunter Homes McGuire Vet Med Ctr, Richmond, VA USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Toronto, Toronto Western Hosp, Hlth Network, Toronto, ON M5T 2S8, Canada. Univ Calif San Diego, La Jolla, CA 92093 USA. Washington Univ, St Louis, MO 63130 USA. Univ So Calif, Los Angeles, CA 90089 USA. N Shore Univ Hosp, Manhasset, NY USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Univ S Florida, Tampa, FL 33620 USA. McGill Ctr Studies Aging, Verdun, PQ, Canada. Colorado Neurol Inst, Englewood, CO USA. Univ Cincinnati Univ Neurol Inc, Cincinnati, OH USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Chicago, Chicago, IL 60637 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Virginia, Hlth Sci Ctr, Charlottesville, VA 22903 USA. Univ Penn, Philadelphia, PA 19104 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Creighton Univ, Omaha, NE 68178 USA. Univ Alabama, Birmingham, AL USA. Movement Disorder Clin, Vernon, BC, Canada. NINDS, Bethesda, MD 20892 USA. Quintiles Cardiac Alert, London, England. RP Blindauer, K (reprint author), Med Coll Wisconsin, Milwaukee, WI 53226 USA. RI Dewey, Richard/A-4288-2013; Curran, Tom/D-7515-2011 OI Dewey, Richard/0000-0002-6615-5035; NR 12 TC 125 Z9 125 U1 3 U2 19 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2003 VL 60 IS 12 BP 1721 EP 1728 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 752QM UT WOS:000187178700007 ER PT J AU Kang, DW Chalela, JA Ezzeddine, MA Warach, S AF Kang, DW Chalela, JA Ezzeddine, MA Warach, S TI Association of ischemic lesion patterns on early diffusion-weighted imaging with TOAST stroke subtypes SO ARCHIVES OF NEUROLOGY LA English DT Article ID CAROTID-ARTERY DISEASE; BRAIN INFARCTION; EMBOLIC SOURCE; TERRITORIES; DIAGNOSIS AB Background: Different topographic patterns in patients who experience an acute ischemic stroke may be related to specific stroke causes. Objective: To determine if lesion patterns on early diffusion-weighted imaging (DWI) are associated with stroke subtypes determined by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Design: Cross-sectional study. Setting: General community hospital. Patients: We studied 172 consecutive ischemic stroke patients with a symptomatic lesion on DWI performed within 24 hours of stroke onset. Main Outcome Measures: Lesion patterns on DWI were classified into single lesions (corticosubcortical, cortical, subcortical greater than or equal to15 mm, or subcortical < 15 mm), scattered lesions in one vascular territory (small scattered lesions or confluent with additional lesions), and multiple lesions in multiple vascular territories (in the unilateral anterior circulation, in the posterior circulation, in bilateral anterior circulations, or in anterior and posterior circulations). Results: We found an overall significant relationship between DWI lesion patterns and TOAST stroke subtypes (P < .001). Corticosubcortical single lesions (P = .01), multiple lesions in anterior and posterior circulations (P = .03), and multiple lesions in multiple cerebral circulations (P = .008) were associated with cardioembolism. Multiple lesions in the unilateral anterior circulation (P = .04) and small scattered lesions in one vascular territory (P = .06) were related to large-artery atherosclerosis. Nearly half (11/23) of the patients with a single subcortical lesion that was 15 mm or larger were classified as having cryptogenic strokes (P = .001), although 9 of these patients had a classic lacunar syndrome without cortical hypoperfusion. Conclusions: Early DWI lesion patterns are associated with specific stroke causes. Conventional 15-mm criteria for lacunes, however, may underestimate the diagnosis of small-vessel occlusion with DWI. C1 NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. Emory Univ, Dept Neurosurg, Atlanta, GA 30322 USA. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Room B1D-733, Bethesda, MD 20892 USA. NR 17 TC 100 Z9 111 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2003 VL 60 IS 12 BP 1730 EP 1734 DI 10.1001/archneur.60.12.1730 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 752QM UT WOS:000187178700009 PM 14676047 ER PT J AU Cusick, M Chew, EY Ferris, F Cox, TA Chan, CC Kador, PF AF Cusick, M Chew, EY Ferris, F Cox, TA Chan, CC Kador, PF TI Effects of aldose reductase inhibitors and galactose withdrawal on fluorescein angiographic lesions in galactose-fed dogs SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID RETINAL VESSEL CHANGES; DIABETIC-RETINOPATHY; GLUCOSE CONTROL; MURAL CELLS; CAPILLARIES; PROGRESSION; COMPLICATIONS; LOCALIZATION; PREVENTION; PERICYTES AB Objective: To assess the effect of aldose reductase inhibitor (ARI) M79175 (2-methyl-6-fluoro-spiro-chroman-4-5'-imidazolidine-2',4'-dione) administration and galactose withdrawal on the progression of retinal changes using fluorescein angiography in galactose-fed dogs. Methods: Thirty male beagles were randomized into 4 groups. Three dogs were fed a normal control diet containing 30% nonnutritive fiber for 74 months (control group), 11 dogs a 30% galactose diet for 74 months (continuous galactose group), 8 dogs a 30% galactose diet for 36 months followed by replacement with a normal diet for 36 months (galactose withdrawal group), and 8 dogs a 30% galactose diet supplemented with M79175 for 34 months followed by replacement with a normal diet and removal of M79175 treatment for 38 months (ARI-treated galactose withdrawal group). Stereoscopic color fundus photography and fluorescein angiography, performed at baseline and follow-up, were assessed for the clinical development of retinopathy, including the first appearance of hyperfluorescence, varying severity of retinal nonperfusion, and retinal neovascularization. Histopathologic features were examined in selected dogs. Results: All dogs in the 3 groups fed the 30% galactose diet developed areas of hyperfluorescence and nonperfusion. Of these dogs, only those supplemented with the ARI did not develop areas of nonperfusion greater than or equal to half the field and retinal neovascularization. Parametric survival analysis showed significant differences (galactose withdrawal group vs ARI-treated galactose withdrawal group) in the median times to the development of nonperfusion greater than or equal to half the field (P=.003) and retinal neovascularization (P=.03). Conclusion: Normalization of glycemic control with galactose withdrawal and ARI treatment may delay the onset and progression of retinal lesions in galactose-fed dogs. Clinical Relevance: Perfect glycemic control after a period of poor control does not completely prevent the progression of retinal lesions. Therapy with ARIs may potentially be important in the prevention of retinal lesions associated with diabetic eye disease. C1 NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Natl Inst Hlth Res Scholars Program, Bethesda, MD 20817 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, NIH, 31 Ctr Dr,Bldg 31,Room 6A52,Mail Stop Code 2510, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 EY999999] NR 32 TC 21 Z9 21 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2003 VL 121 IS 12 BP 1745 EP 1751 DI 10.1001/archopht.121.12.1745 PG 7 WC Ophthalmology SC Ophthalmology GA 751XK UT WOS:000187115200010 PM 14662595 ER PT J AU Dodds, AP Cannon, RE Suggs, CA Wright, JT AF Dodds, AP Cannon, RE Suggs, CA Wright, JT TI MRNA expression and phenotype of odontogenic tumours in the v-Ha-ras transgenic mouse SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE v-Ha-ras; histology; odontogenic tumours; gene expression ID GENE-EXPRESSION; IMMUNOHISTOCHEMICAL DEMONSTRATION; AMELOGENIN GENE; AMELOBLASTOMA; ENAMELYSIN; DIFFERENTIATION; PROTEINS; MICE; SKIN; TUMORIGENESIS AB Ameloblastomas are the most common odontogenic neoplasia in humans, and although typically considered locally invasive and benign, frequently recur subsequent to surgical resection. The Tg.AC transgenic mouse carrying the v-Ha-ras oncogene has been found to spontaneously develop ameloblastoma-like tumours (35% by 1 year of age) that are rare in the wild type FVB background strain. Objective: The purpose of this study was to characterise the mRNA expression of genes in the mouse tumours that are either expressed in human ameloblastomas or essential. for normal odontogenesis and to correlate the expression to the histological phenotype. Study methods: Histological, immunohistochemical and RT-PCR studies were used to evaluate clinically demonstrable odontogenic tumours occurring spontaneously in seven Tg.AC v-Ha-ras transgenic mice (homozygous, at 7 months of age or heterozygous at 11 months of age). Results: Most genes profiled were expressed in all tumour samples, however three (amelogenin, matrix metalloproteinase-20 (MMP-20) and Dlx7) displayed differential expression. In addition, only the most highly differentiated tumour stained positively for collagen. In most cases, the variable expression could be explained by reference to the histological phenotype, although differences in gene expression were apparent within the Type 2 and the mixed phenotype tumours. Conclusions: These data confirm that many of the genes thought to be important in odontogenesis and odontogenic tumour formation in humans are also expressed in these murine ameloblastoma-like tumours however genes associated with terminal differentiation of ameloblasts demonstrate differential expression between the tumour phenotypes. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, UNC Sch Dent, Dept Pediat Dent, Chapel Hill, NC 27599 USA. NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Dodds, AP (reprint author), Univ N Carolina, UNC Sch Dent, Dept Pediat Dent, Manning Dr, Chapel Hill, NC 27599 USA. NR 39 TC 5 Z9 5 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD DEC PY 2003 VL 48 IS 12 BP 843 EP 850 DI 10.1016/S0003-9969(03)00178-X PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 743ZC UT WOS:000186602600006 PM 14596874 ER PT J AU Johnson, MD Vnencak-Jones, CL Toms, SA Moots, PM Weil, R AF Johnson, MD Vnencak-Jones, CL Toms, SA Moots, PM Weil, R TI Allelic losses in oligodendroglial and oligodendroglioma-like neoplasms - Analysis using microsatellite repeats and polymerase chain reaction SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR; IN-SITU HYBRIDIZATION; ANAPLASTIC OLIGODENDROGLIOMA; GENETIC SIGNATURE; PCV CHEMOTHERAPY; HUMAN GLIOMAS; 1P; INSTABILITY; 19Q; OLIGOASTROCYTOMAS AB Context.-Oligodendroglial tumors are heterogenous neoplasms with histologic features shared with other central nervous system tumors, such as dysembryoplastic neuroepithelial tumors. Objective.-We examined a series of tumors, identified as possessing oligodendroglial components at the time of intraoperative examination, to see if molecular subsets based on the oligodendroglial component could be recognized. Design.-DNA was extracted from fresh brain tumor tissue and corresponding peripheral blood or normal tissues. Genotypes for multiple loci were determined by polymerase chain reaction amplification using fluorescent-labeled primers for markers on chromosomes 1p, 17p, and 19q. Results.-Of the 12 oligodendrogliomas, 6 (60%) of 10 informative cases for 1p exhibited loss of heterozygosity (LOH). Six (50%) of 12 informative cases for 19q exhibited LOH. Each case also showed LOH at 1p. Three (25%) of 12 informative cases exhibited LOH at 17p for the dinucleotide repeat within the TP53 gene. In oligoastrocytomas, none of 4 informative cases showed LOH at I p, 1 (25%) showed LOH at 19q, and 2 (50%) at 17p. One case also displayed microsatellite instability at 3 of 8 markers. In the 3 anaplastic oligodendrogliomas, 1 was not informative for I p and none of the informative tumors exhibited LOH at I p or 17p; 1 case (33%) exhibited LOH at 19q. Of the 14 informative anaplastic oligoastrocytomas, LOH was seen in 5 (36%) at both 1p and 19q and in 2 (14%) at 17p. Those with allelic loss at TP53 were astrocytoma predominant. No dysembryoplastic neuroepithelial tumors exhibited LOH at any marker on 1p, 17p, or 19q. Conclusions.-These findings suggest that routine screening for allelic losses, in samples intraoperatively determined to have an oligodendroglial component, will reveal prognostically or therapeutically relevant information in the majority of cases. C1 Vanderbilt Univ Sch Med, Dept Pathol, Nashville, TN 37232 USA. Vanderbilt Univ Sch Med, Dept Neurosurg, Nashville, TN 37232 USA. Vanderbilt Univ Sch Med, Dept Neurol, Nashville, TN 37232 USA. Tennessee Valley Hlth Care Syst, Nashville, TN USA. NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Johnson, MD (reprint author), Vanderbilt Univ Sch Med, Dept Pathol, T3218 MCN,21st Ave S, Nashville, TN 37232 USA. NR 30 TC 16 Z9 17 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 2003 VL 127 IS 12 BP 1573 EP 1579 PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 751XY UT WOS:000187116800006 PM 14632576 ER PT J AU Russo, CR Lauretani, F Bandinelli, S Bartali, B Cavazzini, C Guralnik, JM Ferrucci, L AF Russo, CR Lauretani, F Bandinelli, S Bartali, B Cavazzini, C Guralnik, JM Ferrucci, L TI High-frequency vibration training increases muscle power in postmenopausal women SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE bone density; exercise; muscles; postmenopause; rehabilitation; vibration; women ID BONE-MINERAL DENSITY; WHOLE-BODY VIBRATION; MECHANICAL STIMULI; LOW-MAGNITUDE; STRENGTH; EXERCISE; OSTEOPOROSIS; SARCOPENIA; CHILDREN AB Objective: To test whether training on a high-frequency (28Hz) vibrating platform improves muscle power and bone characteristics in postmenopausal women. Design: Randomized controlled trial with 6-month follow-up. Setting: Outpatient clinic in a general hospital in Italy. Participants: Twenty-nine postmenopausal women (intervention group, n = 14; matched controls, n = 15). Intervention: Participants stood on a ground-based oscillating platform for three 2-minute sessions for a total of 6 minutes per training session, twice weekly for 6 months. The controls did not receive any training. Both groups were evaluated at baseline and after 6 months. Main Outcome Measure: Muscle power, calculated from ground reaction forces produced by landing after jumping as high as possible on a forceplate, cortical bone density, and biomarkers of bone turnover. Results: Over 6 months, muscle power improved by about 5% in women who received the intervention, and it remained unchanged in controls (P=.004). Muscle force remained stable in both the intervention and control groups. No significant changes were observed in bone characteristics. Conclusion: Reflex muscular contractions induced by vibration training improve muscle power in postmenopausal women. C1 NIA, Longitudinal Studies Sect,ASTRA Unit, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. INRCA, Lab Clin Epidemiol, Dept Geriatr, Florence, Italy. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect,ASTRA Unit, Clin Res Branch, Gerontol Res Ctr, 5600 Nathan Shock Dr,Rm 6BN, Baltimore, MD 21224 USA. RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 NR 25 TC 103 Z9 112 U1 3 U2 12 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2003 VL 84 IS 12 BP 1854 EP 1857 DI 10.1016/S0003-9993(03)00357-5 PG 4 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 751JY UT WOS:000187064400019 PM 14669194 ER PT J AU Hicks, GE Fritz, JM Delitto, A Mishock, J AF Hicks, GE Fritz, JM Delitto, A Mishock, J TI Interrater reliability of clinical examination measures for identification of lumbar segmental instability SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE diagnosis; low back pain; rehabilitation; reliability and validity ID LOW-BACK-PAIN; SPINAL INSTABILITY; STABILIZING SYSTEM; AGREEMENT; MOTION; MOBILITY AB Objective: To determine the interrater reliability of common clinical examination procedures proposed to identify patients with lumbar segmental instability. Design: Single group repeated-measures interrater reliability study. Setting: Outpatient physical therapy (PT) clinic and university PT department. Participants: A consecutive sample of 63 subjects (38 women, 25 men; 81% with previous episodes of low back pain [LBP]) with current LBP was examined by 3 pairs of raters. Interventions: Not applicable. Main Outcome Measures: Repeat measurements of clinical signs and tests proposed to identify lumbar segmental instability. Results: Kappa values for the trunk range of motion (ROM) findings varied (range,.00-.69). The prone instability test (kappa=.87) showed greater reliability than the posterior shear test (kappa=.22). The Beighton Ligamentous Laxity Scale (LLS) for generalized ligamentous laxity showed high reliability (intraclass correlation coefficient =.79). Judgments of pain provocation (K range,.25-55) were generally more reliable than judgments of segmental mobility (K range, -.02 to.26) during passive intervertebral motion testing. Conclusions: The results agree with previous studies suggesting that segmental mobility testing is not reliable. The prone instability test, generalized LLS, and aberrant motion with trunk ROM demonstrated higher levels of reliability. C1 NIA, Clin Res Branch, Baltimore, MD 21224 USA. Univ Pittsburgh, Dept Phys Therapy, Pittsburgh, PA USA. Joyner Sports Med Inst, Altoona, PA USA. RP Hicks, GE (reprint author), Harbor Hosp, 3001 S Hanover St,5th Floor, Baltimore, MD 21225 USA. NR 39 TC 92 Z9 96 U1 2 U2 9 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD DEC PY 2003 VL 84 IS 12 BP 1858 EP 1864 DI 10.1016/S0003-9993(03)00365-4 PG 7 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 751JY UT WOS:000187064400020 PM 14669195 ER PT J AU Abdo, KM Johnson, JD Nyska, A AF Abdo, KM Johnson, JD Nyska, A TI Toxicity and carcinogenicity of Elmiron in F344/N rats and B6C3F(1) mice following 2 years of gavage administration SO ARCHIVES OF TOXICOLOGY LA English DT Article DE Elmiron; sodium pentosan polysulfate; rodents; toxicity; carcinogenicity ID GLYCOGEN-STORAGE-DISEASE; PENTOSAN POLYSULFATE; PREFERENTIAL LOCALIZATION; HEPATOCELLULAR-CARCINOMA; H-3 PENTOSANPOLYSULFATE; URINARY-TRACT; INDUCTION; CIRRHOSIS; PHASE AB Elmiron (sodium pentosan polysulfate) is used for the relief of urinary bladder pain associated with interstitial cystitis. The National Toxicology Program (NTP) tested this compound because of its orphan drug status and lack of information about its chronic toxicity and carcinogenicity. Groups of 50 male and 50 female F344/N rats were given Elmiron in de-ionized water by gavage at doses of 0, 14, 42, or 126 mg/kg to males and 0, 28, 84, or 252 mg/kg to females once daily, 5 days per week, for up to 2 years. The same numbers of male and female B6C3F(1) mice were dosed similarly with 0, 56, 168, or 504 mg/kg. Elmiron administration produced no effect on the body weight of rats, male mice, or low- and mid-dose groups of female mice. The body weights of the high-dose female mice were significantly decreased relative to those of controls. Pairwise comparison showed that survival of all dosed groups of rats and mice was similar to that of the controls. Elmiron was not carcinogenic in F344/N rats. An increased incidence of liver hemangiosarcoma provided evidence of some carcinogenic activity for Elmiron in male B6C3F(1) mice. Increased incidences of liver hemangiosarcoma, hepatocellular neoplasms (predominantly adenomas), and malignant lymphomas revealed carcinogenic activity of Elmiron in female B6C3F(1) mice. Elmiron administration produced elevated occurrences of nonneoplastic lesions, such as vacuolated histiocytes in the rectum, lung, spleen (males only), and mesenteric lymph node in rats and liver, rectum, mesenteric lymph node, and spleen in mice. Myxomatous change, chronic inflammation, and squamous metaplasia (mice only) were observed in the large intestine, and lymphohistiocytic hyperplasia was found to be increased in the spleen of rats of both sexes treated with the highest dose. In the latter lesion, the histiocytes contained pale, finely granular cytoplasm and were not considered to represent the same change as the vacuolated histiocytes seen in the mesenteric lymph node and rectum. Under the conditions of these 2-year studies, Elmiron was carcinogenic to mice but not rats. C1 NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. Battelle Mem Inst, Columbus, OH 43201 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. RP Abdo, KM (reprint author), NIEHS, Environm Toxicol Program, NIH, MD EC-35,POB 12233, Res Triangle Pk, NC 27709 USA. NR 28 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD DEC PY 2003 VL 77 IS 12 BP 702 EP 711 DI 10.1007/s00204-003-0472-9 PG 10 WC Toxicology SC Toxicology GA 749WL UT WOS:000186953000006 PM 14508637 ER PT J AU Mahadevan, V Morrison, K Wilson, M Souto-Carneiro, MM Brown, M Zoumakis, E Lipsky, PE Goldbach-Mansky, RT AF Mahadevan, V Morrison, K Wilson, M Souto-Carneiro, MM Brown, M Zoumakis, E Lipsky, PE Goldbach-Mansky, RT TI Alterations in peripheral blood memory B-cells in rheumatoid arthritis patients: Correction with anti TNF therapy and correlation with serum interleukin-6. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2003 VL 48 IS 12 BP 3618 EP 3618 PG 1 WC Rheumatology SC Rheumatology GA 752QR UT WOS:000187179100043 ER PT J AU Mallah, M Aksentijevich, I Austin, J Jones, J Mangra, N Chae, JC Kastner, D Goldbach-Mansky, R AF Mallah, M Aksentijevich, I Austin, J Jones, J Mangra, N Chae, JC Kastner, D Goldbach-Mansky, R TI Genotype-phenotype correlation in seven patients with Neonatal Onset Multisystem Inflammatory Disease (NOMID). SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 23-28, 2003 CL ORLANDO, FLORIDA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2003 VL 48 IS 12 BP 3630 EP 3630 PG 1 WC Rheumatology SC Rheumatology GA 752QR UT WOS:000187179100064 ER PT J AU Miller, EA Pankow, JS Millikan, RC Bray, MS Ballantyne, CM Bell, DA Heiss, G Li, RL AF Miller, EA Pankow, JS Millikan, RC Bray, MS Ballantyne, CM Bell, DA Heiss, G Li, RL TI Glutathione-S-transferase genotypes, smoking, and their association with markers of inflammation, hemostasis, and endothelial function: the atherosclerosis risk in communities (ARIC) study SO ATHEROSCLEROSIS LA English DT Article DE GSTM1; GSTT1; inflammation; smoking ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; M1 GSTM1; SUSCEPTIBILITY; CHOLESTEROL; VARIABILITY; CANCER; GSTT1; FIBRINOLYSIS; EPIDEMIOLOGY AB Recent epidemiologic studies suggest that polymorphisms of glutathione-S-transferases M1 and T1 (GSTM1/GSTT1) modify the effects of cigarette smoking on risk of coronary heart disease (CHD). Since GSTs are able to detoxify numerous toxic compounds and products of oxidative stress, it is possible that GST genotypes may also modify the capacity of smoking to invoke a chronic inflammatory response. A cross-sectional analysis, using a subset of participants (n = 989) in a large (n = 15, 792) biracial cohort, was used to evaluate levels of nine markers of inflammation, hemostasis, and endothelial function by different combinations of GST genotypes and cigarette smoking status. Participants with the GSTM1 null (GSTM1-0) genotype and greater than or equal to20 pack-years of smoking had the highest mean levels of CRP, fibrinogen, von Willebrand factor, ICAM-1, and VCAM-1 and lowest mean levels of albumin compared to other combinations of genotype and smoking. However, a formal test for interaction between GSTM1 genotype and smoking was statistically significant only for albumin. By contrast, participants who had the functional GSTT1 genotype (GSTT1-1) and smoked greater than or equal to20 pack-years had the highest mean levels of only CRP and fibrinogen. The results of this study provide some limited evidence that GSTM1 and GSTT1 polymorphisms modify the effect of smoking on inflammation, hemostasis, and endothelial function. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NIEHS, Environm Genom Sect, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. Univ Tennessee, Ctr Hlth Sci, Ctr Genom & Bioinformat, Memphis, TN 38163 USA. RP Pankow, JS (reprint author), Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. RI Ballantyne, Christie/A-6599-2008 NR 28 TC 44 Z9 45 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD DEC PY 2003 VL 171 IS 2 BP 265 EP 272 DI 10.1016/j.atherosclerosis.2003.07.007 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 756AB UT WOS:000187442700014 PM 14644396 ER PT J AU Ruchkin, DS Grafman, J Cameron, K Berndt, RS AF Ruchkin, DS Grafman, J Cameron, K Berndt, RS TI Working memory retention systems: A state of activated long-term memory SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Review DE coherence; event-related potentials; imaging; long-term memory; memory; short-term memory; working memory ID EVENT-RELATED POTENTIALS; POSITRON EMISSION TOMOGRAPHY; IMMEDIATE SERIAL-RECALL; CEREBRAL-BLOOD-FLOW; SELECTIVE ATTENTION; BRAIN POTENTIALS; SPATIOTEMPORAL PATTERNS; VERBAL INFORMATION; IMAGING COGNITION; LEXICAL DECISION AB High temporal resolution event-related brain potential and electroencephalographic coherence studies of the neural substrate of short-term storage in working memory indicate that the sustained coactivation of both prefrontal cortex and the posterior cortical systems that participate in the initial perception and comprehension of the retained information are involved in its storage. These studies further show that short-term storage mechanisms involve an increase in neural synchrony between prefrontal cortex and posterior cortex and the enhanced activation of long-term memory representations of material held in short-term memory. This activation begins during the encoding/comprehension phase and evidently is prolonged into the retention phase by attentional drive from prefrontal cortex control systems. A parsimonious interpretation of these findings is that the long-term memory systems associated with the posterior cortical processors provide the necessary representational basis for working memory, with the property of short-term memory decay being primarily due to the posterior system. in this view, there is no reason to posit specialized neural systems whose functions are limited to those of short-term storage buffers. Prefrontal cortex provides the attentional pointer system for maintaining activation in the appropriate posterior processing systems. Short-term memory capacity and phenomena such as displacement of information in short-term memmory are determined by limitations on the number of pointers that can be sustained by the prefrontal control systems. C1 Univ Maryland, Sch Med, Dept Physiol, Program Neurosci, Baltimore, MD 21201 USA. NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Washington Coll, Dept Psychol, Chestertown, MD 21620 USA. Univ Maryland, Sch Med, Dept Neurol, Program Neurosci, Baltimore, MD 21201 USA. RP Ruchkin, DS (reprint author), Univ Maryland, Sch Med, Dept Physiol, Program Neurosci, Baltimore, MD 21201 USA. EM druchkin@mindspring.com; grafmanj@ninds.hih.gov; katherine.cameron@washcoll.edu; rberndt@umaryland.edu OI Grafman, Jordan H./0000-0001-8645-4457 FU NINDS NIH HHS [NS11199] NR 112 TC 188 Z9 203 U1 3 U2 34 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD DEC PY 2003 VL 26 IS 6 BP 709 EP + PG 29 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 837FQ UT WOS:000222614300032 PM 15377128 ER PT J AU Hickok, G Buchsbaum, B AF Hickok, G Buchsbaum, B TI Temporal lobe speech perception systems are part of the verbal working memory circuit: Evidence from two recent fMRI studies SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB In the verbal domain, there is only very weak evidence favoring the view that working memory is an active state of long-term memory. We strengthen existing evidence by reviewing two recent fMRI studies of verbal working memory, which clearly demonstrate activation in the superior temporal lobe, a region known to be involved in processing speech during comprehension tasks. C1 Univ Calif Irvine, Dept Cognit Sci, Irvine, CA 92697 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Hickok, G (reprint author), Univ Calif Irvine, Dept Cognit Sci, Irvine, CA 92697 USA. EM gshickok@uci.edu NR 14 TC 9 Z9 9 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD DEC PY 2003 VL 26 IS 6 BP 740 EP + PG 11 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 837FQ UT WOS:000222614300045 ER PT J AU Ruchkin, DS Grafman, J Cameron, K Berndt, RS AF Ruchkin, DS Grafman, J Cameron, K Berndt, RS TI Working memory: Unemployed but still doing day labor - Response SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID SHORT-TERM-MEMORY; FILLER-GAP CONSTRUCTIONS; BRAIN POTENTIAL EVIDENCE; SEMANTIC INFORMATION; WORD SEQUENCES; RETENTION; COMPREHENSION; PERFORMANCE; SIMILARITY; PATTERNS AB The goal of our target article is to establish that electrophysiological data constrain models of short-term memory retention operations to schemes in which activated long-term memory is its representational basis. The temporary stores correspond to neural circuits involved in the perception and subsequent processing of the relevant information, and do not involve specialized neural circuits dedicated to the temporary holding of information outside of those embedded in long-term memory. The commentaries ranged from general agreement with the view that short-term memory stores correspond to activated long-term memory (e.g., Abry, Sato, Schwartz, Loevenbruck & Cathiard [Abry etal.], Cowan, Fuster, Grote, Hickok & Buchsbaum, Keenan, Hyona & Kaakinen [Keenan et al.], Martin, Morra), to taking a definite exception to this view (e.g., Baddeley, Duzel, Logie & Della Sala, Kroger, Majerus, Van der Linden, Colette & Salmon [Majerus et al.], Vallar). C1 Univ Maryland, Sch Med, Dept Physiol, Program Neurosci, Baltimore, MD 21201 USA. NINDS, NIH, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Washington Coll, Dept Psychol, Chestertown, MD 21620 USA. Univ Maryland, Sch Med, Dept Neurol, Program Neurosci, Baltimore, MD 21201 USA. RP Ruchkin, DS (reprint author), Univ Maryland, Sch Med, Dept Physiol, Program Neurosci, Baltimore, MD 21201 USA. EM druchkin@mindspring.com; grafmanj@ninds.hih.gov; katherine.cameron@washcoll.edu; rberndt@umaryland.edu NR 43 TC 0 Z9 0 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD DEC PY 2003 VL 26 IS 6 BP 760 EP 777 PG 18 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 837FQ UT WOS:000222614300066 ER PT J AU De Weerd, P Desimone, R Ungerleider, LG AF De Weerd, P Desimone, R Ungerleider, LG TI Impairments in spatial generalization of visual skills after V4 and TEO lesions in macaques (Macaca mulatta) SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID INFERIOR TEMPORAL CORTEX; EXTRASTRIATE AREA V4; INFEROTEMPORAL CORTEX; RHESUS-MONKEY; ORIENTATION DISCRIMINATION; TEXTURE-DISCRIMINATION; CORTICAL CONNECTIONS; SELECTIVE ATTENTION; DIRECTED ATTENTION; COLOR CONSTANCY AB The authors tested the spatial generalization of shape and color discriminations in 2 monkeys, in which 3 visual field quadrants were affected, respectively, by lesions in area V4, TEO, or both areas combined. The fourth quadrant served as a normal control. The monkeys were trained to discriminate stimuli presented in a standard location in each quadrant, followed by tests of discrimination performance in new locations in the same quadrant. In the quadrant affected by the V4 + TEO lesion, the authors found temporary but striking deficits in spatial generalization of shape and color discriminations over small distances, suggesting a contribution of areas V4 and TEO to short-range spatial generalization of visual skills. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. RP De Weerd, P (reprint author), Univ Maastricht, Dept Psychol, Neurocognit Grp, Mailbox 616, NL-6200 MO Maastricht, Netherlands. NR 65 TC 4 Z9 4 U1 2 U2 4 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD DEC PY 2003 VL 117 IS 6 BP 1441 EP 1447 DI 10.1037/0735-7044.117.6.1441 PG 7 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 755KP UT WOS:000187402300030 PM 14674862 ER PT J AU Stetler-Stevenson, M AF Stetler-Stevenson, M TI Flow cytometry in lymphoma diagnosis and prognosis: useful? SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE flow cytometry; lymphoma; prognosis; immunophenotype AB Flow cytometry has become an important tool in the diagnosis of mature lymphoid neoplasms and the determination of prognosis in selected cases. The advantages of flow cytometry are based largely on its ability to analyse, rapidly and simultaneously, multiple cell properties in a quantitative manner. Flow cytometric immunophenotyping is useful in diagnosing lymphoma under the WHO classification system, where lymphoid neoplasms are separated into distinct clinical entities based upon morphology, immunophenotype, genetic abnormalities and clinical features. Flow cytometry can quantify the expression of proteins associated with a good or poor prognosis, detect multidrug resistance, and measure cell proliferation, making it useful in measuring prognostic indicators in lymphoid neoplasia. The unique attributes of flow cytometry therefore make it a valuable technique in the diagnosis and classification of lymphomas as well as the assessment of prognostic markers in lymphoma patients. C1 NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2N-108,Mail Stop 1500, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov NR 66 TC 16 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD DEC PY 2003 VL 16 IS 4 BP 583 EP 597 DI 10.1053/ybeha.2003.279 PG 15 WC Hematology SC Hematology GA V41ZH UT WOS:000202837300004 PM 14592644 ER PT J AU Jia, L Schweizer, J Wang, Y Cerna, C Wong, H Revilla, M AF Jia, L Schweizer, J Wang, Y Cerna, C Wong, H Revilla, M TI Effect of nitric oxide on cytotoxicity of Taxol: enhanced Taxol transcellular permeability SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Taxol; nitric oxide; S-nitrosocaptopril; permeability; cytotoxicity ID S-NITROSOCAPTOPRIL CRYSTALS; PROSTATE-CANCER CELLS; MULTIDRUG-RESISTANCE; PACLITAXEL TAXOL; P-GLYCOPROTEIN; CELLULAR PERMEABILITY; CACO-2 CELLS; APOPTOSIS; NEUROBLASTOMA; DONOR AB The present studies were aimed at testing the hypothesis that nitric oxide (NO) may enhance Taxol-induced cytotoxicity in carcinoma cells by increasing influx of Taxol into intracellular compartments. Prostate carcinoma cells (PC-3, LNCaP) and neuroblastoma cells (SKNDZ, CHP212) were used to investigate both transmembrane permeability and cytotoxicity of Taxol in the presence and absence of S-nitrosocaptopril (CapNO), a nitric oxide donating compound. The order of permeability rate of Taxol across the four cell lines was SKNDZ > LNCaP > PC-3 > CHP212. Pretreatment of the cell lines with CapNO (100 muM) enhanced permeability of Taxol across prostate PC-3 and LNCaP cells, but not neuroblastoma SKNDZ and CHP212 cells. Taxol inhibited cell growth at nanomolar levels with IC(50)s of 0.21, 17.4, 96.4 and 842.9 nM corresponding to SKNDZ, PC-3, LNCaP and CHP212 cells, respectively. However, CapNO inhibited proliferation of the four cell lines at millimolar levels with IC50s ranging from 0.3 to 1.1 mM. Enhancing effect of CapNO (100 muM) on Taxol cytotoxicity were found in PC-3 and LNCaP cells, but not in SKNDZ and CHP212. The findings suggest that the cytotoxic potency of Taxol is mainly dependent upon the cell membrane permeabilization to Taxol, and the enhancing effect of CapNO on Taxol-induced cytotoxicity is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. (C) 2003 Elsevier Inc. All rights reserved. C1 Inst Drug Dev, Canc Therapy & Res Ctr, San Antonio, TX 78245 USA. RP Jia, L (reprint author), NCI, EPN, NIH, Rm 8042,6130 Execut Blvd, Rockville, MD 20852 USA. EM Jiale@mail.nih.gov FU NCI NIH HHS [R25 CA80936] NR 45 TC 18 Z9 18 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 1 PY 2003 VL 66 IS 11 BP 2193 EP 2199 DI 10.1016/j.bcp.2003.07.013 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748DR UT WOS:000186847300014 PM 14609744 ER PT J AU Spiegel, S Milstien, S AF Spiegel, S Milstien, S TI Exogenous and intracellularly generated sphingosine 1-phosphate can regulate cellular processes by divergent pathways SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 679th Meeting of the Biochemical-Society CY JUL 02-04, 2003 CL COLCHESTER, ENGLAND SP Biochem Soc DE cell growth and survival; G-protein-coupled receptor (GPCR); sphingosine kinase; sphingosine 1-phosphate (S1P); sphingosine 1-phosphate receptor; tetrahydrobiopterin ID NECROSIS-FACTOR-ALPHA; PROTEIN-COUPLED RECEPTORS; C6 GLIOMA-CELLS; SACCHAROMYCES-CEREVISIAE; INHIBITS APOPTOSIS; SIGNALING PATHWAYS; KINASE; SPHINGOSINE-1-PHOSPHATE; GROWTH; EDG-1 AB S1P (sphingosine 1-phosphate) is the ligand for a family of specific G-protein-coupled receptors that regulate a wide variety of important cellular functions, including vascular maturation, angiogenesis, cell growth, survival, cytoskeletal rearrangements and cell motility. However, S1P also may have intracellular functions. in this review, we discuss two examples that clearly indicate that intracellularly generated and exogenous S1P can regulate biological processes by divergent pathways. C1 Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. NIH, Natl Inst Mental Hlth, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. FU NCI NIH HHS [CA 61774]; NIAID NIH HHS [AI 50094]; NIGMS NIH HHS [GM 43880] NR 45 TC 97 Z9 100 U1 0 U2 4 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC PY 2003 VL 31 BP 1216 EP 1219 PN 6 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 754ED UT WOS:000187289000025 PM 14641029 ER PT J AU Beisswenger, PJ Howell, SK Nelson, RG Mauer, M Szwergold, BS AF Beisswenger, PJ Howell, SK Nelson, RG Mauer, M Szwergold, BS TI alpha-oxoaldehyde metabolism and diabetic complications SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT 679th Meeting of the Biochemical-Society CY JUL 02-04, 2003 CL COLCHESTER, ENGLAND SP Biochem Soc DE 3-deoxyglucosone; diabetic complications; glycation; glyceraldehyde-3-phosphate dehydragenase (GAPDH); methylglyoxal; alpha-oxoaldehyde ID GLYCOSYLATION END-PRODUCTS; OXIDATIVE STRESS; IN-VIVO; MAILLARD REACTION; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; PHYSIOLOGICAL CONDITIONS; 3-DEOXYGLUCOSONE LEVELS; FRUCTOSE 3-PHOSPHATE; METHYLGLYOXAL LEVELS; CROSS-LINKING AB The factors responsible for variable susceptibility to diabetic nephropathy are not clear. According to the non-enzymatic glycation hypothesis, diabetes-related tissue damage occurs due to a complex mixture of toxic products, including alpha-oxoaldehydes, which are inherently toxic as well as serving as presursors for advanced glycation end-products. Protective mechanisms exist to control this unavoidable glycation, and these are determined by genetic or environmental factors that can regulate the concentrations of the reactive. sugars or end-products. in diabetes these protective mechanisms become more important, since glycation stress increases, and less efficient defence systems against this stress could lead to diabetic complications. Some of these enzymatic control mechanisms, including those that regulate alpha-oxoaldlelhydes, have been identified. We have observed significant increases in production of the alpha-oxoaldehydes methylglyoxal and 3-deoxyglucosone in three human populations with biopsy-proven progression of nephropathy. The increase in methylglyoxal could be secondary to defects in downstream glycolytic enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) that regulate its production, or in detoxification mechanisms such as glyoxalase. Other mechanisms, however, appear to be responsible for the observed increase in 3-deoxyglucosone levels. We present results of our studies on the mechanisms responsible for variable production of alpha-oxoaldehydes by measuring the activity and characteristics of these enzymes in cells from complication-prone and -resistant diabetic patients. New therapeutic interventions designed to control these endogenous mechanisms could potentially enhance protection against excessive glycation and prevent or reverse complications of long-term diabetes. C1 Dartmouth Coll Sch Med, Dept Med Diabetes Endocrinol & Metab, Lebanon, NH 03756 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03756 USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85014 USA. Univ Minnesota, Dept Pediat Nephrol, Minneapolis, MN 55455 USA. RP Beisswenger, PJ (reprint author), Dartmouth Coll Sch Med, Dept Med Diabetes Endocrinol & Metab, 1 Med Ctr Dr, Lebanon, NH 03756 USA. EM paul.j.beisswenger@hitchcock.org RI Nelson, Robert/B-1470-2012 FU NIDDK NIH HHS [R01 DK 62995, R01 DK 62901] NR 66 TC 85 Z9 94 U1 0 U2 7 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 EI 1470-8752 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD DEC PY 2003 VL 31 BP 1358 EP 1363 PN 6 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 754ED UT WOS:000187289000059 PM 14641063 ER PT J AU Morozov, A Kellendonk, C Simpson, E Tronche, F AF Morozov, A Kellendonk, C Simpson, E Tronche, F TI Using conditional mutagenesis to study the brain SO BIOLOGICAL PSYCHIATRY LA English DT Article DE gene targeting; Cre recombinase; tetracycline; transactivator; brain ID LONG-TERM POTENTIATION; YAC TRANSGENIC MICE; MOUSE ES CELLS; CRE RECOMBINASE; GENE-EXPRESSION; MEDIATED RECOMBINATION; MAMMALIAN-CELLS; NERVOUS-SYSTEM; GLUCOCORTICOID RECEPTOR; NEUROTROPHIC FACTOR AB Conditional genetic modifications are used to determine how individual molecules contribute to the function of defined neuronal circuits in the mouse brain. Among various techniques for these genetic modifications, the tetracycline transactivator and the Cre-loxP systems have proved to be most successful in recent years. Here we describe the basic principles, recent developments, and potential applications of these methodologies. We discuss their impact on the study of general brain function and their use for modeling different brain disorders. C1 NIMH, Unit Behav Genet, Mol Pathophysiol Lab, US Dept HHS,NIH, Bethesda, MD 20892 USA. Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. Columbia Univ, Howard Hughes Med Inst, New York, NY 10032 USA. Coll France, Inst Biol, CNRS, F-75231 Paris, France. RP Morozov, A (reprint author), NIMH, Unit Behav Genet, Mol Pathophysiol Lab, US Dept HHS,NIH, NIMH Bldg 49,Room B1EE16,49 Convent Dr,MSC 4405, Bethesda, MD 20892 USA. OI Simpson, Eleanor/0000-0002-9092-2230 NR 68 TC 51 Z9 52 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2003 VL 54 IS 11 BP 1125 EP 1133 DI 10.1016/S0006-3223(03)00467-0 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 747EM UT WOS:000186792300001 PM 14643079 ER PT J AU Winterer, G Coppola, R Egan, MF Goldberg, TE Weinberger, DR AF Winterer, G Coppola, R Egan, MF Goldberg, TE Weinberger, DR TI Functional and effective frontotemporal connectivity and genetic risk for schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; genetics; frontotemporal connectivity; P300 ID EVENT-RELATED FMRI; TO-NOISE RATIO; PREFRONTAL CORTEX; WORKING-MEMORY; EEG COHERENCE; INTRACEREBRAL POTENTIALS; TARGET DETECTION; PARIETAL CORTEX; VERBAL FLUENCY; VISUAL-STIMULI AB Background: Functional neuroimaging and electrophysiologic studies have found disturbed frontotemporal interaction in schizophrenia. We sought to determine whether abnormalities of frontotemporal connectivity are trait markers of genetic risk for schizophrenia. Methods: We investigated 64 schizophrenia patients, 79 of their clinically unaffected siblings, and 88 unrelated normal controls with an auditory oddball electroencephalogram (EEG) evoked potential paradigm. We measured: 1) frontotemporal event-related EEG-coherence (i.e. a measure of functional connectivity); and 2) we performed structural equation modeling of the effective connectivity between the frontal P300 and temporoparietal P300-amplitude. Results: Schizophrenic patients and their siblings showed a reduction of frontotemporal coherence. At peak activation during the P300 time-window, a negative ("inhibitory") frontotemporal path coefficient was found in normal controls, whereas a positive coefficient was seen in schizophrenic patients with siblings being intermediate. Intra-class correlations between sib-pairs and relative risk estimates of the applied connectivity measures were non-significant. Topographic correlation matrix analyses suggested that the altered functional and effective frontotemporal connectivity indirectly reflect regional abnormalities of increased activation variance. Conclusions: Impaired interaction of the frontotemporal macro-circuit indirectly reflects genetically determined abnormalities of frontal and temporoparietal microcircuits. The reasons why frontotemporal connectivity appears to be a poor predictor of genetic risk for schizophrenia are discussed. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Winterer, G (reprint author), Univ Mainz, Psychiat Klin & Poliklin, Untere Zahlbacher Str 8, D-55131 Mainz, Germany. NR 70 TC 94 Z9 96 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2003 VL 54 IS 11 BP 1181 EP 1192 DI 10.1016/S0006-3223(03)00532-8 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 747EM UT WOS:000186792300007 PM 14643085 ER PT J AU McInnis, MG Dick, DM Willour, VL Avramopoulos, D MacKinnon, DF Simpson, SG Potash, JB Edenberg, HJ Bowman, ES McMahon, FJ Smiley, C Chellis, JL Huo, YQ Diggs, T Meyer, ET Miller, M Matteini, AT Rau, NL DePaulo, JR Gershon, ES Badner, JA Rice, JP Goate, AM Detera-Wadleigh, SD Nurnberger, JI Reich, T Zandi, PP Foroud, TM AF McInnis, MG Dick, DM Willour, VL Avramopoulos, D MacKinnon, DF Simpson, SG Potash, JB Edenberg, HJ Bowman, ES McMahon, FJ Smiley, C Chellis, JL Huo, YQ Diggs, T Meyer, ET Miller, M Matteini, AT Rau, NL DePaulo, JR Gershon, ES Badner, JA Rice, JP Goate, AM Detera-Wadleigh, SD Nurnberger, JI Reich, T Zandi, PP Foroud, TM TI Genome-wide scan and conditional analysis in bipolar disorder: Evidence for genomic interaction in the National Institute of Mental Health Genetics Initiative bipolar pedigrees SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar disorder; linkage; conditional analysis; genetics ID OLD ORDER AMISH; SCHIZOPHRENIA-SUSCEPTIBILITY LOCUS; MANIC-DEPRESSIVE ILLNESS; SEROTONIN TRANSPORTER; LINKAGE ANALYSIS; SUGGESTIVE EVIDENCE; CHROMOSOME-X; GENES; SCREEN; ASSOCIATION AB Background: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied. Methods: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions. Results: One region, on 16p13, was significant at the genome-wide p < .05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p &LE; .01). Conditional analysis assuming epistasis identified a significant increase in linkage at four regions. Families linked to 6q24 showed a significant increase in nonparametric logarithms of the odds (NPL) scores at 5q11 and 7q21. Epistasis also was observed between 20p12 and 13q21, and 16p13 and 9q21. Conclusions: The findings are presented in rank order of nominal significance. Several of these regions have been previously implicated in independent studies of either bipolar disorder or schizophrenia. The strongest finding is at 16p13 at D16S748 with an NPL of 3.3, there is evidence of epistasis between this locus and 9q21. Application of conditional analyses is potentially useful in larger sample collections to identify susceptibility genes of modest influence that may not be identified in a genome-wide scan aimed to identify single gene effects. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIMH, Mood & Anxiety Disorders Unit, Intramural Program, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. RP McInnis, MG (reprint author), Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. RI McMahon, Francis/A-7290-2009; Meyer, Eric/C-1029-2011; McInnis, Melvin/F-6963-2012; Avramopoulos, Dimitrios/J-4392-2012; OI Meyer, Eric/0000-0002-1998-7162; McInnis, Melvin/0000-0002-0375-6247; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X; Edenberg, Howard/0000-0003-0344-9690 FU NIMH NIH HHS [K20-MH-01088, R01 MH59535, R01 MH59545, R01 MH61613, R01-MH-59533, U01MH46282]; PHS HHS [46274, 46280, 54701, 54723, 54794] NR 71 TC 65 Z9 65 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 1 PY 2003 VL 54 IS 11 BP 1265 EP 1273 DI 10.1016/j.biopsych.2003.08.001 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 747EM UT WOS:000186792300016 PM 14643094 ER PT J AU Gellein, K Garruto, RM Syversen, T Sjobakk, TE Flaten, TP AF Gellein, K Garruto, RM Syversen, T Sjobakk, TE Flaten, TP TI Concentrations of Cd, Co, Cu, Fe, Mn, Rb, V, and Zn in formalin-fixed brain tissue in amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam determined by high-resolution ICP-MS SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE cadmium; cobalt; copper; iron; manganese; rubidium; vanadium; zinc; trace elements; double focusing inductively coupled plasma-mass spectrometry ID MOTOR-NEURON DISEASE; NEUTRON-ACTIVATION ANALYSIS; TRACE-ELEMENTS; ALZHEIMERS-DISEASE; NEUROFIBRILLARY DEGENERATION; NEURODEGENERATIVE DISORDERS; CLINICAL-FEATURES; ENDEMIC DISEASE; KII PENINSULA; SPINAL-CORD AB Amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) are neurodegenerative disorders that occurred with extremely high frequency among the native population on Guam, especially in the 1950s and 1960s, but have substantially declined over the last half-century. The etiology of these diseases is unknown, but the most plausible hypothesis centers on imbalances in essential and toxic metals. We have determined the concentrations of Cd, Co, Cu, Fe, Mn, Rb, V, and Zn in formalin-fixed brain tissue collected during the period 1979-1983 from eight Guamanian patients with ALS, four with PDC, and five control subjects using high-resolution inductively coupled plasma-mass spectrometry. The concentrations of Cd are markedly and significantly elevated both in gray and white matter in ALS, but not in PDC patients. The concentrations of Zn are elevated for both patient groups, in both gray and white matter, but only the difference in gray matter for PDC is significant. For the other metals, no significant differences are found. C1 Norwegian Univ Sci & Technol, Dept Chem, Trondheim, Norway. Norwegian Univ Sci & Technol, Dept Clin Neurosci, Trondheim, Norway. SUNY Binghamton, Dept Anthropol, Binghamton, NY USA. SUNY Binghamton, Dept Biol Sci, Binghamton, NY USA. NIH, Bethesda, MD USA. RP Sjobakk, TE (reprint author), Norwegian Univ Sci & Technol, Dept Chem, Trondheim, Norway. RI Flaten, Trond Peder/I-3756-2013 NR 64 TC 22 Z9 23 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD WIN PY 2003 VL 96 IS 1-3 BP 39 EP 60 DI 10.1385/BTER:96:1-3:39 PG 22 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 761PF UT WOS:000187916600004 PM 14716085 ER PT J AU Chen, Z Dunson, DB AF Chen, Z Dunson, DB TI Random effects selection in linear mixed models SO BIOMETRICS LA English DT Article DE Bayes factor; homogeneity test; latent variables; longitudinal data; MCMC; model averaging; variable selection; variance components ID COVARIANCE-MATRIX; LONGITUDINAL DATA; VARIABLE SELECTION; HOMOGENEITY; TESTS AB We address the important practical problem of how to select the random effects component in a linear mixed model. A hierarchical Bayesian model is used to identify any random effect with zero variance. The proposed approach reparameterizes the mixed model so that functions of the covariance parameters of the random effects distribution are incorporated as regression coefficients on standard normal latent variables. We allow random effects to effectively drop out of the model by choosing mixture priors with point mass at zero for the random effects variances. Due to the reparameterization, the model enjoys a conditionally linear structure that facilitates the use of normal conjugate priors. We demonstrate that posterior computation can proceed via a simple and efficient Markov chain Monte Carlo algorithm. The methods are illustrated using simulated data and real data from a study relating prenatal exposure to polychlorinated biphenyls and psychomotor development of children. C1 Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Chen, Z (reprint author), Univ Penn, Dept Biostat & Epidemiol, 625 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. NR 31 TC 82 Z9 84 U1 5 U2 23 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2003 VL 59 IS 4 BP 762 EP 769 DI 10.1111/j.0006-341X.2003.00089.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 756UE UT WOS:000187501100003 PM 14969453 ER PT J AU Albert, PS Shih, JH AF Albert, PS Shih, JH TI Modeling tumor growth with random onset SO BIOMETRICS LA English DT Article DE animal studies; discrete survival; gompertzian growth; linear mixed models; nonlinear mixed models; shared random effect ID REGRESSION; DISEASE; CANCER; TIME AB The longitudinal assessment of tumor volume is commonly used as an endpoint in small animal studies in cancer research. Groups of genetically identical mice are injected with mutant cells from clones developed with different mutations. The interest is on comparing tumor onset (i.e., the time of tumor detection) and tumor growth after onset, between mutation groups. This article proposes a class of linear and nonlinear growth models for jointly modeling tumor onset and growth in this situation. Our approach allows for interval-censored time of onset and missing-at-random dropout due to early sacrifice, which are common situations in animal research. We show that our approach has good small-sample properties for testing and is robust to some key unverifiable modeling assumptions. We illustrate this methodology with an application examining the effect of different mutations on tumorigenesis. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, Biometr Res Branch, Execut Plaza N,Room 8136, Bethesda, MD 20892 USA. NR 21 TC 8 Z9 8 U1 1 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2003 VL 59 IS 4 BP 897 EP 906 DI 10.1111/j.0006-341X.2003.00104.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 756UE UT WOS:000187501100018 PM 14969468 ER PT J AU Dunson, DB Herring, AH AF Dunson, DB Herring, AH TI Bayesian inferences in the Cox model for order-restricted hypotheses SO BIOMETRICS LA English DT Article DE categorical covariates; Gibbs sampler; Isotonic Regression; monotonicity; multiple comparisons; proportional hazards; survival analysis ID PROPORTIONAL HAZARDS; VARIABLE SELECTION; REGRESSION-MODEL; ALTERNATIVES; STROKE; TIME AB In studying the relationship between an ordered categorical predictor and an event time, it is standard practice to include dichotomous indicators of the different levels of the predictor in a Cox model. One can then use a multiple degree-of-freedom score or partial likelihood ratio test for hypothesis testing. Often, interest focuses on comparing the null hypothesis of no difference to an order-restricted alternative, such as a monotone increase across levels of a predictor. This article proposes a Bayesian approach for addressing hypotheses of this type. We reparameterize the Cox model in terms of a cumulative product of parameters having conjugate prior densities, consisting of mixtures of point masses at one, and truncated gamma densities. Due to the structure of the model, posterior computation can proceed via a simple and efficient Gibbs sampling algorithm. Posterior probabilities for the global null hypothesis and subhypotheses, comparing the hazards for specific groups, can be calculated directly from the output of a single Gibbs chain. The approach allows for level sets across which a predictor has no effect. Generalizations to multiple predictors are described, and the method is applied to a study of emergency medical treatment for stroke. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 27 TC 5 Z9 5 U1 1 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2003 VL 59 IS 4 BP 916 EP 923 DI 10.1111/j.0006-341X.2003.00106.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 756UE UT WOS:000187501100020 PM 14969470 ER PT J AU Nam, JM AF Nam, JM TI Homogeneity score test for the intraclass version of the kappa statistics and sample-size determination in multiple or stratified studies SO BIOMETRICS LA English DT Article DE estimator of common kappa; homogeneity tests; interval estimation; kappa statistics; sample size ID INTERVAL ESTIMATION; TWIN CONCORDANCE; BINARY TRAIT; AGREEMENT; COEFFICIENT AB When the intraclass correlation coefficient or the equivalent version of the kappa agreement coefficient have been estimated from several independent studies or from a stratified study, we have the problem of comparing the kappa statistics and combining the information regarding the kappa statistics in a common kappa when the assumption of homogeneity of kappa coefficients holds. In this article, using the likelihood score theory extended to nuisance parameters (Tarone, 1988, Communications in Statistics-Theory and Methods 17(5), 1549-1556) we present an efficient homogeneity test for comparing several independent kappa statistics and, also, give a modified homogeneity score method using a noniterative and consistent estimator as an alternative. We provide the sample size using the modified homogeneity score method and compare it with that using the goodness-of-fit method (GOF) (Donner, Eliasziw, and Klar, 1996, Biometrics 52, 176-183). A simulation study for small and moderate sample sizes showed that the actual level of the homogeneity score test using the maximum likelihood estimators (MLEs) of parameters is satisfactorily close to the nominal and it is smaller than those of the modified homogeneity score and the goodness-of-fit tests. We investigated statistical properties of several noniterative estimators of a common kappa. The estimator (Donner et al., 1996) is essentially efficient and can be used as an alternative to the iterative MLE. An efficient interval estimation of a common kappa using the likelihood score method is presented. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. RP Nam, JM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Execut Plaza S,Room 8028,6120 Execut Blvd,MSC 7240, Rockville, MD 20852 USA. NR 21 TC 14 Z9 14 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2003 VL 59 IS 4 BP 1027 EP 1035 DI 10.1111/j.0006-341X.2003.00118.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 756UE UT WOS:000187501100032 PM 14969482 ER PT J AU Chatterjee, N Shih, JH AF Chatterjee, N Shih, JH TI On use of bivariate survival models with cure fraction SO BIOMETRICS LA English DT Editorial Material ID DISTRIBUTIONS; ASSOCIATION C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Biometr Res Branch, Div Canc Treatment & Diagnost, Rockville, MD USA. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8038, Rockville, MD USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2003 VL 59 IS 4 BP 1184 EP 1185 DI 10.1111/j.0006-341X.2003.00136.x PG 2 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 756UE UT WOS:000187501100050 ER PT J AU Jeffries, NO AF Jeffries, NO TI A note on 'testing the number of components in a normal mixture' SO BIOMETRIKA LA English DT Article DE likelihood ratio test; normal mixture AB In a recent paper, Lo et al. (2001) propose a test for the likelihood ratio statistic based on the Kullback-Leibler information criterion when testing the null hypothesis that a random sample is drawn from a mixture of k(0) normal components against the alternative hypothesis of a mixture with k(1) normal components with k(0) less than k(1) However, this result requires conditions that are generally not met when the null hypothesis holds. Consequently, the result is not proven and simulations suggest that it may not be correct. C1 NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Jeffries, NO (reprint author), NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 27 Z9 27 U1 1 U2 6 PU BIOMETRIKA TRUST PI LONDON PA UNIV COLLEGE LONDON GOWER ST-BIOMETRIKA OFFICE, LONDON WC1E 6BT, ENGLAND SN 0006-3444 J9 BIOMETRIKA JI Biometrika PD DEC PY 2003 VL 90 IS 4 BP 991 EP 994 DI 10.1093/biomet/90.4.991 PG 4 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 754MT UT WOS:000187321500020 ER PT J AU Balboni, G Salvadori, S Guerrini, R Negri, L Giannini, E Bryant, SD Jinsmaa, Y Lazarus, LH AF Balboni, G Salvadori, S Guerrini, R Negri, L Giannini, E Bryant, SD Jinsmaa, Y Lazarus, LH TI Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R ' analogues: Acquisition of potent delta antagonism SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID DMT-TIC PHARMACOPHORE; N-METHYL PEPTIDES; RESTRICTED CONFORMATIONAL FREEDOM; ALKYLATED DERIVATIVES; RECEPTOR ANTAGONISTS; BIOLOGICAL-ACTIVITY; DIPEPTIDE ANALOGS; DIKETOPIPERAZINES; SUBSTITUENTS; A-(1-11) AB N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R' series of compounds produced no significant affect on the high delta-opioid receptor affinity (K-i = 0.035-0.454 nM), but dramatically decreased that for the p-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R'): phenyl (Ph) (5'-8') elicited a greater reduction in mu-affinity (40-70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of delta-agonism coupled with the appearance of potent 6 antagonism (4'-7') (pA(2) = 8.14-9.47), while 1 exhibited only a 160-fold decreased delta agonism (1') and the delta antagonism of 8 enhanced > 10-fold (pA(2) = 10.62, 8'); and (ii) a consistent loss of P-affinity resulted in enhanced delta-opioid receptor selectivity. With the exception of compound 1, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent delta-selective antagonists. Published by Elsevier Ltd. C1 NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, I-00185 Rome, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Univ Cagliari, Dept Toxicol, I-09126 Cagliari, Italy. RP Lazarus, LH (reprint author), NIEHS, LCBRA, POB 12233, Res Triangle Pk, NC 27709 USA. OI Guerrini, Remo/0000-0002-7619-0918 NR 35 TC 18 Z9 18 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD DEC 1 PY 2003 VL 11 IS 24 BP 5435 EP 5441 DI 10.1016/j.bmc.2003.09.039 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 750ZK UT WOS:000187028200015 PM 14642588 ER PT J AU Batsilas, L Berezhkovskii, AM Shvartsman, SY AF Batsilas, L Berezhkovskii, AM Shvartsman, SY TI Stochastic model of autocrine and paracrine signals in cell culture assays SO BIOPHYSICAL JOURNAL LA English DT Article ID EXTENDED BROWNIAN DYNAMICS; GROWTH-FACTOR RECEPTOR; LIGAND-BINDING; SPATIAL RANGE; DIFFUSION; SIMULATION; SYSTEM; LOOPS; ACTIVATION; RADIATION AB Autocrine signaling systems are commonly studied under cell culture conditions. In a typical cell culture assay, a layer of liquid medium covers a random two-dimensional dispersion of cells, which secrete ligands. In a growing number of experiments, it is important to characterize the spatial range of autocrine and paracrine cell communication. Currently, the spatial distribution of diffusing signals can be analyzed only indirectly, from their effects on the intracellular signaling or physiological responses of autocrine cells. To directly characterize the spatial range of secreted ligands, we propose a stochastic model for autocrine cell cultures and analyze it using a combination of analytical and computational tools. The two main results derived within the framework of this model are 1), an expression for the fraction of autocrine trajectories, i.e., the probability for a ligand to be trapped by the same cell from which it has been secreted; and 2), an expression for the spatial distribution of trapping points of paracrine trajectories. We test these analytical results by stochastic simulations with efficient Brownian dynamics code and apply our model to analyze the spatial operation of autocrine epidermal growth factor receptor systems. C1 Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. Princeton Univ, Lewis Sigler Inst Integrat Gen, Princeton, NJ 08544 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Karpov Inst Phys Chem, Moscow 103064, Russia. RP Shvartsman, SY (reprint author), Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. NR 35 TC 39 Z9 40 U1 0 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC PY 2003 VL 85 IS 6 BP 3659 EP 3665 DI 10.1016/S0006-3495(03)74783-3 PG 7 WC Biophysics SC Biophysics GA 747GX UT WOS:000186797800022 PM 14645058 ER PT J AU Nestorovich, EM Rostovtseva, TK Bezrukov, SM AF Nestorovich, EM Rostovtseva, TK Bezrukov, SM TI Residue ionization and ion transport through OmpF channels SO BIOPHYSICAL JOURNAL LA English DT Article ID ESCHERICHIA-COLI PORIN; OUTER-MEMBRANE PORINS; MATRIX PROTEIN PORIN; FUNCTIONAL-CHARACTERIZATION; BROWNIAN DYNAMICS; MOLECULAR-BASIS; RHODOBACTER-CAPSULATUS; CHARGED RESIDUES; ALPHA-HEMOLYSIN; LIPID-MEMBRANES AB Single trimeric channels of the general bacterial porin, OmpF, were reconstituted into planar lipid membranes and their conductance, selectivity, and open-channel noise were studied over a wide range of proton concentrations. From pH 1 to pH 12, channel transport properties displayed three characteristic regimes. First, in acidic solutions, channel conductance is a strong function of pH; it increases by approximately threefold as the proton concentration decreases from pH 1 to pH 5. This rise in conductance is accompanied by a sharp increase in cation transport number and by pronounced open-channel low-frequency current noise with a peak at similar topH 2.5. Random stepwise transients with amplitudes at similar to1/5 of the monomer conductance are major contributors to this noise. Second, over the middle range (pH 5, pH 9), channel conductance and selectivity stay virtually constant; open channel noise is at its minimum. Third, over the basic range (pH 9, pH 12), channel conductance and cation selectivity start to grow again with an onset of a higher frequency open-channel noise. We attribute these effects to the reversible protonation of channel residues whose pH-dependent charge influences transport by direct interactions with ions passing through the channel. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Bezrukov, SM (reprint author), NICHD, NIH, Bldg 9,Room 1N-124B, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov NR 77 TC 98 Z9 98 U1 1 U2 5 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 DEC PY 2003 VL 85 IS 6 BP 3718 EP 3729 DI 10.1016/S0006-3495(03)74788-2 PG 12 WC Biophysics SC Biophysics GA 747GX UT WOS:000186797800027 PM 14645063 ER PT J AU Tangrea, MA Flaig, MJ Ramesh, A Best, CJM Baibakov, GV Hewitt, SM Mitchell, CD Hartmann, DP Knezevic, V Emmert-Buck, MR Chuaqui, RF AF Tangrea, MA Flaig, MJ Ramesh, A Best, CJM Baibakov, GV Hewitt, SM Mitchell, CD Hartmann, DP Knezevic, V Emmert-Buck, MR Chuaqui, RF TI Layered expression scanning: multiplex analysis of RNA and protein gels SO BIOTECHNIQUES LA English DT Article ID GENE-EXPRESSION; MICROARRAYS; SPECIMENS AB Northern blots and immunoblots are utilized in laboratories worldwide and offer several important features for analyzing mRNA and protein expression, including accuracy, low cost, evaluation of probe specificity, and information on transcript and protein forms based on molecular size. However standard blotting techniques are hampered by three factors. They require a significant amount of input material, are laborious, and are capable of measuring only one protein or transcript at a time. Here we describe a simple yet effective technique for the multiplex analysis of standard RNA and protein gels using the layered expression scanning platform. The method relies on a novel membrane with high-affinity low-capacity binding characteristics. Using this approach, multiple blots from an RNA or protein electrophoresis gel can be simultaneously produced. We believe this method will be widely applicable to expression studies for a broad range of biological systems. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. 20 20 GeneSyst, Rockville, MD USA. Georgetown Univ Hosp, Washington, DC 20007 USA. RP Chuaqui, RF (reprint author), NCI, Pathol Lab, Rm 2A33,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Hewitt, Stephen/0000-0001-8283-1788 NR 11 TC 10 Z9 10 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD DEC PY 2003 VL 35 IS 6 BP 1280 EP 1285 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 753UX UT WOS:000187249900024 PM 14682064 ER PT J AU Post, RM Leverich, GS Nolen, WA Kupka, RW Altshuler, LL Frye, MA Suppes, T McElroy, S Keck, P Grunze, H Walden, J AF Post, RM Leverich, GS Nolen, WA Kupka, RW Altshuler, LL Frye, MA Suppes, T McElroy, S Keck, P Grunze, H Walden, J TI A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network SO BIPOLAR DISORDERS LA English DT Article; Proceedings Paper CT Symposium on Antidepressant use in Bipolar Disorder CY MAY, 2001 CL NEW ORLEANS, LOUISIANA DE adjuncts; antidepressants; bipolar depression; bupropion; morbidity; outcome; relapse; sertraline; switching; venlafaxine ID PLACEBO-CONTROLLED TRIAL; LITHIUM MAINTENANCE TREATMENT; CONTROLLED 18-MONTH TRIAL; DOUBLE-BLIND; AFFECTIVE-DISORDERS; SYMPTOMATOLOGY IDS; I DISORDER; FOLIC-ACID; FOLLOW-UP; RELAPSE AB Objectives: The risk-to-benefit ratio of the use of unimodal antidepressants (ADs) as adjuncts to mood stabilizers continues to be an area of controversy and disagreement among experts in the field. This paper reviews new data on: (1) depression in bipolar illness, (2) switch rates on ADs and (3) risks of AD discontinuation that are pertinent to the ongoing discussion and recommendations. Methods: In the first study reviewed, 258 outpatients with bipolar illness were assessed prospectively on a daily basis using the National Institute of Mental Health-Life Chart Method(TM) (NIMH-LCM) for 1 year. In the second study, 127 bipolar depressed patients were randomized to 10 weeks of sertraline, bupropion, or venlafaxine, as adjuncts to mood stabilizers; non-responders were re-randomized and responders were offered a year of continuation treatment. In the final study, Altshuler et al. retrospectively and prospectively assessed the risk of depressive relapses in patients who remained on ADs after 2 months of euthymia compared with those who discontinued ADs. Results: Despite intensive naturalistic treatment, the 258 outpatients with bipolar illness followed prospectively for 1 year showed three times as many days depressed as days manic, re-emphasizing the considerable depressive morbidity that remains in bipolar disorder despite the number of treatment options available. In the study of bipolar depressed patients randomized to one of three ADs, a range of severities and durations of hypomanic to manic switches were discerned following 175 trials of AD augmentation of treatment with a mood stabilizer. Of the acute 10-week trials, 9.1% were associated with switches into hypomania or mania and another 9.1% with a week or more of hypomania alone (with no to minimal dysfunction). In 73 continuation phase AD trials, 16.4 and 19.2% were similarly associated with hypomanic to manic and hypomanic switches, respectively. In the Altshuler et al. studies, those who remained well on any AD for more than 2 months (only 15-20% of those initially treated) and who continued on ADs showed a lesser rate of relapse into depression over 1 year (35 and 36% in the first and second study, respectively) compared with those who discontinued their ADs (68 and 70% relapsing into depression). Surprisingly, this continuation of ADs was associated with no increase in the rate of switching into mania compared with those stopping ADs. Conclusions: These data reveal that depression and depressive cycling remain a substantial problem in some two-thirds of intensively treated bipolar outpatients. Acute AD augmentation was associated with a modest response rate and 18.2% switched into a hypomanic to manic episode, and 35.6% of the continuation trials showed these two types of switches. Two separate studies suggest that in the very small subgroup who remain well on ADs for at least 2 months, one should consider continuation of this AD augmentation treatment, because AD discontinuation appears associated with a substantially increased risk of depression relapse over the subsequent year with no reduced risk of switching into mania. C1 NIMH, US Dept HHS, NIH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Med Ctr, Utrecht, Netherlands. Altrecht Inst Mental Hlth, Utrecht, Netherlands. Univ Calif Los Angeles, Ambulatory Clin Res Ctr, Los Angeles, CA USA. Vet Affairs Med Ctr, Los Angeles, CA USA. Univ Texas, SW Med Ctr Dallas, Dallas, TX 75235 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Munich, Munich, Germany. Univ Freiberg, Freiberg, Germany. RP Post, RM (reprint author), NIMH, US Dept HHS, NIH, Biol Psychiat Branch, 10 Ctr Dr,MSC 1272,Bldg 10,Room 3S239, Bethesda, MD 20892 USA. RI Nolen, Willem/E-9006-2014 FU NIMH NIH HHS [R01 MH079261] NR 64 TC 97 Z9 97 U1 3 U2 6 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD DEC PY 2003 VL 5 IS 6 BP 396 EP 406 DI 10.1046/j.1399-5618.2003.00065.x PG 11 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 748PE UT WOS:000186869600003 PM 14636363 ER PT J AU Rhodes, MC Nyska, A Seidler, FJ Slotkin, TA AF Rhodes, MC Nyska, A Seidler, FJ Slotkin, TA TI Does terbutaline damage the developing heart? SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE beta-adrenoceptor; cardiac development; preterm labor; terbutaline; tocolysis ID BETA-ADRENERGIC RECEPTORS; MATERNAL SUBCUTANEOUS TERBUTALINE; PHOSPHATIDIC-ACID PHOSPHATASE; ADENYLATE-CYCLASE ACTIVITY; HYPOXIA-INDUCED APOPTOSIS; RAT CARDIAC MYOCYTES; NEONATAL-RAT; DNA-SYNTHESIS; PRENATAL DEXAMETHASONE; MYOCARDIAL NECROSIS AB BACKGROUND: beta(2)-Adrenoceptor (PAR) agonists, such as terbutaline, are widely used to arrest preterm labor. They also cross the placenta where they stimulate receptors in fetal tissues, which in turn use betaAR input for trophic control of cell replication and differentiation. METHODS: As rats are altricial, we administered terbutaline in two different postnatal exposure periods (10 mg/kg given daily on Days 2-5 or 11-14). RESULTS: Hearts were examined twenty-four hours after the last dose and on postnatal day 30 for cardiac damage. Neither treatment paradigm caused an increase in cardiac abnormalities compared to controls but quantitative analysis of the number of nuclei indicated reductions in females. CONCLUSIONS: These findings do not support earlier case reports of outright myocardial necrosis after terbutaline tocolysis in human infants. Nevertheless, the significant statistical association between terbutaline and cardiac anomalies in epidemiological studies suggest that terbutaline may sensitize the developing heart to other insults that affect development. (C) 2003 Wiley-Liss, Inc. C1 Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Slotkin, TA (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Box 3813, Durham, NC 27710 USA. EM t.slotkin@duke.edu FU NICHD NIH HHS [R01 HD09713]; NIEHS NIH HHS [T32 ES07031] NR 82 TC 1 Z9 1 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD DEC PY 2003 VL 68 IS 6 BP 449 EP 455 DI 10.1002/bdrb.10043 PG 7 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 760YA UT WOS:000187861800001 PM 14745978 ER PT J AU Choksi, NY Jahnke, GD St Hilaire, C Shelby, M AF Choksi, NY Jahnke, GD St Hilaire, C Shelby, M TI Role of thyroid hormones in human and laboratory animal reproductive health SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Review DE thyroid hormones; animal; human; review; reproductive health; reproduction; reproductive tract; development; thyroid gland; fertility; rat; comparative physiology ID THYROXINE-BINDING GLOBULIN; DEVELOPMENTAL EXPRESSION; NEONATAL-HYPOTHYROIDISM; RECEPTOR EXPRESSION; MOLECULAR-CLONING; RAT; PREGNANCY; HYPERTHYROIDISM; PITUITARY; PROTEIN AB The highly conserved nature of the thyroid gland and the thyroid system among mammalian species suggests it is critical to species survival. Studies show the thyroid system plays a critical role in the development of several organ systems, including the reproductive tract. Despite its highly conserved nature, the thyroid system can have widely different effects on reproduction and reproductive tract development in different species. The present review focuses on assessing the role of thyroid hormones in human reproduction and reproductive tract development and comparing it to the role of thyroid hormones in laboratory animal reproduction and reproductive tract development. The review also assesses the effects of thyroid dysfunction on reproductive tract development and function in humans and laboratory animals. Consideration of such information is important in designing, conducting, and interpreting studies to assess the potential effects of thyroid toxicants on reproduction and development. Published 2003 Wiley-Liss, Inc. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Sci Int Inc, Res Triangle Pk, NC USA. Sci Int Inc, Alexandria, VA USA. RP Shelby, M (reprint author), NIEHS, POB 12233,MD EC-32, Res Triangle Pk, NC 27709 USA. EM Shelby@niehs.nih.gov FU NIEHS NIH HHS [N01-ES--85425] NR 67 TC 49 Z9 54 U1 3 U2 9 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD DEC PY 2003 VL 68 IS 6 BP 479 EP 491 DI 10.1002/bdrb.10045 PG 13 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 760YA UT WOS:000187861800005 PM 14745982 ER PT J AU Aplan, PD AF Aplan, PD TI The rhythm of blood SO BLOOD LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Aplan, PD (reprint author), NCI, Bethesda, MD 20892 USA. RI Aplan, Peter/K-9064-2016 NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 102 IS 12 BP 3861 EP 3861 DI 10.1182/blood-2003-09-3186 PG 1 WC Hematology SC Hematology GA 750JH UT WOS:000186987200010 ER PT J AU Brown, MJ Nijhara, R Hallam, JA Gignac, M Yamada, KM Erlandsen, SL Delon, J Kruhlak, M Shaw, S AF Brown, MJ Nijhara, R Hallam, JA Gignac, M Yamada, KM Erlandsen, SL Delon, J Kruhlak, M Shaw, S TI Chemokine stimulation of human peripheral blood T lymphocytes induces rapid dephosphorylation of ERM proteins, which facilitates loss of microvilli and polarization SO BLOOD LA English DT Article ID SCANNING ELECTRON-MICROSCOPY; CORTICAL ACTIN ORGANIZATION; CELL-ADHESION; IN-VIVO; THREONINE 558; EZRIN/RADIXIN/MOESIN PROTEINS; IMMUNOLOGICAL SYNAPSE; SPATIAL-DISTRIBUTION; LEUKOCYTE ADHESION; PHYSIOLOGICAL FLOW AB Lymphocyte microvilli mediate initial rolling-adhesion along endothelium but are lost during transmigration from circulation to tissue. However, the mechanism for resorption of lymphocyte microvilli remains unexplored. We show that chemokine stimulation of human peripheral blood T (PBT) cells is sufficient to induce rapid resorption of microvilli. Microvilli in other cells are regulated by ezrin/radixin/ moesin (ERM) proteins, which link the plasma membrane to the cortical F-actin cytoskeleton; maintenance of these linkages requires ERM activation, reflected by phosphorylation at a specific carboxy-terminal threonine residue. Carboxyphosphorylated-ERM (cpERM) proteins in resting PBT cells show a punctate peripheral distribution consistent with localization to microvilli. cpERM dephosphorylation begins within seconds of stimulation by chemokines (stromal derived factor 1alpha [SDF-1alpha] or secondary lymphoid tissue cytokine), and ERM proteins lose their punctate distribution with kinetics paralleling the loss of microvilli. The cpERM proteins are preferentially associated with the cytoskeleton at rest and this association is lost with chemokine-induced dephosphorylation. Transfection studies show that a dominant-negative ERM construct destroys microvilli, whereas a construct mimicking cpERM facilitates formation of microvilli, retards chemokine-induced loss of microvilli, and markedly impairs chemokine-induced polarization. Thus, chemokine induces rapid dephosphorylation and inactivation of cpERM, which may in turn facilitate 2 aspects of cytoskeletal reorganization involved in lymphocyte recruitment: loss of microvilli and polarization. (C) 2003 by The American Society of Hematology. C1 NCI, Human Immunol Sect, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. SAIC Frederick, Image Anal Lab, Frederick, MD USA. Craniofacial Dev Biol & Regenerat Branch, Natl Inst Dent & Carniofacial Res, Bethesda, MD USA. Univ Minnesota, Sch Med, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. INSERM, CNRS, Inst Cochin,U567,UMR 8104, Dept Cellular Biol, Paris, France. RP Shaw, S (reprint author), NCI, Human Immunol Sect, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. OI Yamada, Kenneth/0000-0003-1512-6805 NR 55 TC 90 Z9 90 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 DEC 1 PY 2003 VL 102 IS 12 BP 3890 EP 3899 DI 10.1182/blood-2002-12-3807 PG 10 WC Hematology SC Hematology GA 750JH UT WOS:000186987200015 PM 12907449 ER PT J AU Yao, L Salvucci, C Cardones, AR Hwang, ST Aoki, Y De La Luz Sierra, M Sajewicz, A Pittaluga, S Yarchoan, R Tosato, G AF Yao, L Salvucci, C Cardones, AR Hwang, ST Aoki, Y De La Luz Sierra, M Sajewicz, A Pittaluga, S Yarchoan, R Tosato, G TI Selective expression of stromal-derived factor-1 in the capillary vascular endothelium plays a role in Kaposi sarcoma pathogenesis SO BLOOD LA English DT Article ID CELL-ADHESION MOLECULE-1; GROWTH-FACTOR RECEPTOR-3; BLOOD MONONUCLEAR-CELLS; HIV-1 TAT PROTEIN; PERIPHERAL-BLOOD; BONE-MARROW; FLK-1/KDR RECEPTOR; DENDRITIC CELLS; CHEMOKINE SDF-1; FLOW CONDITIONS AB Kaposi sarcoma (KS), the most common neoplasm in patients with AIDS, typically presents with multiple skin lesions characterized by "spindle cells," the vast majority of which are infected with KSHV (Kaposi sarcoma herpes' virus, also named HHV-8). In patients with AIDS, the presence of cell-associated KSHV DNA in blood is predictive of subsequent KS development, but the mechanisms by which circulating KSHV-infected cells contribute to AIDS-KS pathogenesis are unclear. Here, we show that the chemokine stromal-derived factor-1 (SDF-1), which is constitutively expressed by skin capillary endothelium and displayed on the endothelial cell surface in association with heparan sulfate, can trigger specific arrest of KSHV-infected cat Is under physiologic, shear flow conditions. Moreover, in the presence of soluble SDF-1 gradients, SDF-1 expressed on the endothelial barrier can promote transendothelial migration of KSHV-infected, cells. By triggering specific adhesion of circulating KSHV-infected cells and favoring their entry into the extravascular cutaneous space, endothelial cell-associated SDF-1 in cutaneous capillaries may dictate the preferential occurrence of KS in the skin. (C) 2003 by The American Society of Hematology. C1 NCI, Expt Transplantat & Immunol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, CCR, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Expt Transplantat & Immunol Branch, CCR, NIH, Bldg 10,Rm 12N226,MSC 1907, Bethesda, MD 20892 USA. NR 49 TC 49 Z9 50 U1 1 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 DEC 1 PY 2003 VL 102 IS 12 BP 3900 EP 3905 DI 10.1182/blood-2003-02-0641 PG 6 WC Hematology SC Hematology GA 750JH UT WOS:000186987200016 PM 12907452 ER PT J AU Koh, CY Ortaldo, JR Blazar, BR Bennett, M Murphy, WJ AF Koh, CY Ortaldo, JR Blazar, BR Bennett, M Murphy, WJ TI NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; CLASS-I MOLECULES; BONE-MARROW-TRANSPLANTATION; APOPTOSIS-INDUCING LIGAND; BLOOD STEM-CELLS; NKG2D RECEPTOR; FAS LIGAND; MEDIATED APOPTOSIS; MYELOID-LEUKEMIA; MURINE NKG2D AB Natural killer (NK) cells are composed of subsets characterized by the expression of inhibitory or activating receptors, or both, specific for different major histocompatibility complex (MHC) class I determinants. We have previously shown that inhibitory receptor blockade of syngeneic NK cells was an effective means of ex vivo purging of leukemia-contaminated bone marrow and that the transplantation of mice with the purged bone marrow cells (BMCs) resulted in long-term, relapse-free survival. We have extended the investigation to assess the antitumor effects mediated by NK cells H2-allogeneic to tumor cells. We demonstrate that various tumor cell lines are More susceptible to lysis by H2-allogeneic NK cells than by syngeneic NK cells in vitro even though comparable percentages of Ly49 NK cells were present. Using allogeneic NK cells to purge leukemia-contaminating BMCs before transplantation resulted in a higher proportion of mice with long-term survival than using syngeneic NK cells. Allogeneic NK cells did not suppress hematopoietic reconstitution as measured by granulocyte/monocyte-colony-forming unit (CFU-GM), complete blood count (CBC), and donor chimerism at various days after transplantation. Inhibitory receptor blockade of allogeneic NK cells also significantly increased these antitumor effect at lower NK/tumor ratios compared with those of syngeneic NK cells. These results demonstrate that H2-allogeneic NK cells mediate more potent antitumor effects than syngeneic NK cells without adverse hematologic effects and thus may be useful in cancer therapy. (C) 2003 by The American Society of Hematology. C1 Univ Nevada, Sch Med, Appl Res Facil, Dept Microbiol & Immunol, Reno, NV 89557 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75230 USA. RP Koh, CY (reprint author), Univ Nevada, Sch Med, Appl Res Facil, Dept Microbiol & Immunol, Bldg 344,MS 199, Reno, NV 89557 USA. RI Koh, Crystal/D-9986-2013 FU NCI NIH HHS [R01 CA72669] NR 68 TC 24 Z9 27 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 DEC 1 PY 2003 VL 102 IS 12 BP 4067 EP 4075 DI 10.1182/blood-2003-04-1367 PG 9 WC Hematology SC Hematology GA 750JH UT WOS:000186987200038 PM 12893752 ER PT J AU Chung, HK Young, HA Goon, PKC Heidecker, G Princler, GL Shimozato, O Taylor, GP Bangham, CRM Derse, D AF Chung, HK Young, HA Goon, PKC Heidecker, G Princler, GL Shimozato, O Taylor, GP Bangham, CRM Derse, D TI Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines SO BLOOD LA English DT Article ID VIRUS TYPE-I; LEUKEMIA LYMPHOMA VIRUS; REED-STERNBERG CELLS; HTLV-I; HODGKIN LYMPHOMA; IMMUNE-RESPONSES; GENE-EXPRESSION; MESSENGER-RNA; IL-13; RECEPTOR AB Human T-cell leukemia virus type 1 (HTLV-1) infection profoundly alters T-cell gene expression, and the dysregulated synthesis of cytokines could influence the course and pathologic consequences of infection. In the process of screening T-cell lines for T helper 1 (Th1) and Th2 cytokine mRNAs, we observed that interleukin-13 (IL-13) mRNA was highly expressed in HTLV-1-infected, IL-2-dependent T-cell lines. IL-9 and interferon gamma (IFN-gamma) mRNAs were also expressed at high levels in chronically infected cell lines. IL-5 mRNA was detected in 60% of the HTLV-1-infected cell lines, but mRNAs for IL-4, IL-10, IL-2, and IL-15 were either below detection limits or did not correlate with HTLV-1 infection. Transcriptional activation of the IL-13 promoter by the HTLV-1 Tax trans-regulatory protein was demonstrated in Jurkat T cells transiently transfected with an IL-13 promoter-reporter plasmid. The clinical relevance of these observations was demonstrated by immunofluorescent staining and flow cytometry of lymphocytes obtained from HTLV-1-infected patients. These studies revealed that IL-13 production was directly related to the level of Tax expression in the infected CD4(+) T cells soon after in vitro culture. As IL-13 plays key roles in tumor immunosurveillance, asthma, and central nervous system inflammation, it may contribute to the pathophysiology of HTLV-1-associated diseases. (C) 2003 by The American Society of Hematology. C1 NCI, Canc Res Ctr, Basic Res Lab, Frederick, MD 21702 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. Univ London Imperial Coll Sci Technol & Med, Sch Med, Div Med, Dept Immunol, London SW7 2AZ, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, Div Med, Dept Genitourinary Med & Communicable Dis, London SW7 2AZ, England. RP Derse, D (reprint author), NCI, Canc Res Ctr, Basic Res Lab, Frederick, MD 21702 USA. RI Young, Howard/A-6350-2008; OI Young, Howard/0000-0002-3118-5111; Bangham, Charles/0000-0003-2624-3599 NR 49 TC 30 Z9 31 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 DEC 1 PY 2003 VL 102 IS 12 BP 4130 EP 4136 DI 10.1182/blood-2003-04-1043 PG 7 WC Hematology SC Hematology GA 750JH UT WOS:000186987200046 PM 12920029 ER PT J AU Dempsey, NJ Ojalvo, LS Wu, DW Little, JA AF Dempsey, NJ Ojalvo, LS Wu, DW Little, JA TI Induction of an embryonic globin gene promoter by short-chain fatty acids SO BLOOD LA English DT Article ID KRUPPEL-LIKE FACTOR; TRANSCRIPTION FACTOR SP3; MOUSE ERYTHROLEUKEMIA-CELLS; CREB-BINDING-PROTEIN; LOCUS-CONTROL REGION; GAMMA-GLOBIN; FETAL-HEMOGLOBIN; ERYTHROID-CELLS; TRANSGENIC MICE; FACTOR EKLF AB Short-chain fatty acids (SCFAs) and dimethyl sulfoxide (DMSO) induce adult erythroid differentiation in murine erythro-leukemia (MEL) cells, but only SCFAs concurrently up-regulate expression from the endogenous embryonic globin gene epsilon(y). The epsilon(y) promoter, linked to a reporter gene and stably transfected into MEL cells, was tested during adult erythroid differentiation. Both the epsilon(y)-CACCC site at -114 bp and enhancer sequences (hypersensitive site 2 [HS2]) from the beta-globin locus control region (LCR) were essential to maximal SCFA-mediated induction of expression from these constructs in MEL cells. Gel-shift analyses of binding activity from SCFA-induced MEL cell nuclear extracts showed in vitro binding by specificity proteins 1 and 3 (SP1, SP3) and basic or erythroid Kruppel-like factors (BKLF, EKLF) at the epsilon(y)-CACCC site. In a functional analysis, transient cotransfections in nonerythroid NIH/3T3 cells of SP1, SP3, BKLF, or EKLF and HS2 epsilon(y) promoter-luciferase constructs, with or without coactivators (p300, CREB-binding protein [CBP], or p300/CBP-associated factor [PCAF]) and SCFAs, were performed. SP1, SP3, and EKLF further increased expression from HS2 epsilon(y) promoter constructs following exposure to SCFAs. This effect was variably augmented by coactivators and was diminished in EKLF mutants that were unable to undergo histone/factor-acetyl transferase (H/FAT)-mediated acetylation. In addition, acetylation of SP1 was detectable in NIH/3T3 cells following exposure to SCFAs. In sum, LCR sequence and an embryonic globin gene promoter CACCC site were essential to that promoter's up-regulation during SCFA-mediated induction of adult erythroid differentiation in vitro. Of factors that interact at the CACCC site, SCFA-mediated acetylation is implicated in SP1 and EKLF, and may be a mechanism through which SCFAs induce embryonic/fetal globin gene promoters during adult erythroid differentiation. (C) 2003 by The American Society of Hematology. C1 Univ Minnesota, Dept Internal Med, LCDB, NIH, Bethesda, MD USA. NIDDK, LCDB, NIH, Bethesda, MD USA. RP Little, JA (reprint author), Univ Minnesota, Dept Internal Med, LCDB, NIH, Bldg 50,Rm 3154,9000 Rockville Pike, Bethesda, MD USA. FU NIDDK NIH HHS [K08-DK02489-02] NR 69 TC 12 Z9 12 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 DEC 1 PY 2003 VL 102 IS 12 BP 4214 EP 4222 DI 10.1182/blood-2002-12-3766 PG 9 WC Hematology SC Hematology GA 750JH UT WOS:000186987200058 PM 12920040 ER PT J AU Nomura, Y Fukuda, H Terao, Y Hikosaka, O Segawa, M AF Nomura, Y Fukuda, H Terao, Y Hikosaka, O Segawa, M TI Abnormalities of voluntary saccades in Gilles de la Tourette's syndrome: pathophysiological consideration SO BRAIN & DEVELOPMENT LA English DT Article; Proceedings Paper CT Meeting of the International-Child-Neurology-Association CY SEP 23, 2002 CL BEIJING, PEOPLES R CHINA SP Int Child Neurol Assoc DE Tourette's syndrome (TS); voluntary saccades; visually-guided saccades (VGS); memory-guided saccades (MGS); distracted saccades (DS); involuntary eye movements ID NIGRA PARS RETICULATA; EYE-MOVEMENTS; BASAL GANGLIA; NEURONS AB Gilles de la Tourette's syndrome (TS) is a neurobehavioral disorder. Although the etiology and the pathophysiology of TS are still unknown, the involvement of the basal ganglia has long been postulated. On the other hand, saccadic eye movement was shown to be a useful measure to assess order and disorder of the function of the basal ganglia. To investigate the dysfunction of the basal ganglia of TS, we examined voluntary saccades in children with TS in comparison with the saccades in age-matched control children. Two kinds of saccades, visually-guided saccades (VGS) and memory-guided saccades (MGS) were evaluated. During the MGS, distracted saccades (DS), which indicate the distractibility, were examined. The results revealed the abnormalities in the parameters of the MGS, i.e. longer latencies and hypometric amplitudes, and decrease in the frequency of MGS. Whereas, the frequency of DS, the saccade to the predicted cue was significantly lower in younger patients (6-<9-years) than normal, but it was higher in the older TS children (9-<12-years). In addition, some of the patients showed large involuntary saccades, usually associated with eye blinks, during the task performance. These results suggest that in TS the basal ganglia fails to disinhibit the saccade neuron in the superior colliculus with the input of the frontal eye field to the striatum, and later allow the neurons to evoke non-goal directed saccades. In reference to abnormal saccades in other basal ganglia disorders with dopamine deficiency and to animal experiments with MPTP monkeys, these findings postulate primary hypodopaminergic state followed by upward regulation of dopamine receptors later in TS. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Segawa Neurol Clin Children, Chiyoda Ku, Tokyo 1010062, Japan. Natl Inst Ind Hlth, Kawasaki, Kanagawa, Japan. Univ Tokyo, Dept Neurol, Tokyo, Japan. NEI, NIH, Bethesda, MD 20892 USA. RP Nomura, Y (reprint author), Segawa Neurol Clin Children, Chiyoda Ku, 2-8 Surugadai Kanda, Tokyo 1010062, Japan. EM nomura_y@kt.rim.or.jp NR 23 TC 8 Z9 10 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0387-7604 J9 BRAIN DEV-JPN JI Brain Dev. PD DEC PY 2003 VL 25 SU 1 BP S48 EP S54 DI 10.1016/S0387-7604(03)90009-X PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 762QZ UT WOS:000187994800010 PM 14980373 ER PT J AU Nelson, EL Prieto, D Alexander, TG Pushko, P Lofts, LA Rayner, JO Kamrud, KI Fralish, B Smith, JF AF Nelson, EL Prieto, D Alexander, TG Pushko, P Lofts, LA Rayner, JO Kamrud, KI Fralish, B Smith, JF TI Venezuelan equine encephalitis replicon immunization overcomes intrinsic tolerance and elicits effective anti-tumor immunity to the 'self' tumor-associated antigen, neu in a rat mammary tumor model SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Review DE breast cancer; immunotherapy; neu; rat tumor model; replicon vector ID SEMLIKI-FOREST-VIRUS; TRANSGENIC BALB/C MICE; COLONY-STIMULATING FACTOR; CYTOTOXIC T-LYMPHOCYTES; GROWTH-FACTOR RECEPTOR; PROTECT GUINEA-PIGS; BREAST-CANCER; DNA VACCINATION; IN-VITRO; HER-2/NEU PROTEIN AB Many tumor-associated antigens (TAAs) represent 'self' antigens and as such, are subject to the constraints of immunologic tolerance. There are significant barriers to eliciting anti-tumor immune responses of sufficient magnitude. We have taken advantage of a Venezuelan equine encephalitis-derived alphavirus replicon vector system with documented in vivo tropism for immune system dendritic cells. We have overcome the intrinsic tolerance to the 'self' TAA rat neu and elicited an effective anti-tumor immune response using this alphavirus replicon vector system and a designed target antigen in a rigorous rat mammary tumor model. We have demonstrated the capacity to generate 50% protection in tumor challenge experiments (p=0.004) and we have confirmed the establishment of immunologic memory by both second tumor challenge and Winn Assay (p=0.009). Minor antibody responses were identified and supported the establishment of T helper type 1 (Th1) anti-tumor immune responses by isotype. Animals surviving in excess of 300 days with established effective anti-tumor immunity showed no signs of autoimmune phenomena. Together these experiments support the establishment of T lymphocyte dependent, Th1-biased anti-tumor immune responses to a non-mutated 'self' TAA in an aggressive tumor model. Importantly, this tumor model is subject to the constraints of immunologic tolerance present in animals with normal developmental, temporal, and anatomical expression of a non-mutated TAA. These data support the continued development and potential clinical application of this alphaviral replicon vector system and the use of appropriately designed target antigen sequences for anti-tumor immunotherapy. C1 Univ Calif Irvine, Sch Biol Sci, Sch Med & Mol Biol & Biochem, Dept Med,Div Hematol Oncol, Irvine, CA USA. NCI, SAIC Frederick, FCRC, Frederick, MD 21701 USA. USA, Med Res Inst Infect Dis, Ft Detrick, Frederick, MD USA. AlphaVax Inc, Res Triangle Pk, NC USA. RP Nelson, EL (reprint author), Univ Calif Irvine, Sch Biol Sci, Sch Med & Mol Biol & Biochem, Dept Med,Div Hematol Oncol, Rm 375B, Irvine, CA USA. FU NCI NIH HHS [N01-CO-12400] NR 115 TC 27 Z9 28 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD DEC PY 2003 VL 82 IS 3 BP 169 EP 183 DI 10.1023/B:BREA.0000004373.09678.bb PG 15 WC Oncology SC Oncology GA 744MP UT WOS:000186636500004 PM 14703064 ER PT J AU Morton, LM Holford, TR Leaderer, B Boyle, P Zahm, SH Zhang, Y Flynn, S Tallini, G Zhang, B Owens, PH Zheng, T AF Morton, LM Holford, TR Leaderer, B Boyle, P Zahm, SH Zhang, Y Flynn, S Tallini, G Zhang, B Owens, PH Zheng, T TI Cigarette smoking and risk of non-Hodgkin lymphoma subtypes among women SO BRITISH JOURNAL OF CANCER LA English DT Article DE lymphoma; non-Hodgkin; smoking; women; case-control studies ID UNITED-STATES; MULTIPLE-MYELOMA; HEMATOLYMPHOPOIETIC MALIGNANCIES; TOBACCO; COHORT; OCCUPATION; INFECTION; LEUKEMIA; ALCOHOL; FRANCE AB Previous studies of the relationship between cigarette smoking and non-Hodgkin lymphoma (NHL) have yielded conflicting results, perhaps because most studies have evaluated the risk for all NHL subtypes combined. Data from a population-based case-control study conducted among women in Connecticut were used to evaluate the impact of cigarette smoking on the risk of NHIL by histologic type, tumour grade, and immunologic type. A total of 601 histologically confirmed, incident cases of NHL and 718 population-based controls provided in-person interviews. A standardised, structured questionnaire was used to collect information on each subject's current smoking status, age at initiation, duration and intensity of smoking, and cumulative lifetime exposure to smoking. Our data suggest that cigarette smoking does not alter the risk of all NHL subtypes combined. However, increased risk of follicular lymphoma appears to be associated with increased intensity and duration of smoking, and cumulative lifetime exposure to smoking. Compared with nonsmokers, women with a cumulative lifetime exposure of 16-33 pack-years and 34 pack-years or greater experience 50% increased risk (OR 1.5, 95% CI 0.9-2.5) and 80% increased risk (OR = 1,8, 95% CI 1.1-3.2), respectively, of follicular lymphoma (P for linear trend 0.05). Our study findings are consistent with several previous epidemiologic studies suggesting that cigarette smoking increases the risk of follicular lymphoma. This research highlights the importance of distinguishing between NHL subtypes in future research on the aetiology of NHL. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. European Inst Oncol, Dept Epidemiol & Biostat, I-20141 Milan, Italy. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3A 1A2, Canada. RP Zheng, T (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Morton, Lindsay/B-5234-2015; OI Boyle, Peter/0000-0001-6251-0610; Morton, Lindsay/0000-0001-9767-2310; Tallini, Giovanni/0000-0003-0113-6682 FU NCI NIH HHS [CA62006-05] NR 35 TC 36 Z9 36 U1 1 U2 3 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 DEC 1 PY 2003 VL 89 IS 11 BP 2087 EP 2092 DI 10.1038/sj.bjc.6601388 PG 6 WC Oncology SC Oncology GA 756PP UT WOS:000187490500012 PM 14647142 ER PT J AU Wolins, N Lozier, J Eggerman, TL Jones, E Aguilar-Cordova, E Vostal, JG AF Wolins, N Lozier, J Eggerman, TL Jones, E Aguilar-Cordova, E Vostal, JG TI Intravenous administration of replication-incompetent adenovirus to rhesus monkeys induces thrombocytopenia by increasing in vivo platelet clearance SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE thrombocytopenia; adenovirus; toxicity; platelet survival; primates ID AGGREGATION; TOXICITY; VECTORS AB A replication-incompetent adenovirus vector was administered to rhesus macaques at 1, 3 and 6 x 10(12) particles/kg doses to investigate its toxicity. Platelet count decrements of 28%, 82% and 90%, respectively, were observed, with corresponding platelet half-lives of 69.0, 25.2 and 22.2 h (compared with 111 h in untreated animals). The platelet decline was equivalent for all three doses for 8 h, and platelet count recovery began as early as 8 h after infusion for low-dose recipients, or as late as 24 h for the medium and high dose recipients. These observations suggest that thrombocytopenia is a saturable, reversible consumptive process. C1 US FDA, Ctr Biol Evaluat & Res, OBRR, Div Hematol,Lab Cellular Hematol, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Vostal, JG (reprint author), US FDA, Ctr Biol Evaluat & Res, OBRR, Div Hematol,Lab Cellular Hematol, Bldg 29,Room 321,8800 Rockville Pike, Bethesda, MD 20892 USA. NR 11 TC 33 Z9 33 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD DEC PY 2003 VL 123 IS 5 BP 903 EP 905 DI 10.1046/j.1365-2141.2003.04719.x PG 3 WC Hematology SC Hematology GA 745NX UT WOS:000186695700016 PM 14632782 ER PT J AU Erdlenbruch, B Alipour, M Fricker, G Miller, DS Kugler, W Eibl, H Lakomek, M AF Erdlenbruch, B Alipour, M Fricker, G Miller, DS Kugler, W Eibl, H Lakomek, M TI Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE alkylglycerol; blood-brain barrier; brain tumor; drug delivery; fluorescence markers; methotrexate; rat brain capillaries; tight junction; confocal microscopy ID ENHANCED CHEMOTHERAPY DELIVERY; TUMOR BARRIERS; DRUG-DELIVERY; DIFFERENTIAL PERMEABILITY; INTRACAROTID INFUSION; PROXIMAL TUBULES; PHASE-II; NUDE RAT; IN-VIVO; CARBOPLATIN AB 1 The blood-brain barrier (BBB) represents the major impediment to successful delivery of therapeutic agents to target tissue within the central nervous system. Intracarotid alkylglycerols have been shown to increase the transfer of chemotherapeutics across the BBB. 2 We investigated the spatial distribution of intracarotid fluorescein sodium and intravenous lissamine-rhodamine B200 (RB 200)-albumin in the brain of normal and C6 glioma-bearing rats after intracarotid co-administration of 1-O-pentylglycerol (200 mm). To elucidate the mechanisms involved in the alkylglycerol-mediated BBB opening, intraluminal accumulation of fluorescein isothiocyanate (FITC)-dextran 40,000 was studied in freshly isolated rat brain capillaries using confocal microscopy during incubation with different alkylglycerols. Furthermore, 1-O-pentylglycerol-induced increase in delivery of methotrexate (MTX) to the brain was evaluated in nude mice. 3 Microscopic evaluation showed a marked 1-O-pentylglycerol-induced extravasation of fluorescein and RB 200-albumin in the ipsilateral normal brain. In glioma-bearing rats, increased tissue fluorescence was found in both tumor tissue and brain surrounding tumor. Confocal microscopy revealed a time- and concentration-dependent accumulation of FITC-dextran 40,000 within the lumina of isolated rat brain capillaries during incubation with 1-O-pentylglycerol and 2-O-hexyldiglycerol, indicating enhanced paracellular transfer via tight junctions. Intracarotid coadministration of MTX and 1-O-pentylglycerol (200 mM) in nude mice resulted in a significant increase in MTX concentrations in the ipsilateral brain as compared to controls without 1-O-pentylglycerol (P<0.005). 4 In conclusion, 1-O-pentylglycerol increases delivery of small and large compounds to normal brain and brain tumors and this effect is mediated at least in part by enhanced permeability of tight junctions. C1 Univ Gottingen, Kinderklin, D-37075 Gottingen, Germany. Inst Pharmazeut Technol & Biopharmazie, D-69120 Heidelberg, Germany. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany. RP Erdlenbruch, B (reprint author), Univ Gottingen, Kinderklin, Robert Koch Str 40, D-37075 Gottingen, Germany. EM erdlenbr@med.uni-goettingen.de NR 45 TC 52 Z9 53 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD DEC PY 2003 VL 140 IS 7 BP 1201 EP 1210 DI 10.1038/sj.bjp.0705554 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 762QF UT WOS:000187993100008 PM 14597599 ER PT J AU Drinkard, BE Hicks, J Danoff, J Rider, LG AF Drinkard, BE Hicks, J Danoff, J Rider, LG TI Fitness as a determinant of the oxygen uptake/work rate slope in healthy children and children with inflammatory myopathy SO CANADIAN JOURNAL OF APPLIED PHYSIOLOGY-REVUE CANADIENNE DE PHYSIOLOGIE APPLIQUEE LA English DT Article DE exercise efficiency; juvenile dermatomyositis; peak VO2 ID MUSCLE-FIBER TYPE; JUVENILE DERMATOMYOSITIS; WORK RATE; RESONANCE-SPECTROSCOPY; MUSCULAR EFFICIENCY; SUBMAXIMAL EXERCISE; HEART-FAILURE; ABNORMALITIES; POLYMYOSITIS; POWER AB There is evidence that the slope of the change in oxygen uptake accompanying changes in work rate (Delta(V) over dot O-2/DeltaW) during moderate incremental exercise is influenced by fitness (peak (V) over dot O-2). We set out to determine whether Delta(V) over dot O-2/DeltaW was related to fitness in a group of healthy children and in children with juvenile dermatomyositis (JDM), a condition associated with decreased peak (V) over dot O-2 We also hypothesized that Delta(V) over dot O-2/DeltaW would be significantly decreased in children with JDM compared to healthy children. Methods: Twelve children (2 boys) with JDM, mean age 11.6 +/- 3.6 yrs, and 20 healthy children (4 boys), mean age 11.3 +/- 2.9 years, performed an incremental exercise test using a cycle ergometer A Delta(V) over dot O-2/DeltaW below the anaerobic threshold was analyzed using linear regression. Correlations between peak (V) over dot O-2 and Delta(V) over dot O-2/DeltaW were calculated, and differences between the JDM and healthy groups were analyzed using independent t-tests. Results: The Delta(V) over dot O-2/DeltaW was significantly correlated with peak (V) over dot O-2 for children with JDM (r = 0.71, p < 0.01), healthy children (r = 0.53, p < 0.01), and all children combined (r = 0. 78, p < 0.001). The Delta(V) over dot O-2/DeltaW (7.4 +/- 1.4 vs. 10.8 +/- 1.2 ml O-2.min(-1.)watt(-1)) and peak oxygen uptake ((V) over dot O(2)peak) (19.2 +/- 5.0 vs. 31.4 +/- 7.2 ml O-2. kg(-1). min(-1)) were significantly lower in children with JDM than in healthy children, respectively (all p less than or equal to 0.001). Conclusion: Fitness is significantly related to Delta(V) over dot O-2/DeltaW in healthy children and those with JDM. Children with JDM have a significantly lower Delta(V) over dot O-2/DeltaW than healthy children. Further study is needed to identify specific factors influencing Delta(V) over dot O-2/DeltaW. C1 Natl Inst Environm Hlth Sci, Dept Rehabil Med, NIH, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, NIH, Bethesda, MD 20892 USA. George Washington Univ, Ctr Med, Dept Exercise Sci, Washington, DC 20052 USA. RP Drinkard, BE (reprint author), Natl Inst Environm Hlth Sci, Dept Rehabil Med, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. OI Rider, Lisa/0000-0002-6912-2458 NR 33 TC 12 Z9 12 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1066-7814 J9 CAN J APPL PHYSIOL JI Can. J. Appl. Physiol.-Rev. Can. Physiol. Appl. PD DEC PY 2003 VL 28 IS 6 BP 888 EP 897 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 756TQ UT WOS:000187499200005 PM 14992126 ER PT J AU Kogevinas, M 't Mannetje, A Cordier, S Ranft, U Gonzalez, CA Vineis, P Chang-Claude, J Lynge, E Wahrendorf, J Tzonou, A Jockel, KH Serra, C Porru, S Hours, M Greiser, E Bo, P AF Kogevinas, M 't Mannetje, A Cordier, S Ranft, U Gonzalez, CA Vineis, P Chang-Claude, J Lynge, E Wahrendorf, J Tzonou, A Jockel, KH Serra, C Porru, S Hours, M Greiser, E Bo, P TI Occupation and bladder cancer among men in Western Europe SO CANCER CAUSES & CONTROL LA English DT Article DE bladder neoplasms; occupation ID LOWER URINARY-TRACT; RISK-FACTORS; EXPOSURE; GERMANY; MALES AB Objectives: We examined which occupations and industries are currently at high risk for bladder cancer in men. Methods: We combined data from 11 case - control studies conducted between 1976 - 1996 in six European countries. The study comprised 3346 incident cases and 6840 controls, aged 30 - 79 years. Lifetime occupational and smoking histories were examined using common coding. Results: Odds ratios for eight a priori defined high-risk occupations were low, and with the exception of metal workers and machinists ( OR = 1.16, 95% CI = 1.02 - 1.32), were not statistically significant. Higher risks were observed for specific categories of painters, metal, textile and electrical workers, for miners, transport operators, excavating-machine operators, and also for non-industrial workers such as concierges and janitors. Industries entailing a high risk included salt mining, manufacture of carpets, paints, plastics and industrial chemicals. An increased risk was found for exposure to PAHs ( OR for highest exposure tertile = 1.23, 95% CI = 1.07 - 1.4). The risk attributable to occupation ranged from 4.2 to 7.4%, with an estimated 4.3% for exposure to PAHs. Conclusions: Metal workers, machinists, transport equipment operators and miners are among the major occupations contributing to occupational bladder cancer in men in Western Europe. In this population one in 10 to one in 20 cancers of the bladder can be attributed to occupation. C1 Municipal Inst Med Res IMIM, Resp & Environm Hlth Res Unit, Barcelona 08003, Spain. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. Univ Rennes 1, INSERM, U435, F-35014 Rennes, France. Univ Dusseldorf, Inst Umweltmed Forsch, D-4000 Dusseldorf, Germany. Catalan Inst Oncol, Dept Epidemiol, Barcelona, Spain. Univ Turin, Canc Epidemiol Unit, I-10124 Turin, Italy. Deutsch Krebsforschungszentrum, Abt Epidemiol, D-6900 Heidelberg, Germany. Univ Copenhagen, Inst Publ Hlth, DK-1168 Copenhagen, Denmark. Inst Med Informat Biometrie & Epidemiol, Essen, Germany. Corp Parc Tauli, Sabadell, Spain. Pompeu Fabra Univ, Barcelona, Spain. Univ Brescia, Inst Occupat Hlth, I-25121 Brescia, Italy. Univ Lyon 1, Inst Epidemiol, F-69365 Lyon, France. Bremen Inst Prevent Res & Social Med, Bremen, Germany. Med Sch Athens, Dept Hyg & Epidemiol, Athens, Greece. RP Kogevinas, M (reprint author), Municipal Inst Med Res IMIM, Resp & Environm Hlth Res Unit, 80 Dr Aiguader Rd, Barcelona 08003, Spain. RI Serra, C/E-6879-2014; Cordier, Sylvaine/F-7919-2013; Kogevinas, Manolis/C-3918-2017 OI Serra, C/0000-0001-8337-8356; NR 32 TC 136 Z9 146 U1 1 U2 16 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2003 VL 14 IS 10 BP 907 EP 914 DI 10.1023/B:CACO.0000007962.19066.9c PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 752WP UT WOS:000187199400001 PM 14750529 ER PT J AU Sturgeon, SR Graubard, BI Schairer, C McAdams, M Hoover, RN Gail, MH AF Sturgeon, SR Graubard, BI Schairer, C McAdams, M Hoover, RN Gail, MH TI Population-density and county-level variation in breast cancer mortality rates among white women residing in the Northeastern and Southern United States SO CANCER CAUSES & CONTROL LA English DT Article DE breast cancer; mortality; United States ID FAMILY HISTORY; RISK-FACTORS; REPRODUCTIVE HISTORY; GEOGRAPHIC-VARIATION; REPLACEMENT THERAPY; LONG-ISLAND; SURVIVAL; AGE; DIAGNOSIS; PROGNOSIS AB Objective: We assessed the contribution of variation in risk factor prevalence to population-density and county-level variation in breast cancer mortality rates. Methods: In 1995 we collected risk factor information in a telephone interview of a random digit dialed sample of: ( 1) 1241 women from counties in the upper and lower tertiles of population density as of 1970 in the Northeast and South of the United States ( Design A); ( 2) 2492 women from counties in the upper and lower tertiles of 1970 - 1979 breast cancer mortality rates in the four populations from Design A, and; ( 3) 276 women in Nassau County in New York State. We calculated 1990 - 94 mortality ratios (MRs) adjusted for breast cancer risk factors. Results: The high/low population-density fully-adjusted MRs in women greater than or equal to 55 years were 1.01 (95% CI 0.9 - 1.2) and 1.00 ( 95% CI 0.8 - 1.2). The fully-adjusted MRs for high versus low mortality counties ranged from 0.95 ( 95% CI 0.8 - 1.2) to 1.29 ( 95% CI 1.0 - 1.6) in women greater than or equal to 55 years. Conclusions: Differences in risk factor prevalence explained higher rates in high-density versus low-density areas in older women. Modest elevations in the adjusted high/low breast cancer MRs among older women in certain groups of counties may reflect unidentified risk factors but more likely are due to chance. C1 Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Sturgeon, SR (reprint author), Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Dept Biostat & Epidemiol, Arnold House 407,715 N Pleasant St, Amherst, MA 01003 USA. EM ssturgeon@schoolph.umass.edu NR 31 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2003 VL 14 IS 10 BP 923 EP 931 DI 10.1023/B:CACO.0000007963.56703.9d PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 752WP UT WOS:000187199400003 PM 14750531 ER PT J AU Norman, SA Berlin, JA Weber, AL Strom, BL Daling, JR Weiss, LK Marchbanks, PA Bernstein, L Voigt, LF McDonald, JA Ursin, G Liff, JM Burkman, RT Malone, KE Simon, MS Folger, SG Deapen, D Wingo, PA Spirtas, R AF Norman, SA Berlin, JA Weber, AL Strom, BL Daling, JR Weiss, LK Marchbanks, PA Bernstein, L Voigt, LF McDonald, JA Ursin, G Liff, JM Burkman, RT Malone, KE Simon, MS Folger, SG Deapen, D Wingo, PA Spirtas, R TI Combined effect of oral contraceptive use and hormone replacement therapy on breast cancer risk in postmenopausal women SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; case control studies; hormone replacement therapy; oral contraceptives; risk factors ID ESTROGEN-PROGESTIN-REPLACEMENT; PLUS PROGESTIN; MAMMARY-GLAND; AGE; PROLIFERATION; REGIMENS; DISEASE; HEALTH; MODEL AB Objective: We examined breast cancer risk related to lifetime exposure to oral contraceptives (OCs) and hormone replacement therapy (HRT) in postmenopausal women. Methods: The Women's Contraceptive and Reproductive Experiences (CARE) Study was a population-based case control study that included 1847 postmenopausal women with incident invasive breast cancer, and 1932 control subjects, identified using random digit dialing. Results: 45% of cases and 49% of controls used both OCs and HRT. OC users were not at increased risk regardless of subsequent HRT exposure. HRT users who had used OCs previously did not have a higher risk of breast cancer than women with no exposure to OCs. We observed a negative interaction (p-value: 0.032) of combined hormone replacement therapy (CHRT) and past OC use. The increase in risk with CHRT was stronger in women who had never used OCs in the past ( odds ratio: 1.05; 95% confidence interval: 1.01 - 1.10 per year of exclusive CHRT use) than in women who had used OCs ( odds ratio: 1.00; 95% confidence interval: 0.97 - 1.03). Conclusions: We found no indication that adverse effects of exposure to OCs or HRT appeared only in the presence of the other hormone or were exacerbated by exposure to the other hormone. C1 Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Wayne State Univ, Karmanos Canc Inst, Populat Studies & Prevent Program, Detroit, MI USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Emory Univ, Sch Publ Hlth, Atlanta, GA USA. Henry Ford Hlth Syst, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Karmanos Canc Inst, Dept Internal Med, Detroit, MI USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. NICHHD, Populat Res Ctr, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. RP Norman, SA (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 801 Blockley Hall,423 Guaridan Dr, Philadelphia, PA 19104 USA. FU NCI NIH HHS [N01-CN-65064, N01-PC-67010, N01-CN-0532, N01-PC-67006]; NICHD NIH HHS [N01-HD-3-3174, Y01-HD-7022, N01-HD-3-3176, N01-HD-3-3175, N01-HD-3-3168, N01-HD-2-3166] NR 31 TC 18 Z9 18 U1 1 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 2003 VL 14 IS 10 BP 933 EP 943 DI 10.1023/B:CACO.0000007967.25865.29 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 752WP UT WOS:000187199400004 PM 14750532 ER PT J AU Hingorani, SR Petricoin, EF Maitra, A Rajapakse, V King, C Jacobetz, MA Ross, S Conrads, TP Veenstra, TD Hitt, BA Kawaguchi, Y Johann, D Liotta, LA Crawford, HC Putt, ME Jacks, T Wright, CVE Hruban, RH Lowy, AM Tuveson, DA AF Hingorani, SR Petricoin, EF Maitra, A Rajapakse, V King, C Jacobetz, MA Ross, S Conrads, TP Veenstra, TD Hitt, BA Kawaguchi, Y Johann, D Liotta, LA Crawford, HC Putt, ME Jacks, T Wright, CVE Hruban, RH Lowy, AM Tuveson, DA TI Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse SO CANCER CELL LA English DT Article ID K-RAS ONCOGENE; TRANSGENIC MICE; METALLOPROTEINASE MATRILYSIN; CYCLOOXYGENASE-2 EXPRESSION; PROTEOMIC PATTERNS; PROGRESSION MODEL; PROSTATE-CANCER; TGF-ALPHA; CARCINOMA; TUMORIGENESIS AB To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients. C1 Univ Penn, Abramson Family Canc Res Inst, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Abramson Family Canc Res Inst, Abramson Canc Ctr, Dept Canc Biol, Philadelphia, PA 19104 USA. US FDA, NCI Clin Proteom Program, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Sidney Kimmel Canc Ctr, Dept Pathol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Sidney Kimmel Canc Ctr, Dept Oncol, Baltimore, MD 21287 USA. NCI, Canc Res Ctr, Pathol Lab, FDA,Clin Proteom Program, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI, Biomed Proteom program, Analyt Chem Lab,Mass Spectrometry Ctr, Ft Detrick, MD 21702 USA. Correlog Syst Inc, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Cell & Dev Biol, Sch Med, Nashville, TN 37232 USA. SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. Ctr Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA. Univ Cincinnati, Coll Med, Dept Surg, Div Surg Oncol, Cincinnati, OH 45219 USA. RP Tuveson, DA (reprint author), Univ Penn, Abramson Family Canc Res Inst, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. RI Crawford, Howard/A-2874-2008; Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 FU NCI NIH HHS [P50-CA-62924, R25-CA87812]; NIDDK NIH HHS [P30 DK050306] NR 60 TC 981 Z9 1001 U1 13 U2 79 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC PY 2003 VL 4 IS 6 BP 437 EP 450 DI 10.1016/S1535-6108(03)00309-X PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 757VY UT WOS:000187583200007 PM 14706336 ER PT J AU Grem, JL Quinn, MG Keith, B Monahan, BP Hamilton, JM Xu, Y Harold, N Nguyen, D Takimoto, CH Rowedder, A Pang, J Morrison, G Chen, A AF Grem, JL Quinn, MG Keith, B Monahan, BP Hamilton, JM Xu, Y Harold, N Nguyen, D Takimoto, CH Rowedder, A Pang, J Morrison, G Chen, A TI A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE pharmacokinetics; pharmacodynamics; antimetabolites ID ADVANCED COLORECTAL-CANCER; RANDOMIZED TRIAL; SOLID TUMORS; CELLULAR PHARMACOLOGY; PROLONGED INFUSION; PANCREATIC-CANCER; LIVER METASTASES; 24-HOUR INFUSION; FLUOROURACIL; PLASMA AB Purpose. Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2'-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods. Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results. During cycle 1, six of eight patients who received 150 or 100 mg/m(2) over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m(2) over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m(2) over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n=6) or diarrhea (n=1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m(2) over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 muM (24 h), 16.3 muM (2 h), and 31.9 muM (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions. Gemcitabine 100-150 mg/m(2) over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m(2) over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses. C1 NCI, Natl Naval Med Ctr, Navy Med Oncol, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Dept Internal Med, Hematol Oncol Sect, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI, Natl Naval Med Ctr, Navy Med Oncol, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM gremj@mail.nih.gov NR 30 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD DEC PY 2003 VL 52 IS 6 BP 487 EP 496 DI 10.1007/s00280-003-0698-5 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 742WT UT WOS:000186541600010 PM 12955469 ER PT J AU Mannisto, S Pietinen, P Virtanen, MJ Salminen, I Albanes, D Giovannucci, E Virtamo, J AF Mannisto, S Pietinen, P Virtanen, MJ Salminen, I Albanes, D Giovannucci, E Virtamo, J TI Fatty acids and risk of prostate cancer in a nested case-control study in male smokers SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DIETARY-FAT; VITAMIN-E; BREAST-CANCER; PLASMA; SERUM; BIOMARKERS; FINLAND; HUMANS; LIPIDS; SIZE AB There is some evidence that alpha-linolenic acid might be positively related to prostate cancer risk. Associations between serum fatty acid composition as well as fatty acid intakes and prostate cancer risk were examined in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The cohort included 29,133 male smokers aged 50-69 years. During 5-8 years of follow-up, 246 prostate cancer cases were diagnosed. One control was selected and matched by age (+/- 1 month) for each case from the cohort subjects alive and free of prostate cancer at the time the case was diagnosed. This study included 198 case-control pairs with baseline serum sample available for both. Fatty acids of serum cholesterol esters were measured as a percentage of total fatty acids, using capillary gas chromatography. Intakes of fatty acids were assessed from a validated self-administered dietary questionnaire. Serum and dietary fatty acids had no consistent association with prostate cancer risk. Serum a-linolenic acid was not related to prostate cancer risk. Twofold risk was found in the highest quartile of serum myristic acid compared with the lowest quartile (odds ratio, 1.93; 95% confidence interval, 1.02-3.64). alpha-Tocopherol supplementation modified the association between serum linoleic acid and prostate cancer risk (P for interaction 0.03); odds ratio was 0.17 (95% confidence interval, 0.04-0.68) in the highest quartile of serum linoleic acid compared with the lowest quartile in men who received a-tocopherol, whereas no association was found in men who did not receive a-tocopherol. In conclusion, we found no overall association between serum or dietary a-linolenic acid or any other unsaturated fatty acid and prostate cancer risk, but high serum linoleic acid was associated with lower risk in men supplemented with a-tocopherol. High serum myristic acid associated with an increased risk of prostate cancer. C1 Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, SF-00300 Helsinki, Finland. Natl Publ Hlth Inst, Dept Hlth & Funct Capac, Helsinki, Finland. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Mannerheimintie 166, SF-00300 Helsinki, Finland. EM satu.mannisto@ktl.fi RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-CN-45035] NR 42 TC 55 Z9 56 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1422 EP 1428 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900006 PM 14693732 ER PT J AU Hill, DA Inskip, PD Shapiro, WR Selker, RG Fine, HA Black, PM Linet, MS AF Hill, DA Inskip, PD Shapiro, WR Selker, RG Fine, HA Black, PM Linet, MS TI Cancer in first-degree relatives and risk of glioma in adults SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEREDITARY PROSTATE-CANCER; BRAIN-TUMORS; FAMILY HISTORY; ERCC2 POLYMORPHISMS; BREAST-CANCER; SWEDEN; POPULATION; EPIDEMIOLOGY; EXPOSURE; PROBANDS AB Relatively few studies have examined glioma risk in relation to history of cancer in first-degree relatives. We sought to describe such risks in a large hospital-based case-control study. Histologically confirmed incident adult glioma cases (n = 489) were identified at three regional referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were frequency-matched on age, sex, race/ethnicity, hospital, and proximity of residence to hospital. Participants received a personal interview, including questions regarding cancer in family members. Odds ratios (ORs) were calculated to estimate the risk of glioma associated with a history of cancer in a first-degree relative using conditional logistic regression and compared with standardized incidence ratios among relatives of cases versus relatives of controls. Among participants reporting a family history of a brain cancer or a brain tumor, risk of glioma was 1.6 [95% confidence interval (CI), 0.5-5.3; n = 5] and 3.0 (95% CI, 0.9-10.8; n = 7), respectively, in comparison with those without such family histories. Participants who had a family history of stomach (OR, 2.2; 95% CI, 1.0-4.6), colon (OR, 1.4; 95% CI, 0.9-2.2), or prostate cancer (OR, 2.1; 95% CI, 1.1-3.8) or Hodgkin disease (OR, 2.4; 95% CI, 0.9-6.3) had an increased glioma risk. OR estimates were similar to the ratios of standardized incidence ratios for cancer in relatives of cases versus controls. Shared environmental or genetic factors in families may influence glioma risk. Our findings suggest that individuals with a family history of specific cancers other than glioma may have an increased glioma risk. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. St Josephs Hosp, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ USA. Western Penn Hosp, Div Neurosurg, Pittsburgh, PA 15224 USA. NCI, Neurooncol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. RP Hill, DA (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NR 43 TC 12 Z9 13 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1443 EP 1448 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900009 PM 14693735 ER PT J AU Castle, PE Phillips, TM Hildesheim, A Herrero, R Bratti, MC Rodriguez, AC Morera, LA Pfeiffer, R Hutchinson, ML Pinto, LA Schiffman, M AF Castle, PE Phillips, TM Hildesheim, A Herrero, R Bratti, MC Rodriguez, AC Morera, LA Pfeiffer, R Hutchinson, ML Pinto, LA Schiffman, M TI Immune profiling of plasma and cervical secretions using recycling immunoaffinity chromatography SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; HUMAN-IMMUNODEFICIENCY-VIRUS; BIOLOGICAL-FLUIDS; CANCER; CYTOKINES; COLLECTION; WOMEN; MUCUS; IMMUNOGLOBULINS; INFERTILITY AB Small volumes of cervical secretions have limited measurements of immunity at the cervix, which may be important to studies of human papillomavirus (HPV). We report the use of recycling immunoaffinity chromatography to efficiently study immune profiles in cervical secretions. Frozen pairs of plasma and cervical secretions (collected on ophthalmic sponges) were selected randomly from women with normal cervical cytology (n = 50) participating in a natural history study of HPV in Guanacaste, Costa Rica. Single 25-mul aliquots of plasma and (diluted) cervical secretions were assayed for interleukin (IL) -1beta, -2, -4, -6, -8, -10, -12, -13, -15, IFN-alpha -beta, -gamma, tumor necrosis factor-alpha, -beta, RANTES (regulated on activation normal T-cell express and secreted), MCP-1 (monocyte chemoattractant protein), -2, -3, macrophage inflammatory protein-1alpha, -1beta (regulated on activation normal T-cell express and secreted), macrophage colony-stimulating factor, IgG, IgA, and cyclooxygenase 2. All of the specimens were tested as blind replicates, and refrozen plasma was retested 4 months later. To evaluate the reproducibility of the repeat measurements and to examine the correlation between plasma and cervical secretions, we calculated kappa values with 95% confidence intervals among categorized analyte values and Spearman correlation coefficients (p) among detectable, continuous analyte values. Measurements of all of the analytes in either plasma or cervical secretions were highly reproducible, with all of the kappa greater than or equal to 0.78 (70% above 0.90), and all of the rho greater than or equal to 0.88 (96% above 0.90). Only IL-1beta (kappa = 0.60 and rho = 0.82) and IL-6 (kappa = 0.50 and rho = 0.78) levels were strongly correlated between plasma and cervical secretions. IFN-gamma, tumor necrosis factor-beta, RANTES, MCP-1, MCP -2, macrophage inflammatory protein-1alpha, and macrophage colony-stimulating factor levels were especially poorly correlated between plasma and cervical secretions (kappa less than or equal to 0.25 and rho less than or equal to 0.25). We conclude that recycling immunoaffinity chromatography is a reproducible method of measuring immune profiles from biological specimens, and immune profiles are not well correlated between plasma and cervical secretions, perhaps necessitating cervical collections to study cervix-specific immunity in HPV natural history studies. C1 NIH, Dept Hlth & Human Serv, Off Director, Off Res Serv,Div Canc Epidemiol & Genet, Bethesda, MD USA. NIH, Dept Hlth & Human Serv, Off Director, Off Res Serv,Div Bioengn & Phys Sci, Bethesda, MD USA. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. Women & Infants Hosp Rhode Isl, Providence, RI 02908 USA. Sci Applicat Int Corp Frederick Inc, Natl Canc Inst, Frederick, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7074,EPS MSC 7234, Bethesda, MD 20892 USA. RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [N01CP2101, N01CP31061] NR 34 TC 10 Z9 11 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1449 EP 1456 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900010 PM 14693736 ER PT J AU Key, TJ Appleby, PN Reeves, GK Roddam, AW Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Falk, RT Miller, R Schatzkin, A Allen, DS Fentiman, IS Key, TJ Wang, DY Thomas, HV Hankinson, SE Toniolo, P Akhmedkhanov, A Koenig, K Shore, RE Zeleniuch-Jacquotte, A Berrino, F Muti, P Krogh, AMV Sieri, S Pala, V Venturelli, E Secreto, G Barrett-Connor, E Laughlin, GA Kabuto, M Stevens, RG Neriishi, K Land, CE Cauley, JA Kuller, LH Helzlsouer, KJ Alberg, AJ Bush, TL Comstock, GW Gordon, GB Miller, SR Longcope, C AF Key, TJ Appleby, PN Reeves, GK Roddam, AW Dorgan, JF Longcope, C Stanczyk, FZ Stephenson, HE Falk, RT Miller, R Schatzkin, A Allen, DS Fentiman, IS Key, TJ Wang, DY Thomas, HV Hankinson, SE Toniolo, P Akhmedkhanov, A Koenig, K Shore, RE Zeleniuch-Jacquotte, A Berrino, F Muti, P Krogh, AMV Sieri, S Pala, V Venturelli, E Secreto, G Barrett-Connor, E Laughlin, GA Kabuto, M Stevens, RG Neriishi, K Land, CE Cauley, JA Kuller, LH Helzlsouer, KJ Alberg, AJ Bush, TL Comstock, GW Gordon, GB Miller, SR Longcope, C CA Endogenous Hormones Breast Cancer TI Free estradiol and breast cancer risk in postmenopausal women: Comparison of measured and calculated values SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HORMONE-BINDING GLOBULIN; TESTOSTERONE-BINDING; HUMAN-PLASMA; DEHYDROEPIANDROSTERONE-SULFATE; PHYSIOLOGICAL CONDITIONS; HUMAN-SERUM; FRACTIONS; DIALYSIS; VALIDITY AB Mathematical methods exist to determine the fractions of sex hormones bound to albumin, bound to sex hormone binding globulin (SHBG), or unbound, using total hormone concentration and SHBG concentration. We used data from eight prospective studies of postmenopausal women to assess the validity of these estimates for fractions of estradiol (E2) and to investigate the impact of using calculated values in breast cancer relative risk (RR) models. Comparisons were made between measured and calculated concentrations of free and non-SHBG-bound E2 in four studies. Relationships between the hormone fractions were investigated and a sensitivity analysis of the calculation performed. Breast cancer RRs were estimated using conditional logistic regression by quintiles of free E2. There is a high correlation (r > 0.91) between calculated and measured values of both free and non-SHBG-bound E2. The calculation is highly sensitive to total hormone concentration but is relatively insensitive to SHBG concentration. In studies with both measured and calculated values, the RRs of breast cancer by quintile of free E2 were almost identical for both estimates; using calculated values in all possible studies the RR in the highest compared with the lowest quintile of free E2 was 2.29 (95% confidence interval, 1.65-3.19). The mathematical method used to calculate fractions of E2 is valid, and RR analyses using calculated values produce similar results to those using measured values. This suggests that for epidemiological studies, it is only necessary to measure total E2 concentration and SHBG concentration, with hormone fractions being obtained by calculation, producing savings in cost, time, and serum. C1 Univ Oxford, Canc Res UK Epidemiol Unit, Oxford OX1 2JD, England. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Amherst, MA 01003 USA. Univ Massachusetts, Sch Med, Dept Med, Amherst, MA 01003 USA. Univ So Calif, Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA. Univ Missouri, Hlth Sci Ctr, Dept Surg, Columbia, MO 65211 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Ellis Fischel Canc Ctr, Canc Screening Serv, Columbia, MO USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Cardiff Univ, Coll Med, Dept Psychol Med, Cardiff CF1 3NS, S Glam, Wales. Brigham & Womens Hosp, Dept Med, Channing Lab, Nurses Hlth Study Res Grp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Cambridge, MA 02138 USA. NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA. NYU, Sch Med, Nelson Inst Environm Med, New York, NY USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY USA. Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. Natl Inst Environm Studies, Environm Risk Res Div, Ibaraki, Japan. Kagoshima Univ, Fac Med, Dept Publ Hlth, Kagoshima 890, Japan. Univ Connecticut, Ctr Hlth, Dept Community Med, Storrs, CT 06269 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. Univ Massachusetts, Sch Med, Dept Obstet & Gynecol, Amherst, MA 01003 USA. Univ Massachusetts, Sch Med, Dept Med, Amherst, MA 01003 USA. RP Roddam, AW (reprint author), Univ Oxford, Radcliffe Infirm, Canc Res UK Epidemiol Unit, Endogenous Hormones & Breast Canc Collaborat Grp, Gibson Bldg, Oxford OX2 6HE, England. EM andrew.roddam@cancer.org.uk RI turton, miranda/F-4682-2011; Perez , Claudio Alejandro/F-8310-2010; Cauley, Jane/N-4836-2015; Sieri, Sabina/K-4667-2016 OI Perez , Claudio Alejandro/0000-0001-9688-184X; Cauley, Jane/0000-0003-0752-4408; Sieri, Sabina/0000-0001-5201-172X NR 30 TC 34 Z9 34 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1457 EP 1461 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900011 ER PT J AU Eng-Wong, J Hursting, SD Venzon, D Perkins, SN Zujewski, JA AF Eng-Wong, J Hursting, SD Venzon, D Perkins, SN Zujewski, JA TI Effect of raloxifene on insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin in premenopausal women at high risk for developing breast cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POSTMENOPAUSAL WOMEN; IGF-I; HEALTHY PREMENOPAUSAL; CELL-PROLIFERATION; MAMMARY-GLAND; FACTOR SYSTEM; SERUM LEVELS; TAMOXIFEN; ESTROGEN; INHIBITION AB Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70degreesC until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (0), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Eng-Wong, J (reprint author), NCI, Div Canc Prevent, 10 Ctr Dr,Bldg 10,Room 12N226, Bethesda, MD 20892 USA. RI Venzon, David/B-3078-2008 NR 45 TC 16 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1468 EP 1473 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900013 PM 14693739 ER PT J AU Muscat, JE Britton, JA Djordjevic, MV Citron, ML Kemeny, M Busch-Devereaux, E Pittman, B Stellman, SD AF Muscat, JE Britton, JA Djordjevic, MV Citron, ML Kemeny, M Busch-Devereaux, E Pittman, B Stellman, SD TI Adipose concentrations of organochlorine compounds and breast cancer recurrence in Long Island, New York SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ALTERED HEPATIC FOCI; SPRAGUE-DAWLEY RATS; POLYCHLORINATED-BIPHENYLS; RISK; PESTICIDES; INDUCTION; SURVIVAL; ESTROGEN; EXPOSURE; WOMEN AB Several studies have measured the association between blood or adipose concentrations of organochlorinated compounds (OCs), such as pesticides and polychlorinated biphenyls (PCBs), and breast cancer. The estrogenic effects of OCs might adversely affect breast cancer recurrence. The participants were 224 women with nonmetastatic breast cancer enrolled in a New York-based case-control study. Supercritical fluid extraction followed by gas chromatography was conducted on adipose surgical specimens to determine OC concentrations. The mean follow-up time from surgery was 3.6 years. Thirty women (13.4%) were diagnosed with a recurrence. The concentration of pesticides and PCBs was correlated with baseline age and body mass index, but not with cancer stage. The highest tertile of total PCB concentration was associated with an increased risk of recurrence [relative risk (RR), 2.9; 95% confidence interval (CI), 1.02-8.2 versus the lowest tertile]. The risk for the highest tertile of the PCB congener Ballschmiter and Zell 118 was 4.0 (95% CI, 1.3-4.9). There was an increased risk for the middle level of the most abundant pesticide, 1,1-dichloro-2,2-di-(4-chlorophenyl)ethylene (RR, 2.3; 95% CI, 0.9-5.7), and for beta-hexachlorocyclohexane, but not for their highest levels. Self-reported home termiticide exposure, alcohol consumption (greater than or equal to1 drink/day), and race were not associated with prognosis. The RR for current cigarette smoking at diagnosis was 2.1 (95% CI, 0.9-5.1). In contrast to previous data showing no relationship between OC exposure and risk of breast cancer in these women, adipose PCB concentrations were associated with tumor recurrence. Pesticide levels were not related to recurrence. C1 Inst Canc Prevent, Valhalla, NY 10595 USA. Mt Sinai Sch Med, Div Environm Hlth Sci, New York, NY USA. NCI, Tobacco Control Res Branch, NIH, Bethesda, MD 20892 USA. ProHlth Care Assoc LLP, Lake Success, NY USA. Queens Hosp Ctr, New York, NY USA. Columbia Univ, Mailmann Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Muscat, JE (reprint author), Inst Canc Prevent, 1 Dana Rd, Valhalla, NY 10595 USA. FU NCI NIH HHS [CA-17613, CA-63021, CA-75262] NR 23 TC 42 Z9 44 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1474 EP 1478 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900014 PM 14693740 ER PT J AU Hecht, SS Chen, ML Yagi, H Jerina, DM Carmella, SG AF Hecht, SS Chen, ML Yagi, H Jerina, DM Carmella, SG TI r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene in human urine: A potential biomarker for assessing polycyclic aromatic hydrocarbon metabolic activation SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LUNG-CANCER RISK; MYELOPEROXIDASE (-463)G->A POLYMORPHISM; TOBACCO-SMOKE CARCINOGENS; DNA ADDUCT FORMATION; COAL-TAR; MOLECULAR EPIDEMIOLOGY; PROTEIN ADDUCTS; HUMAN TISSUES; EXPOSURE; 1-HYDROXYPYRENE AB Individual differences in the metabolic activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAHs) may influence cancer risk. This has been investigated in many studies using genotyping approaches, but the results to date have been inconsistent. We propose that carcinogen metabolite phenotyping would be a more reliable way to determine the role of host metabolism in PAH-related cancer. Many PAHs are metabolically activated by formation of bay-region diol epoxides. Phenanthrene, generally considered to be noncarcinogenic, is the simplest PAH with a bay region and is metabolized to diol epoxides by the same enzymes and with the same stereochemistry as the prototypic carcinogenic PAH, benzo[a]pyrene. The major end product of this metabolic activation pathway is r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, anti-PheT). We have developed a method for the analysis of trans, anti-PheT in human urine. r-1,t-2,4,c-3,-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (trans, syn-PheT) was used as internal standard. After hydrolysis by beta-glucuronidase and sulfatase, solid phase extraction, and high-performance liquid chromatography collection, the sample was silylated and analyzed by gas chromatography-negative ion chemical ionization-mass spectrometry-selected ion monitoring at ink 372. The resulting chromatograms were remarkably clean and trans, anti-PheT was readily detected in all human urine samples. Levels of trans, anti-PheT were 791 +/- 363 pmol/mg creatinine (n = 20) in psoriasis patients treated with a PAH-containing ointment, 25.7 +/- 16.8 pmol/mg creatinine (n = 32) in coke oven workers exposed to PAH, 4.58 +/- 2.95 pmol/mg creatinine (n = 31) in smokers, and 1.51 +/- 1.15 pmol/mg creatinine (n = 30) in nonsmokers. Levels of trans, anti-PheT correlated with levels of 1-hydroxypyrene in the urine of coke oven workers, smokers, and nonsmokers. Thus, trans, anti-PheT appears to be an excellent biomarker of PAH uptake. Levels of trans, anti-PheT were 8,000-19,000 times higher than those can be detected in human urine. We propose that measurement of this metabolite of phenanthrene may be important as part of a carcinogen metabolite-phenotyping approach to determine individual response to PAH exposure. C1 Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hecht, SS (reprint author), Univ Minnesota, Ctr Canc, Mayo Mail Code 806,420 Delaware St SE, Minneapolis, MN 55455 USA. OI Hecht, Stephen/0000-0001-7228-1356 FU NCI NIH HHS [CA-92025, CA-77598] NR 59 TC 52 Z9 55 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1501 EP 1508 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900018 PM 14693744 ER PT J AU Freedman, M Sigurdson, A Doody, MM Mabuchi, K Linet, MS AF Freedman, M Sigurdson, A Doody, MM Mabuchi, K Linet, MS TI Risk of basal cell carcinoma in relation to alcohol intake and smoking SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONMELANOCYTIC SKIN-CANCER; RADIOLOGIC TECHNOLOGISTS; FOLLOW-UP; EXPOSURE; SUNLIGHT; DIET AB We prospectively investigated whether alcohol intake and smoking affect the risk of basal cell carcinoma (BCC) in subjects from the United States Radiological Technologists (USRT) cohort study. We evaluated 68,371 radiological technologists certified during 1926-1982 who were free of cancer at the time they answered a first questionnaire (1983-1989) and who completed a second questionnaire (1994-1998). The first questionnaire provided baseline information on numerous risk factors, including smoking and alcohol intake, and the second provided self-reported cancer diagnoses. During 698,190 person-years of follow-up, we identified 1,360 cases of BCC: 1,036 in women and 324 in men. Cox proportional hazards regression indicated that the trend in BCC was significantly associated with increased alcohol intake (P for trend = 0.001). Compared with those who reported no alcohol consumption, those who drank <1-2, 3-6, 714, and >14 drinks/week had multivariate risks of 1.1 [95% confidence interval (CI), 0.9-1.3], 1.3 (95% CI, 1.1-1.5), 1.4 (95 % CI, 1.2-1.7), and 1.0 (95 % CI, 0.7-1.6), respectively. We found no clear association between smoking and BCC. This is the second large prospective study to report a significant but nonmonotonic trend in increased risk associated with alcohol consumption. C1 NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Freedman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,Dept Hlth & Human Serv, Execut Plaza S,Room 7036,6120 Execut Plaza Blvd, Bethesda, MD 20892 USA. NR 20 TC 10 Z9 12 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 2003 VL 12 IS 12 BP 1540 EP 1543 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 757RU UT WOS:000187575900025 ER PT J AU de Carvalho, M Jenkins, J Nehrebecky, M Lahl, L AF de Carvalho, M Jenkins, J Nehrebecky, M Lahl, L TI The role of estrogens in BRCA1/2 mutation carriers - Reflections on the past, issues for the future SO CANCER NURSING LA English DT Article DE BRCA1/2; estrogen; hereditary cancer; syndrome; prophylactic mastectomy; prophylactic oophorectomy ID BREAST-CANCER RISK; PRIMARY PERITONEAL CARCINOMA; HEREDITARY OVARIAN-CANCER; ORAL-CONTRACEPTIVE USE; UP HERS-II; PROPHYLACTIC OOPHORECTOMY; FAMILY-HISTORY; FOLLOW-UP; POSTMENOPAUSAL WOMEN; ESTROGEN/PROGESTIN REPLACEMENT AB Persons undergoing genetic testing for an inherited predisposition to cancer often raise questions about recommendations for follow-up care. Missing from current guidelines is consideration of the role of estrogens for BRCA1/BRCA2 mutation carriers. Potential implications of hormones for risk of cancer and effectiveness of risk-reduction strategies need to be considered in the design of comprehensive guidelines for high-risk women. Patients who are mutation carriers may ask questions about the use of oral contraceptives, hormone replacement, and utility of current screening modalities. Controversy exists, even when considering these issues for the general population, but become more imperative when considering young, unaffected women who carry an inherited genetic mutation making decisions that may have long-term health consequences. Many patients have considered estrogen ablation via prophylactic surgeries as risk-reduction interventions. This article reviews data regarding these issues, makes recommendations based on available information, and offers future perspectives for those identified at high risk for cancer because of genetic predisposition. Although questions remain regarding the potential implications of hormones for risk of cancer and effectiveness of risk-reduction strategies, all information should be considered when educating and caring for such patients. C1 NCI, NIH, Bethesda, MD 20892 USA. RP de Carvalho, M (reprint author), NCI, NIH, 10 Ctr Dr,MSC 1658, Bethesda, MD 20892 USA. NR 69 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD DEC PY 2003 VL 26 IS 6 BP 421 EP 430 PG 10 WC Oncology; Nursing SC Oncology; Nursing GA 753QT UT WOS:000187242600001 PM 15022973 ER PT J AU Soret, J Gabut, M Dupon, C Kohlhagen, G Stevenin, J Pommier, Y Tazi, J AF Soret, J Gabut, M Dupon, C Kohlhagen, G Stevenin, J Pommier, Y Tazi, J TI Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in mammalian cells lacking topoisomerase 1 SO CANCER RESEARCH LA English DT Article ID PRE-MESSENGER-RNA; SR PROTEINS; DNA TOPOISOMERASES; IN-VITRO; COVALENT COMPLEXES; TERMINAL DOMAIN; KINASE-ACTIVITY; CAMPTOTHECIN; MECHANISM; INHIBITION AB DNA topoisomerase I (Topo I) specifically phosphorylates arginine-serine-rich (SR proteins) splicing factors and is potentially involved in pre-mRNA-splicing regulation. Using a Topo I-deficient murine B lymphoma-derived subclone (P388-45/C) selected for its resistance to high dosage of the antitumor drug camptothecin, we show that Topo I depletion results in the hypophosphorylation of SR proteins and impairs exonic splicing enhancer (ESE)-dependent but not constitutive splicing. The Affymetrix GeneChip system analysis revealed that several alternatively spliced genes, characterized by small exons and large introns, are down-regulated in Topo I-deficient cells. Given that ectopic expression of green fluorescent protein-Topo I fusion in Topo I-deficient cells restores both wild-type phosphorylation of SR proteins and ESE-dependent splicing, we conclude that Topo I-mediated phosphorylation plays a specific role in ESE-regulated splicing. C1 CNRS UMR 5535, Inst Med Genet, Montpellier, France. Inst Federatif 122, Montpellier, France. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, Strasbourg, France. RP Tazi, J (reprint author), CNRS UMR 5535, Inst Med Genet, Montpellier, France. NR 50 TC 56 Z9 56 U1 0 U2 1 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 DEC 1 PY 2003 VL 63 IS 23 BP 8203 EP 8211 PG 9 WC Oncology SC Oncology GA 756DQ UT WOS:000187450900022 PM 14678976 ER PT J AU Tian, F Byfield, SD Parks, WT Yoo, S Felici, A Tang, BW Piek, E Wakefield, LM Roberts, AB AF Tian, F Byfield, SD Parks, WT Yoo, S Felici, A Tang, BW Piek, E Wakefield, LM Roberts, AB TI Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR; E-CADHERIN; TRANSCRIPTIONAL REPRESSION; MAMMARY-TUMOR; RECEPTOR; EXPRESSION; PROTEIN; GENE; CARCINOMA AB The role of transforming growth factor 13 in breast cancer is controversial with tumor suppressor and pro-oncogenic activities having been demonstrated. To address whether the same or different signal transduction pathways mediate these opposing activities, we manipulated the Smad2/3 signaling pathway in cells of common origin but differing degrees of malignancy derived from MCF10A human breast cells. We show that interference with endogenous Smad2/3 signaling enhances the malignancy of xenografted tumors of premalignant and well-differentiated tumor cells but strongly suppresses lung metastases of more aggressive carcinoma cells after tail vein injection. Overexpression of Smad3 in the same cells has opposite effects. The data demonstrate that the Smad2/3 signaling pathway mediates tumor suppressor and prometastatic signals, depending on the cellular context. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Room C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. OI Parks, W. Tony/0000-0001-7341-3277 NR 55 TC 124 Z9 140 U1 0 U2 1 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 DEC 1 PY 2003 VL 63 IS 23 BP 8284 EP 8292 PG 9 WC Oncology SC Oncology GA 756DQ UT WOS:000187450900033 PM 14678987 ER PT J AU Platz, EA Leitzmann, MF Michaud, DS Willett, WC Giovannucci, E AF Platz, EA Leitzmann, MF Michaud, DS Willett, WC Giovannucci, E TI Interrelation of energy intake, body size, and physical activity with prostate cancer in a large prospective cohort study SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; MALE HEALTH-PROFESSIONALS; MAMMARY CARCINOGENESIS; CALORIC RESTRICTION; BINDING-PROTEINS; SOMATOMEDIN-C; DIETARY-FAT; INSULIN; RISK; CARCINOMA AB Energy restriction reduces prostate tumor growth in transplantable tumor models in rodents, which suggests that excessive energy intake may contribute to the risk of prostate cancer. The association of total energy intake across the normal range with prostate cancer has not been consistent in epidemiological studies. We prospectively evaluated the joint associations of energy intake and body size or physical activity with prostate cancer. Participants were 46,786 male health professionals ages 40-75 years at baseline in 1986 who were free of cancer diagnosis. Between 1986 and 2000, we documented 2896 incident prostate cancer cases (excluding stage T1a) by review of medical records and histopathology reports. Of these, 339 were metastatic or fatal cases. We used Cox proportional hazards regression to estimate the multi-variate relative risk (RR) of prostate cancer associated with energy intake measured using a food frequency questionnaire, overall and stratified by body mass index, waist size, physical activity, as well as by age and family history of prostate cancer. There was no association between energy intake and total prostate cancer incidence. However, a modest increased risk of metastatic or fatal disease with energy intake was suggested [RR comparing extreme quintiles: 1.38, 95% confidence interval (CI) 0.96-1.98, P(trend) = 0.06]. This association was most pronounced in men with a lower body mass index (in stratum < 24 kg/m(2): RR = 1.76, 95% CI 0.92-3.39; P(interaction) = 0.04), smaller waist size [in stratum less than or equal to 37 inches: RR = 1.91, 95% CI 0.83-4.36; P(interaction) = 0.03], and who were more physically active [in stratum greater than or equal to median: RR = 1.74, 95% CI 0.93-3.26; P(interaction) = 0.09]. Also, the association of energy intake with metastatic and fatal prostate cancer was restricted to men who were younger [in stratum :5 65 years old: RR = 2.60, 95% CI 1.26-5.39; P(interaction) = 0.04] or who had a positive family history [RR = 3.33, 95% CI 1.26-8.76; P(interaction) = 0.04]. Although energy intake is known to be imperfectly measured by questionnaire, we observed a positive association between energy intake and metastatic or fatal prostate cancer among men who were leaner, more physically active, younger, and who had a family history of prostate cancer. Our observations suggest the testable hypothesis that the elevated risk of clinically important prostate cancer in men with a high energy intake may be attributable to certain metabolic profiles that favor enhanced growth factor production over an increase in adiposity. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. James Buchanan Brady Urol Inst, Baltimore, MD USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Room E6138, Baltimore, MD 21205 USA. RI Michaud, Dominique/I-5231-2014 FU NCI NIH HHS [CA55075]; NHLBI NIH HHS [HL35464] NR 40 TC 38 Z9 39 U1 0 U2 4 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 DEC 1 PY 2003 VL 63 IS 23 BP 8542 EP 8548 PG 7 WC Oncology SC Oncology GA 756DQ UT WOS:000187450900069 PM 14679023 ER PT J AU Kempner, ES Miller, JH AF Kempner, ES Miller, JH TI The molecular biology of Euglena gracilis. XV. Recovery from centrifugation-induced stratification SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE Euglena gracilis; centrifugation-induced stratification; recovery process ID PRESSURE; INVOLVEMENT; RETICULUM AB The contents of Euglena gracilis cells can be separated in vivo by ultracentrifugation. Within the unbroken cell, each set of components forms a distinct layer according to their respective densities. The degree of segregation increases with both the g-force and the time of centrifugation, up to a maximum at 100,000 X g for 1 h, when six distinct strata can be observed. When returned to normal growth conditions, essentially all the cells return to the normal state and growth pattern. Greater g-forces or longer exposures do not alter the observable strata, but the ability of the cells to recover is diminished. Smaller g-forces result in less separation of cellular contents and all cells recover, even after 18 h of exposure. Euglena cells stratified at 100,000 X g for 1 h were returned to normal growth conditions; recovery was followed microscopically and by the rate of utilization of oxygen as well as that of the single carbon source. The cells recovered their normal state within 1 to 2 h, which is only a tenth of the normal doubling time. The mechanism for this recovery involves a natural process of change in cell shape caused by contraction and relaxation of the pellicle, a cell surface structure. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Kempner, ES (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. NR 23 TC 2 Z9 2 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD DEC PY 2003 VL 56 IS 4 BP 219 EP 224 DI 10.1002/cm.10145 PG 6 WC Cell Biology SC Cell Biology GA 748JH UT WOS:000186858400002 PM 14584024 ER PT J AU Paul, DB Shi, YB AF Paul, DB Shi, YB TI Distinct expression profiles of transcriptional coactivators for thyroid hormone receptors during Xenopus laevis metamorphosis SO CELL RESEARCH LA English DT Article DE transcription coactivators; thyroid hormone receptor; Xenopus laevis; metamorphosis; histone acetylation ID NUCLEAR RECEPTOR; HISTONE ACETYLTRANSFERASES; PROTEIN METHYLTRANSFERASE; MOLECULAR-CLONING; GENE-EXPRESSION; ACTIVATION; SUPERFAMILY; ACETYLATION; BINDING; TIF2 AB The biological effects of thyroid hormone (T-3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T-3 . T-3 regulates a series of orchestrated developmental changes, which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog. T-3 is presumed to bind to TRs, which in turn recruit coactivators, leading to gene activation. The best-studied coactivators belong to the p 160 or SRC family. Members of this family include SRC1/ NCoA-1, SRC2/TIF2/GRIP1, and SRC3/pCIP/ACTR/AIB-1/RAC-3/TRAM-1. These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP. Here, we studied the expression patterns of these coactivators during various stages of development. Amongst the coactivators cloned in Xenopus laevis, SRC3 was found to be dramatically upregulated during natural and T-3- induced metamorphosis, and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels. These results support the view that these coactivators participate in gene regulation by TR during metamorphosis. C1 NICHD, LGRD, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, LGRD, NIH, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 47 TC 13 Z9 13 U1 2 U2 2 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD DEC PY 2003 VL 13 IS 6 BP 459 EP 464 PG 6 WC Cell Biology SC Cell Biology GA 760VY UT WOS:000187857000004 ER PT J AU Ochillo, RF Robinson, TJ McNairy, SA McClure, SA AF Ochillo, RF Robinson, TJ McNairy, SA McClure, SA TI Research Centers in Minority Institutions (RCMI) SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Editorial Material DE Minority Institutions; RCMI program AB The Research Centers in Minority Institutions (RCMI) Program was initiated in the United States of America in 1985 as a congressionally mandated program. The mission of the RCMI Program is to expand the national capacity for the conduct of biomedical and behavioral research by developing the research infrastructure at institutions granting doctoral degrees in health or health-related sciences, that have 50% or greater enrollment of minorities (African Americans, Hispanics, Native Hawaiians and Pacific Islanders, Native Americans and Alaska Natives) that are underrepresented in the biomedical sciences. The program administration is based in the National Center for Research Resources (NCRR), at the National Institutes of Health (NIH), an agency of the Department of Health and Human Services (DHHS). Since its inception, the program has provided critical resources (core research laboratories, equipment, personnel, supplies, etc.) at each of the RCMI-funded institutions. This article is intended to provide an overview of the RCMI Program, outline the research areas and list contact persons for additional information on research and core resources at each of the current RCMI sites. C1 Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. Morgan State Univ, Sch Comp Math & Nat Sci, Baltimore, MD 21251 USA. Morgan State Univ, RCMI Program, Baltimore, MD 21251 USA. Natl Ctr Res Resources, Div Res Infrastruct, NIH, Bethesda, MD 20892 USA. RP Ochillo, RF (reprint author), Morgan State Univ, Dept Biol, 1700 E Cold Spring Lane, Baltimore, MD 21251 USA. EM rochillo@moac.morgan.edu NR 0 TC 1 Z9 1 U1 0 U2 1 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD DEC PY 2003 VL 49 IS 8 BP 1183 EP 1186 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 774JZ UT WOS:000188977500001 PM 14983984 ER PT J AU Glabus, MF Horwitz, B Holt, JL Kohn, PD Gerton, BK Callicott, JH Meyer-Lindenberg, A Berman, KF AF Glabus, MF Horwitz, B Holt, JL Kohn, PD Gerton, BK Callicott, JH Meyer-Lindenberg, A Berman, KF TI Interindividual differences in functional interactions among prefrontal, parietal and parahippocampal regions during working memory SO CEREBRAL CORTEX LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; BASAL GANGLIA; INDIVIDUAL-DIFFERENCES; CORTICAL INTERACTIONS; NETWORK ANALYSIS; VISUAL PATHWAYS; GUIDED SACCADES; RHESUS-MONKEY; FMRI SIGNAL; CORTEX AB To clarify the neural systems deployed by individual subjects during working memory (WM), we collected functional neuroimaging data from healthy subjects, and constructed a model of 2-back WM using structural equation modeling (SEM). A group model was constructed, and models for each subject were validated against it. The group model consisted principally of regions in the prefrontal and parietal cortex, with considerable interindividual variance in the single-subject models. To explore this variance, subjects were split into two groups based on performance. Performance level and self-reported strategy scores were used in a correlation analysis against path weights between nodes of individual models. High performers utilized a left hemisphere sub-network involving inferior parietal lobule and Broca's area, whereas lower performers utilized a right hemisphere sub-network with interactions between inferior parietal lobule and dorsolateral prefrontal cortex. Further, we observed an interaction between the parahippocampal formation and the inferior parietal lobule that was related to the different strategies used by the individuals to perform the task. Strategy and performance level appear to be intricately related in this task, with neural systems supporting verbal processing producing better performance than those associated with spatial processing. These results demonstrate that individual behavioral characteristics are reflected in specific neurofunctional patterns at the system level and that these can be captured by analytical techniques such as SEM. C1 NIH, Dept Hlth & Human Serv, Unit Integrat Neuroimaging, Bethesda, MD 20892 USA. NIMH, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Glabus, MF (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Psychiat, POB 33932,1501 Kings Highway, Shreveport, LA 71130 USA. RI Callicott, Joseph/C-9102-2009; OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 74 TC 77 Z9 77 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD DEC PY 2003 VL 13 IS 12 BP 1352 EP 1361 DI 10.1093/cercor/bhg082 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 745QJ UT WOS:000186699300008 PM 14615300 ER PT J AU Ju, C McCoy, JP Chung, CJ Graf, MLM Pohl, LR AF Ju, C McCoy, JP Chung, CJ Graf, MLM Pohl, LR TI Tolerogenic role of Kupffer cells in allergic reactions SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ENCAPSULATED DICHLOROMETHYLENE DIPHOSPHONATE; CD8(+) T-CELLS; ENDOTHELIAL-CELLS; IMMUNE-RESPONSES; PROTEIN ADDUCTS; NATURAL-KILLER; DRUG-REACTIONS; LIVER; TOLERANCE; INDUCTION AB Drug-induced allergic reactions (DIARs), including allergic hepatitis, cutaneous reactions, and blood dyscrasias, are unpredictable and can be life threatening. Although current studies suggest that DIARs are caused by immunogenic drug-protein adducts, it remains unclear what factors determine the susceptibility to DIARs. We hypothesized that most individuals may be resistant to DIARs in part because they become immunologically tolerant to drug-protein adducts in the liver, an organ with tolerogenic properties. Because animal models of DIARs are elusive, we tested this hypothesis using a murine model of 2,4-dinitrochlorobenzene (DNCB)-induced delayed type hypersensitivity reaction that is mediated by immunogenic 2,4-dinitrophenylated (DNP)-protein adducts. Intravenous pretreatment of mice with DNP-BSA led to its accumulation in hepatic Kupffer cells (KC) and induced immunological tolerance to subsequent DNCB sensitization. Tolerance could be abrogated by prior depletion of KC or induced in naive mice by transferring a T cell-depleted, KC-enriched fraction of liver nonparenchymal cells from mice tolerized 1 month earlier by DNP-BSA pretreatment. These findings implicate KC as a primary and sustained inducer of tolerance against DNP-protein adducts and suggest a similar role in modulating allergic reactions against drug-protein adducts. Perhaps genetic and/or environmental factors affecting the activities of these cells may play a role in determining individual susceptibility to DIARs. C1 Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80202 USA. NHLBI, Flow Cytometry Core Facil, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Ju, C (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80202 USA. EM Cynthia.Ju@UCHSC.EDU NR 48 TC 25 Z9 25 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 2003 VL 16 IS 12 BP 1514 EP 1519 DI 10.1021/tx0341761 PG 6 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 755AM UT WOS:000187365700004 PM 14680364 ER PT J AU Karaczyn, AA Bal, W North, SL Bare, RM Hoang, VM Fisher, RJ Kasprzak, KS AF Karaczyn, AA Bal, W North, SL Bare, RM Hoang, VM Fisher, RJ Kasprzak, KS TI The octapeptidic end of the C-terminal tail of histone H2A is cleaved off in cells exposed to carcinogenic nickel(II) SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID POLYACRYLAMIDE-GEL-ELECTROPHORESIS; ACID UREA TRITON; OXIDATIVE DAMAGE; DNA; PROTEINS; IDENTIFICATION; NUCLEOSOME; AMINO AB We have demonstrated previously that Ni(II) binds to the C-terminal-TESHHKAKGK motif of isolated bovine histone H2A. At physiological pH, the bound Ni(II) assists in hydrolysis of the E-S peptide bond in this motif that results in a cleavage of the terminal octapeptide SHHKAKGK off the histone's C-tail. To test if the hydrolysis could also occur in living cells, we cultured CHO (Chinese hamster ovary), NRK-52 (rat renal tubular epithelium), and HPL1D (human lung epithelium) cells with 0.1-1 mM Ni(II) for 3-7 days. As found by gel electrophoresis, Western blotting, and liquid chromatography/mass spectrometry, histones extracted from the cells contained a new fraction of histone H2A lacking the terminal octapeptide (q-H2A). The abundance of q-H2A increased with Ni(H) concentration and exposure time. It can be anticipated that the truncation of histone H2A may alter chromatin structure and affect gene expression. The present results provide evidence for novel mechanisms of epigenetic effects of Ni(II) that may be involved in nickel toxicity and carcinogenesis. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Polish Acad Sci, Inst Biochem & Biophys, PL-02106 Warsaw, Poland. SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA. RP Kasprzak, KS (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. EM kasprkaz@mail.ncifcrf.gov RI Fisher, Robert/B-1431-2009 NR 28 TC 34 Z9 36 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 2003 VL 16 IS 12 BP 1555 EP 1559 DI 10.1021/tx0300277 PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 755AM UT WOS:000187365700009 PM 14680369 ER PT J AU Sullivan, AE Goodman, JE Yager, JD AF Sullivan, AE Goodman, JE Yager, JD TI Catechol-O-methyltransferase (COMT) and catechol estrogens in breast cancer. SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. NCI, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. EM asulliva@jhsph.edu; jyager@hsph.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 2003 VL 16 IS 12 MA 20 BP 1665 EP 1665 PG 1 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 755AM UT WOS:000187365700041 ER PT J AU Colgate, KC Huang, XW Kolbanovskiy, A Skorvaga, M Van Houten, B Amin, S Geacintov, NE AF Colgate, KC Huang, XW Kolbanovskiy, A Skorvaga, M Van Houten, B Amin, S Geacintov, NE TI Effects of methylation and temperature on nucleotide excision repair of stereoisomeric benzo[a]pyrene diol epoxide-N2-dG adducts in a 5-MeCG*p53 codon 273 sequence context catalyzed by UvrABC proteins from B-caldotenax. SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Meeting Abstract CT 226th National Meeting of the American-Chemical-Society CY SEP 07-11, 2003 CL NEW YORK, NEW YORK SP Amer Chem Soc C1 NYU, Dept Chem, New York, NY 10003 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. NYU, Dept Chem, New York, NY USA. EM kcc208@nyu.edu RI kolbanovskiy, aleksandr/I-7278-2013 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 2003 VL 16 IS 12 MA 66 BP 1676 EP 1677 PG 2 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 755AM UT WOS:000187365700087 ER PT J AU Sachs, JN Petrache, HI Woolf, TB AF Sachs, JN Petrache, HI Woolf, TB TI Interpretation of small angle X-ray measurements guided by molecular dynamics simulations of lipid bilayers SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE bilayer thickness; electron density profile; lipid headgroup; Fourier reconstruction; form factors; lipid volume ID ELECTRON-DENSITY PROFILES; GEL PHASE; PHOSPHOLIPID-BILAYERS; HYDRATION FORCES; LECITHIN BILAYERS; COMPONENT VOLUMES; CHANNEL LIFETIME; SURFACE-TENSION; FULL HYDRATION; MEMBRANE AB Reconstruction and interpretation of lipid bilayer structure from X-ray scattering often rely on assumptions regarding the molecular distributions across the bilayer. It is usually assumed that changes in head-head spacings across the bilayer, as measured from electron density profiles, equal the variations in hydrocarbon thicknesses. One can then determine the structure of a bilayer by comparison to the known structure of a lipid with the same headgroup. Here we examine this procedure using simulated electron density profiles for the benchmark lipids DMPC and DPPC. We compare simulation and experiment in both real and Fourier space to address two main aspects: (i) the measurement of head-head spacings from relative electron density profiles, and (ii) the determination of the absolute scale for these profiles. We find supporting evidence for the experimental procedure, thus explaining the robustness and consistency of experimental structural results derived from electron density profiles. However, we also expose potential pitfalls in the Fourier reconstruction that are due to the limited number of scattering peaks. Volumetric analysis of simulated bilayers allows us to propose an improved, yet simple method for scale determination. In this way we are able to remove some of the restrictions imposed by limited scattering data in constructing reliable electron density profiles. (C) 2003 Elsevier Ireland Ltd. All rights reserved. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. RP Petrache, HI (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bldg 9,Rm 1E116, Bethesda, MD 20892 USA. NR 61 TC 40 Z9 41 U1 0 U2 9 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD DEC PY 2003 VL 126 IS 2 BP 211 EP 223 DI 10.1016/j.chemphyslip.2003.08.001 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 759RY UT WOS:000187751700009 PM 14623455 ER PT J AU Stanyon, R Bonvicino, CR Svartman, M Seuanez, HN AF Stanyon, R Bonvicino, CR Svartman, M Seuanez, HN TI Chromosome painting in Callicebus lugens, the species with the lowest diploid number (2n=16) known in primates SO CHROMOSOMA LA English DT Article ID IN-SITU HYBRIDIZATION; PLATYRRHINI; MONKEY; CEBIDAE; FISH; HOMOLOGIES; REARRANGEMENTS; KARYOTYPE; EVOLUTION; ALOUATTA AB Cytogenetic studies have shown that New World primates are karyologically diverse and highly derived. The genus Callicebus is the best example of this karyological diversity, with diploid numbers ranging from 2n=50 to 2n=16. We report on Callicebus lugens, which has the lowest diploid number (2n=16) yet found in the primate order and represents a striking example of extreme karyotypic shuffling. To better understand the genomic rearrangements that have resulted in this extremely low diploid number, we mapped chromosome homologies between C. lugens and humans by in situ hybridization. The total number of hybridization signals was 42, excluding the Y chromosome, with a total of 34 syntenic associations not found in humans. This species has one of the most derived karyotypes among the Platyrrhini. Fusion has been the predominant mode of karyological evolution, although fissions and inversions have also transformed the C. lugens karyotype. Remarkably in such a highly rearranged karyotype, the synteny of 11 human chromosomes (4, 5, 9, 12, 13, 14, 17, 18, 20, 21, and X) was maintained intact, even if most of these human-homologous gene clusters were translocated. Other human syntenies, such as homologues to human chromosomes 10 and 16, were highly fragmented. Comparisons of the C. lugens-human homology map with those of other New World primates have not yet helped establish a phylogenic arrangement between congeneric species or link Callicebus with any other genus. C1 NCI, Comparat Mol Cytogenet Core, Genet Branch, Frederick, MD 21702 USA. Inst Nacl Canc, Diretoria Pesquisa, Div Genet, Rio De Janeiro, Brazil. Inst Oswaldo Cruz, Dept Trop Med, BR-20001 Rio De Janeiro, Brazil. Univ Fed Rio de Janeiro, Dept Genet, Rio De Janeiro, Brazil. RP Stanyon, R (reprint author), NCI, Comparat Mol Cytogenet Core, Genet Branch, Frederick, MD 21702 USA. RI Svartman, Marta/B-4528-2008; Bonvicino, Cibele /O-3390-2014; OI Svartman, Marta/0000-0003-3239-1862; Stanyon, Roscoe/0000-0002-7229-1092 NR 27 TC 35 Z9 35 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD DEC PY 2003 VL 112 IS 4 BP 201 EP 206 DI 10.1007/s00412-003-0261-5 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 754QV UT WOS:000187342700006 PM 14608465 ER PT J AU Means-Markwell, M Linnoila, RI Williams, J Janne, PA Kaye, F O'Neil, K Johnson, BE AF Means-Markwell, M Linnoila, RI Williams, J Janne, PA Kaye, F O'Neil, K Johnson, BE TI Prospective study of the airways and pulmonary parenchyma of patients at risk for a second lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SPIRAL COMPUTED-TOMOGRAPHY; FLUORESCENCE BRONCHOSCOPIC SURVEILLANCE; PLACEBO-CONTROLLED TRIAL; CARCINOMA IN-SITU; BRONCHIAL EPITHELIUM; FORMER SMOKERS; FOLLOW-UP; SQUAMOUS METAPLASIA; ACTION PROJECT; PRIMARY TUMORS AB surgical resection alone, but additional patients will need to be studied. Purpose: We conducted our study to compare the number of preneoplastic lesions in the airways and nodules in the pulmonary parenchyma of patients with resected non-small cell lung cancer with the patients whose treatment included chest radiotherapy. Experimental Design: Patients were eligible if they had successfully resected stage I and II non-small cell lung cancer or advanced stage non-small cell or small cell lung cancer treated with chest radiotherapy with or without chemotherapy and were free of cancer for >2 years. Patients underwent a history and physical examination, white light and fluorescence bronchoscopy, and computerized tomography of the chest. The airway epithelium was examined for preneoplastic histological changes, and the pulmonary parenchyma was examined for the presence of nodules. Results: Twenty-nine patients at risk for lung cancer were studied between 1997 and 1999. Two patients treated with chest radiotherapy had an area of moderate dysplasia (n = 1) and carcinoma in situ (n = 1), whereas one patient treated with surgical resection alone had an area of mild dysplasia. Six other patients had metaplasia detected in their airway epithelium. Ten of the 13 patients treated with chest radiotherapy had pulmonary nodules compared with 5 of the 13 patients treated with surgical resection alone. Conclusions: Mild dysplasia, moderate dysplasia, severe dysplasia, and carcinoma in situ are unusual in patients with resected lung cancer who have stopped smoking for an extended period of time. Patients with lung cancer treated with chest irradiation may be at higher risk for preneoplastic lesions and pulmonary nodules than patients treated with surgical resection alone, but additional patients will need to be studied. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02445 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Natl Canc Inst, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD USA. Natl Naval Med Res Inst, Dept Med, Bethesda, MD USA. Natl Naval Med Res Inst, Dept Pathol, Bethesda, MD USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Room D1234,44 Binney St, Boston, MA 02445 USA. EM BEJOHNSON@PARTNERS.ORG RI kaye, frederic/E-2437-2011 NR 37 TC 2 Z9 3 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 BP 5915 EP 5921 PN 1 PG 7 WC Oncology SC Oncology GA 756FC UT WOS:000187454300017 PM 14676115 ER PT J AU Dowlati, A Lazarus, HM Hartman, P Jacobberger, JW Whitacre, C Gerson, SL Ksenich, P Cooper, BW Frisa, PS Gottlieb, M Murgo, AJ Remick, SC AF Dowlati, A Lazarus, HM Hartman, P Jacobberger, JW Whitacre, C Gerson, SL Ksenich, P Cooper, BW Frisa, PS Gottlieb, M Murgo, AJ Remick, SC TI Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT International Conference on Molecular Targets and Cancer Therapeutics CY OCT 29-NOV 02, 2001 CL MIAMI BEACH, FLORIDA SP AACR, NCI, EORTC ID PROTEIN-KINASE-C; CHRONIC LYMPHOCYTIC-LEUKEMIA; CARCINOMA-CELLS; LYMPHOMA; APOPTOSIS; GROWTH; CANCER; ACTIVATORS; TOXICITY; CRITERIA AB Purpose: Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine. Experimental Design: We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled. Results: The dose-limiting toxicity was myalgia. The MTD and recommended Phase 11 dose of bryostatin 1 was 50 mug/m(2)/24 h followed by vincristine 1.4 mg/m(2) (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting greater than or equal to 6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h. Conclusions: Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted. C1 Univ Hosp Cleveland, Dev Therapeut Program, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH USA. NCI, Bethesda, MD 20892 USA. RP Dowlati, A (reprint author), Univ Hosp Cleveland, Div Hematol & Oncol, 11100 Euclid Ave, Cleveland, OH 44106 USA. FU NCI NIH HHS [P30 CA43703, R01-CA73413, U01 CA62502]; NCRR NIH HHS [M01-RR-00080] NR 28 TC 39 Z9 39 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 DEC 1 PY 2003 VL 9 IS 16 BP 5929 EP 5935 PN 1 PG 7 WC Oncology SC Oncology GA 756FC UT WOS:000187454300019 PM 14676117 ER PT J AU Kim, IY Lee, DH Lee, DK Kim, BC Kim, HT Leach, FS Linehan, WM Morton, RA Kim, SJ AF Kim, IY Lee, DH Lee, DK Kim, BC Kim, HT Leach, FS Linehan, WM Morton, RA Kim, SJ TI Decreased expression of bone morphogenetic protein (BMP) receptor type II correlates with insensitivity to BMP-6 in human renal cell carcinoma cells SO CLINICAL CANCER RESEARCH LA English DT Article ID OSTEOGENIC PROTEIN-1; IDENTIFICATION; REGULATORS AB Purpose: Bone morphogenetic proteins (BMPs) are members of a family of pleiotropic growth factors that play a critical role during renal development as well as maintaining kidney horneostasis. In the present study, we investigated the potential role of BMP receptors (BMPRs) in renal cell carcinoma (RCC) cells. Experimental Design: Immumohistochemistry was used to investigate the expression of BMPRs in human RCC tissues. As an in vitro model of RCC, three cell lines were used: 112, 117, and 181. Northern blot, immunoblot, and reverse transcription-PCR were used to study the expression of BMPRs in the cell lines. Finally, cells were transfected using LipofectAMINE. Results: Normal human kidney tissues express the three BMPRs: types RIA, RIB, and RII. In contrast, human RCC cells frequently exhibit a loss of expression of BMP-RII. In tissue culture, BMP-6 inhibits in a dose-dependent manner the proliferation of 112 cells but not of 117 and 181 cells. Assays for BMPRs demonstrated that 117 and 181 cells express low levels of BMP-RII RNA. When these two BMP-6 resistant cell lines were infected with the adenovirus containing the constitutively active form of BMP-RIA or -RIB in combination with a BMP-6-responsive luciferase reporter construct, luciferase activity increased. Finally, when these cell lines were transfected with BMP-RII, BMP-6-sensitivity was restored. Conclusions: These results demonstrate that human RCC tissues frequently have decreased levels of expression of BMP-RII and that the human RCC cell lines 117 and 181 are resistant to the growth-inhibitory effect of BMP-6 because they have decreased levels of expression of BMP-RII. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD USA. Ewha Womans Univ, Dept Urol, Seoul, South Korea. RP Kim, SJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 18 TC 34 Z9 35 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 DEC 1 PY 2003 VL 9 IS 16 BP 6046 EP 6051 PN 1 PG 6 WC Oncology SC Oncology GA 756FC UT WOS:000187454300033 PM 14676131 ER PT J AU Hanauske-Abel, HM Wolff, EC Hardegen, N Clement, PMJ McLendon, GL Hanauske, AR Cracchiolo, BM Park, MH AF Hanauske-Abel, HM Wolff, EC Hardegen, N Clement, PMJ McLendon, GL Hanauske, AR Cracchiolo, BM Park, MH TI The antiproliferative action of doxorubicin and a novel analog: Arrest of GI/S transit does not result from inhibition of eIF-5A hydroxylation. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. NIDCR, NIH, Bethesda, MD USA. Princeton Univ, Princeton, NJ 08544 USA. Univ Hamburg, Hamburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6072S EP 6073S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300018 ER PT J AU Tarasova, N Seth, R Michejda, CJ AF Tarasova, N Seth, R Michejda, CJ TI Structure-activity relationships of transmembrane inhibitors of P-glycoprotein. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6072S EP 6072S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300017 ER PT J AU Brantley, E Stinson, S Kohlhagen, G Antony, S Sausville, E Pommier, Y AF Brantley, E Stinson, S Kohlhagen, G Antony, S Sausville, E Pommier, Y TI Anti-tumor2-(4-Aminophenyl)-5-fluoro-benzothiazole (5F203, NSC 703786) induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 breast cancer cells. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Dev Therapeut Program, Frederick, MD 21701 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6075S EP 6075S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300028 ER PT J AU Szekely, Z Hariprakasha, HK Kosakowska-Cholody, T Michejda, CJ AF Szekely, Z Hariprakasha, HK Kosakowska-Cholody, T Michejda, CJ TI Sequence specific DNA binding agents: Synthesis and properties of new potently cytotoxic cyclopropa[c]benz[e]indole derivatives. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6075S EP 6075S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300029 ER PT J AU Kosakowska-Cholody, T Cholody, WM Hariprakasha, HK Michejda, CJ Hollingshead, MG Pommier, Y Antony, S Kar, S Carr, BI AF Kosakowska-Cholody, T Cholody, WM Hariprakasha, HK Michejda, CJ Hollingshead, MG Pommier, Y Antony, S Kar, S Carr, BI TI wmc79 and hkh40a - Potent agents against gastrointestinal cancers: Molecular targets and mechanism of action. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Frederick, MD 21701 USA. Avalon, Germantown, MD USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6077S EP 6078S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300037 ER PT J AU Peggins, JO Emmerling, DC Bollinger, LH Ryan, MJ Sells, DM Grossi, IM Tomaszewski, JE AF Peggins, JO Emmerling, DC Bollinger, LH Ryan, MJ Sells, DM Grossi, IM Tomaszewski, JE TI Toxicologic evaluation of the pyrrolobenzodiazepine dimer SJG-136 (NSC-694501) in beagle dogs and Fischer-344 rats. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, NIH, Rockville, MD USA. Battelle Mem Inst, Columbus, OH 43201 USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6083S EP 6083S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300060 ER PT J AU Zhai, SP Pingpank, J Sparreboom, A Figg, WD Alexander, R AF Zhai, SP Pingpank, J Sparreboom, A Figg, WD Alexander, R TI Melphalan pharmacokinetics and pharmacodynamics in phase I Trial of hepatic arterial infusion with venous filtration in patients with metastatic liver tumor. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6085S EP 6085S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300067 ER PT J AU Siu, LL Chen, X Tsao, M Dancey, J Pond, GR Klein, M Winquist, E AF Siu, LL Chen, X Tsao, M Dancey, J Pond, GR Klein, M Winquist, E TI A phase I/Il Study of erlotinib (Tarceva) in combination with cisplatin in patients with recurrent or metastatic squamous cell cancer of the head and neck (HNSCC). SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Princess Margaret Hosp, Phase Consortim 2, Toronto, ON M4X 1K9, Canada. NCI, Rockville, DC USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6091S EP 6091S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300093 ER PT J AU Thomas, MB Faria, S Tamm, E Rashid, A Charnsangavej, C Dancey, J Abbruzzese, J AF Thomas, MB Faria, S Tamm, E Rashid, A Charnsangavej, C Dancey, J Abbruzzese, J TI A phase II Study of OSI-774 in unresectable hepatocellular carcinoma. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6092S EP 6092S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300095 ER PT J AU Oza, AM Elit, L Eisenhauer, E Hoskins, PJ Biagi, J Carey, M Dubuc-Lissoir, J Dundas, G Stuart, G Matthews, S Tsao, M Dancey, J Fyles, A AF Oza, AM Elit, L Eisenhauer, E Hoskins, PJ Biagi, J Carey, M Dubuc-Lissoir, J Dundas, G Stuart, G Matthews, S Tsao, M Dancey, J Fyles, A TI Phase II study of erlotinib (Tarceva, OSI774) in women with recurrent or metastatic endometrial cancer - NCICIND 148. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6094S EP 6094S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300105 ER PT J AU Liang, YZ Gawad, C Azorsa, D Walker, R Meltzer, PS AF Liang, YZ Gawad, C Azorsa, D Walker, R Meltzer, PS TI Targeting BRAF by siRNA in human melanoma. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Natl Inst Hlth, NHGRI, Canc Genet Branch, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6096S EP 6096S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300111 ER PT J AU Hwang, K Acharya, MR Sausville, EA Zhai, SP Woo, EW Figg, WD Sparreboom, A AF Hwang, K Acharya, MR Sausville, EA Zhai, SP Woo, EW Figg, WD Sparreboom, A TI Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6108S EP 6109S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300160 ER PT J AU Xiao, JJ Byrd, JC Marcucci, G Chen, J Grever, M Covey, JM Wright, J Chan, KK AF Xiao, JJ Byrd, JC Marcucci, G Chen, J Grever, M Covey, JM Wright, J Chan, KK TI Bioactivation of depsipeptide FK228. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Ohio State Univ, Coll Med, Columbus, OH 43210 USA. Ohio State Univ, Coll Publ Hlth & Pharm, Columbus, OH 43210 USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6110S EP 6110S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300166 ER PT J AU Antony, S Jayaraman, M Kohlhagen, G Cushman, M Pommier, Y AF Antony, S Jayaraman, M Kohlhagen, G Cushman, M Pommier, Y TI Cellular topoisomerase I inhibition and antiproliferative activity induced by MJ-III-65, a novel indenoisoquinoline. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Natl Inst Hlth, Ctr Canc Res, Bethesda, MD USA. Purdue Univ, W Lafayette, IN 47907 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6112S EP 6112S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300173 ER PT J AU Antony, S Jayaraman, M Laco, G Kohlhagen, G Cushman, M Pommier, Y AF Antony, S Jayaraman, M Laco, G Kohlhagen, G Cushman, M Pommier, Y TI Differential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 and camptothecin. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Natl Canc Inst, Mol Pharmacol Lab, NIH, Bethesda, MD USA. Purdue Univ, Dept Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6113S EP 6114S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300180 ER PT J AU Koeppel, F Annereau, JP Poindessous, V Szakacs, G Gottesman, M Raymond, E Van Laar, ES Waters, SJ Tucker, J Paules, R Larsen, AK AF Koeppel, F Annereau, JP Poindessous, V Szakacs, G Gottesman, M Raymond, E Van Laar, ES Waters, SJ Tucker, J Paules, R Larsen, AK TI Acquired irofulven-resistance is associated with a unique transcriptional profile and unchanged sensitivity to other anticancer agents. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 ENS, CNRS, UMR 8113, Cachan, France. Inst Gustave Roussy, Villejuif, France. NCI, LCB, NIH, Bethesda, MD 20892 USA. Inst Gustave Roussy, Dept Med, Villejuif, France. MGI Pharma Inc, Bloomington, MN USA. NIEHS, Res Triangle Pk, NC 27709 USA. RI Szakacs, Gergely/A-2580-2009 OI Szakacs, Gergely/0000-0002-9311-7827 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6117S EP 6117S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300194 ER PT J AU Weil, RJ Schwartz, SA White, B Li, HM Moore, J Shaktour, B Larsen, P Shyr, Y Caprioli, RM AF Weil, RJ Schwartz, SA White, B Li, HM Moore, J Shaktour, B Larsen, P Shyr, Y Caprioli, RM TI High-throughput molecular diagnosis of gliomas using direct-tissue MALDI-MS analysis. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6118S EP 6119S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300200 ER PT J AU Weinstein, JN Reinhold, WC Nishizuka, S Bussey, K Kohn, KW Pommier, Y Zeeberg, B Kim, S Lababidi, S AF Weinstein, JN Reinhold, WC Nishizuka, S Bussey, K Kohn, KW Pommier, Y Zeeberg, B Kim, S Lababidi, S TI Integrating genomic, proteomic, and bioinformatic analyses for cancer drug discovery. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC ID MOLECULAR PHARMACOLOGY; EXPRESSION DATABASE; CELL-LINES; INFORMATION; PATTERNS C1 NCI, Bethesda, MD 20892 USA. NR 15 TC 0 Z9 0 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6124S EP 6124S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300225 ER PT J AU Bover, LC Holbeck, S Scudiero, DA Zurita, AJ Sausville, E Pasqualini, R Arap, W AF Bover, LC Holbeck, S Scudiero, DA Zurita, AJ Sausville, E Pasqualini, R Arap, W TI Targeting the NCI 60-cell panel by Biopanning and Rapid Analysis of Selective Interactive Ligands. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6125S EP 6125S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300230 ER PT J AU Kaur, G Belleoti, D Riccardi, E Fisher-Nielsen, K Thillanathan, J Hollingshead, M Burger, AM Sausville, EA Giavazzi, R AF Kaur, G Belleoti, D Riccardi, E Fisher-Nielsen, K Thillanathan, J Hollingshead, M Burger, AM Sausville, EA Giavazzi, R TI Anti-angiogenic effect of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG, nsc707545), a novel Hsp-90 inhibitor. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Frederick, MD 21701 USA. Mario Negri Inst Pharmacol Res, I-24100 Bergamo, Italy. SAIC, Frederick, MD USA. Sunny Brook Hosp Women, Toronto, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6139S EP 6139S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300283 ER PT J AU Isaacs, JS Jung, YJ Neckers, LM AF Isaacs, JS Jung, YJ Neckers, LM TI A novel role for ARNT in mediating Hsp90-dependent HIF-1 alpha stability. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6140S EP 6140S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300287 ER PT J AU Ng, SS Figg, WD Sparreboom, A AF Ng, SS Figg, WD Sparreboom, A TI Taxane-mediated antiangiogenesis: Influence of formulation vehicles and binding proteins. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6144S EP 6144S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300300 ER PT J AU Shailubhai, K Dheer, SK Picker, D Kaur, G Sausville, E Jacob, GS AF Shailubhai, K Dheer, SK Picker, D Kaur, G Sausville, E Jacob, GS TI Atiprimod is a novel anti-angiogenic and anti-cancer drug candidate. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Callisto Pharmaceut Inc, New York, NY USA. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6146S EP 6146S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300310 ER PT J AU Sayers, TJ Brooks, AD Onksen, J Elliott, PJ Murphy, WJ AF Sayers, TJ Brooks, AD Onksen, J Elliott, PJ Murphy, WJ TI The proteasome inhibitor VELCADE (TM) sensitizes tumor cells to TRAIL-mediated apoptosis. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Combinatorx, Boston, MA USA. NCI, SAIC Frederick, Frederick, MD USA. Univ Nevada, Reno, NV 89557 USA. RI Sayers, Thomas/G-4859-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6158S EP 6158S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300359 ER PT J AU Junji, T AF Junji, T TI Activation of the PI3K/Akt pathway by tobacco components via nicotinic acetylcholine receptors induces Akt-dependent proliferation and NFkB-dependent survival in lung cancer cells. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6175S EP 6175S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300437 ER PT J AU Wan, XL Kalburgi, S Heiman, L AF Wan, XL Kalburgi, S Heiman, L TI Effects of mTOR inhibitor, rapamycin and the ester analogue CCI-779 on rhabdomyosarcoma. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6179S EP 6179S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300454 ER PT J AU Steeg, PS Halverson, D Figg, WD Hollingshead, M Ouatas, T AF Steeg, PS Halverson, D Figg, WD Hollingshead, M Ouatas, T TI Inhibition of breast cancer metastatic outgrowth in vivo by Medroxyprogesterone acetate (MPA) as a glucocorticoid receptor agonist. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6183S EP 6183S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300468 ER PT J AU Ramanathan, RK Remick, SC Mulkerin, D Takimoto, C Doroshow, J Hamilton, A Lorusso, P Potter, D Grem, J Mani, S Venook, A Egorin, M Ivy, P Murgo, A Schran, H Hayes, M Peng, B AF Ramanathan, RK Remick, SC Mulkerin, D Takimoto, C Doroshow, J Hamilton, A Lorusso, P Potter, D Grem, J Mani, S Venook, A Egorin, M Ivy, P Murgo, A Schran, H Hayes, M Peng, B TI Pharmacokinetics (PK) of Imatinib mesylate (STI-571, Gleevec (TM)) in patients (pts) with advanced malignancies and varying degrees of liver dysfunction (LD). SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MA SP AACR, NCI, EORTC C1 Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Wisconsin, Madison, WI USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Kaplan Comprehens Canc Ctr, New York, NY USA. Wayne State Univ, Detroit, MI USA. NCI, Med Branch, Bethesda, MD 20892 USA. Weller AECOM, Bronx, NY USA. Univ Calif San Francisco, Ctr Canc, San Francisco, CA 94143 USA. Novartis Pharmaceut, E Hanover, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 1 PY 2003 VL 9 IS 16 SU S BP 6197S EP 6197S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300528 ER PT J AU Rudek, MA Zhao, M Zabelina, Y Hallur, G Khan, S Bauer, KS Colevas, AD Wolff, AC Baker, SD AF Rudek, MA Zhao, M Zabelina, Y Hallur, G Khan, S Bauer, KS Colevas, AD Wolff, AC Baker, SD TI In vitro and in vivo assessment of the metabolism of N,N-dimethylamino-benzoylphenylurea (BPU) in humans. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 SKCCC Johns Hopkins, Baltimore, MD USA. Univ Maryland, Baltimore, MD 21201 USA. NCI, CTEP, Invest Drug Branch, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6197S EP 6197S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300526 ER PT J AU Sparreboom, A Xie, R Baker, SD Wolff, AC McIntire, GL Swindell, CS Karlson, MO AF Sparreboom, A Xie, R Baker, SD Wolff, AC McIntire, GL Swindell, CS Karlson, MO TI Semi-mechanistic models for DRA-paclitaxel pharmacokinetics/pharmacodynamics. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. Uppsala Univ, Uppsala, Sweden. SKCCC Johns Hopkins, Baltimore, MD USA. Protarga Inc, King Of Prussia, PA USA. RI Sparreboom, Alex/B-3247-2008 NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6198S EP 6199S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300532 ER PT J AU Leger, F Loos, WJ Fourcade, J Bugat, R Goffinet, M Mathijssen, RH Verweij, J Chatelut, E AF Leger, F Loos, WJ Fourcade, J Bugat, R Goffinet, M Mathijssen, RH Verweij, J Chatelut, E TI Factors affecting pharmacokinetic variability of oral topotecan: A population analysis. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Inst Claudius Regaud, Toulouse, France. Erasmus MC, Dr Daniel Den Hoed Canc Ctr, Rotterdam, Netherlands. NCI, Bethesda, MD 20892 USA. RI Chatelut, Etienne/I-7916-2014 NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6199S EP 6199S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300533 ER PT J AU Ten Tije, AJ Baker, SD Dinh, M Loos, WJ Figg, WD Verweij, J Sparreboom, A AF Ten Tije, AJ Baker, SD Dinh, M Loos, WJ Figg, WD Verweij, J Sparreboom, A TI Disposition of polyoxyethylated excipients in humans: Imptications for drug safety and formulation approaches. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Erasmus MC, Rotterdam, Netherlands. Johns Hopkins Univ, Baltimore, MD USA. NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6199S EP 6199S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300534 ER PT J AU Mackay, HJ Major, P Townsley, C Mackenzie, M Vincent, M Boudreau, T Tsao, M Hedley, D Wright, J Siu, L Moore, M Oza, AM AF Mackay, HJ Major, P Townsley, C Mackenzie, M Vincent, M Boudreau, T Tsao, M Hedley, D Wright, J Siu, L Moore, M Oza, AM TI A phase II trial of the proteosome inhibitor PS-341 (Bortezomib; Velcade)in patients with metastatic colorectal cancer. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Princess Margaret Hosp Phase II Consortium, Toronto, ON, Canada. NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6201S EP 6201S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300542 ER PT J AU Westwell, AD Berry, JM Bradshaw, TD Chew, EH Matthews, CS Monks, A Schwalbe, CH Stevens, MF AF Westwell, AD Berry, JM Bradshaw, TD Chew, EH Matthews, CS Monks, A Schwalbe, CH Stevens, MF TI Phenolic oxidation products as novel antitumour agents. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Nottingham, Nottingham NG7 2RD, England. NCI, Frederick, MD 21701 USA. Aston Univ, Birmingham B4 7ET, W Midlands, England. NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6205S EP 6205S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300555 ER PT J AU Donohue, SJ Tosca, PJ Ryan, MJ Stonerook, M Grossi, IM Tomaszewski, JE AF Donohue, SJ Tosca, PJ Ryan, MJ Stonerook, M Grossi, IM Tomaszewski, JE TI Toxicologic effects of the lysyl prodrug of (4-amino-3-methylphenyl)-5-fluorobenzothiazole; lysyl 5F-BT) (NSC 710305) administered as an intravenous infusion to non-human primates. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. Battelle Mem Inst, Columbus, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6212S EP 6212S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300585 ER PT J AU Grubbs, CJ Christov, KT Luber, RA Lemon, W You, M AF Grubbs, CJ Christov, KT Luber, RA Lemon, W You, M TI Differential therapeutic effects on cell proliferation, apoptosis and RNA gene expression of the FTI inhibitor R115777 on N-methylnitrosourea induced rat mammary tumors with or without HaRas mutations. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Alabama, Birmingham, AL USA. Univ Illinois, Chicago, IL USA. NCI, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6212S EP 6212S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300584 ER PT J AU Hollingshead, MG Kaur, G Borgel, S Carter, J Fisher-Nielsen, M Thillanathan, J Borsotti, P Giavazzi, R Sausville, E AF Hollingshead, MG Kaur, G Borgel, S Carter, J Fisher-Nielsen, M Thillanathan, J Borsotti, P Giavazzi, R Sausville, E TI In vivo efficacy of PPI-2458 (NSC 720735), a novel fumagillin analog with oral bioavailability. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Frederick, MD 21701 USA. SAIC Frederick, Frederick, MD USA. Mario Negri Inst Pharmacol Res, I-24100 Bergamo, Italy. NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6213S EP 6213S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300589 ER PT J AU Borgel, SD Carter, JP Sausville, EE Hollingshead, MG AF Borgel, SD Carter, JP Sausville, EE Hollingshead, MG TI The impact of tumor location on the activity of 17-DMAG (NSC 707545), a water soluble geldanamycin analog. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 SAIC Frederick, Frederick, MD USA. NCI, Dev Therapeut Program, DCTD, Frederick, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6215S EP 6215S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300596 ER PT J AU Glaze, ER Lambert, AL Page, J Egorin, M Eiseman, J Holleran, J Tomaszewski, JE AF Glaze, ER Lambert, AL Page, J Egorin, M Eiseman, J Holleran, J Tomaszewski, JE TI Toxicity studies with 17-(Dimethylaminoethylamino)-17-demethoxygeldamnycin (17-DMAG; NSC-707545) in rats and dogs. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Rockville, MD USA. So Res Inst, Birmingham, AL USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. NR 0 TC 2 Z9 2 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6215S EP 6215S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300597 ER PT J AU Xu, F Sahni, H Setnek, S Johnson, H Gupta, A Zhang, D Beasley, J De Coronado, S Wagner, U Rosso, K Malone, C Singer, D Marks, C Tarnowski, B Buetow, K AF Xu, F Sahni, H Setnek, S Johnson, H Gupta, A Zhang, D Beasley, J De Coronado, S Wagner, U Rosso, K Malone, C Singer, D Marks, C Tarnowski, B Buetow, K TI Mouse models of human cancer web-based resources. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Ctr Bioinformat, Rockville, MD USA. NCI, Div Canc Biol, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 1 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6215S EP 6215S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300595 ER PT J AU Bonomi, CA Borgel, SD Carter, JP Melillo, G Scudiero, DA Shoemaker, RH Sausville, EA Hollingshead, MG AF Bonomi, CA Borgel, SD Carter, JP Melillo, G Scudiero, DA Shoemaker, RH Sausville, EA Hollingshead, MG TI Multi-fold improvements in tumor cell detection and drug screening sensitivity using luciferase based technology. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 SAIC Frederick, Frederick, MD USA. NCI, Dev Therapeut Program, DCTD, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6217S EP 6217S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300604 ER PT J AU Gore, L Witta, S Pierson, AS Basche, M Holden, SN O'Bryant, C Raj, S Schultz, MK Grolnic, S Persky, M Morrow, M Wright, J Eckhardt, SG AF Gore, L Witta, S Pierson, AS Basche, M Holden, SN O'Bryant, C Raj, S Schultz, MK Grolnic, S Persky, M Morrow, M Wright, J Eckhardt, SG TI A phase I study of PS-341 (P), carboplatin (C), and etoposide (E) in patients (pts) with advanced solid tumors. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. Childrens Hosp, Denver, CO 80218 USA. NCI, Invest Drug Branch, CTEP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6221S EP 6222S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300621 ER PT J AU Hotte, SJ Oza, A Winquist, EW Jasas, K Degendorfer, P Dancey, JE Hirte, HW AF Hotte, SJ Oza, A Winquist, EW Jasas, K Degendorfer, P Dancey, JE Hirte, HW TI Phase II study of topotecan (T) in combination with the novel kinase inhibitor ucUCN-01 in patients with advanced cancer. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 PMH Phase II Consortium, Toronto, ON, Canada. NCI, CTEP, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6223S EP 6223S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300627 ER PT J AU Arlen, PM Gulley, JL Parker, C Skarupa, L Pazdur, M Panicali, D Beetham, P Tsang, KY Schlom, J Dahut, WL AF Arlen, PM Gulley, JL Parker, C Skarupa, L Pazdur, M Panicali, D Beetham, P Tsang, KY Schlom, J Dahut, WL TI A randomized pilot study of concurrent docetaxel plus PSA poxvaccine versus vaccine alone in metastatic Androgen Independent Prostate Cancer (AIPC). SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Bethesda, MD 20892 USA. Therion Biol, Cambridge, MA USA. RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6226S EP 6226S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300643 ER PT J AU Khan, T Hixon, JA Stauffer, JK Lincoln, E Back, T Wigginton, JM AF Khan, T Hixon, JA Stauffer, JK Lincoln, E Back, T Wigginton, JM TI IL-12 induced regression of orthotopic neuroblastoma tumors: Potential role for reversal of intrinsic mechanisms of resistance to tumor cell apoptosis. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Pediat Oncol Branch, CCR, Frederick, MD 21701 USA. SAIC Frederick, IRSP, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6227S EP 6227S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300645 ER PT J AU Rapisarda, A Uranchimeg, B Sordet, O Pommier, Y Shoemaker, RH Melillo, G AF Rapisarda, A Uranchimeg, B Sordet, O Pommier, Y Shoemaker, RH Melillo, G TI Topoisomerase1 mediated inhibition of hypoxia inducible factor-1 (HIF-1): Mechanism and therapeutic implications. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, SAIC, Frederick, MD 21701 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6233S EP 6233S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300671 ER PT J AU Nguyen, P Lee, MJ Lee, S Lee, SJ Kang, WK Kim, SJ Zajac-Kaye, M Gentleman, S Nishioka, D Sackett, DL Trepel, JB AF Nguyen, P Lee, MJ Lee, S Lee, SJ Kang, WK Kim, SJ Zajac-Kaye, M Gentleman, S Nishioka, D Sackett, DL Trepel, JB TI The retinoblastoma protein associates with the microtubule cytoskeleton. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, NIH, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Washington, DC 20057 USA. NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6235S EP 6235S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300678 ER PT J AU Smith, V Strach, J Burger, AM Maier, A Sausville, EA Camalier, RF Fiebig, HH AF Smith, V Strach, J Burger, AM Maier, A Sausville, EA Camalier, RF Fiebig, HH TI Correlation studies of two structurally similar Hsp90 inhibitors to aid the prediction of response. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Oncotest GmbH, Freiburg, Germany. Klin Tumorbiol, Freiburg, Germany. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6235S EP 6235S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300676 ER PT J AU Chung, FJ Lee, MJ Lee, S Nguyen, P Bottaro, DP Bonvini, P Karp, JE Henkart, PA Oh, HJ Hwang, SG Rubin, JS Trepel, JB AF Chung, FJ Lee, MJ Lee, S Nguyen, P Bottaro, DP Bonvini, P Karp, JE Henkart, PA Oh, HJ Hwang, SG Rubin, JS Trepel, JB TI beta-catenin signaling regulates proliferation of peripheral lymphocytes and leukemia cells. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sydney Kimmel Canc Care, Baltimore, MD 21218 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6237S EP 6237S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300685 ER PT J AU Mimnaugh, EG Xu, WP Vos, M Neckers, LM AF Mimnaugh, EG Xu, WP Vos, M Neckers, LM TI Targeting the Hsp90 molecular chaperone while inhibiting proteasomal proteolysis promotes protein ubiquitination, produces prominent ER-derived cytosolic vacuolization and provokes additive antitumor activity. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Rockville, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6245S EP 6245S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300718 ER PT J AU Liu, ZF Zhang, YL Hua, YS Covey, JM Chan, KK AF Liu, ZF Zhang, YL Hua, YS Covey, JM Chan, KK TI In vitro and in vivo metabolism of a sulfur-containing heteroarotionoid SHetA2. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. NCI, Bethesda, MD 20892 USA. Ohio State Univ, Coll Med, Columbus, OH 43210 USA. Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. RI Liu, Zhongfa/G-8549-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6248S EP 6248S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300727 ER PT J AU Raben, D Weng, E Kane, M Song, J Meyers, A Eckhardt, G Raben, A Gollamudi, S Hu, K Harrison, L Quon, H Dancey, J AF Raben, D Weng, E Kane, M Song, J Meyers, A Eckhardt, G Raben, A Gollamudi, S Hu, K Harrison, L Quon, H Dancey, J TI Preliminary report on toxicity of a phase I trial of gefitinib (Iressa (TM)) in combination with radiation/chemotherapy for patients with locally advanced head and neck cancer (LAHNC). SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. Cristiana Hosp, Wilmington, DE USA. Monmouth Med Ctr, Longbranch, NJ USA. Beth Israel Med Ctr, New York, NY 10003 USA. Univ Penn, Philadelphia, PA 19104 USA. NCI, CTEP, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6249S EP 6249S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300731 ER PT J AU Qian, D Wang, XF Ren, MQ Kato, YH Wei, YF Zhang, L Morris, C Becker, K Fan, JS Nakanishi, O Pili, R AF Qian, D Wang, XF Ren, MQ Kato, YH Wei, YF Zhang, L Morris, C Becker, K Fan, JS Nakanishi, O Pili, R TI Histone deacetylase inhibitor MS-275 inhibits prostate tumor growth. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. NIA, Baltimore, MD 21224 USA. Nihon Schering KK, Chiba, Japan. NR 0 TC 1 Z9 1 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6255S EP 6255S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300760 ER PT J AU Jia, L Tomaszewski, JE Noker, PE Gorman, GS Yang, DJ AF Jia, L Tomaszewski, JE Noker, PE Gorman, GS Yang, DJ TI Pharmacokinetic profiling of (-)-Gossypol (NSC 726190), a novel anti-cancer agent. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, NIH, Rockville, MD USA. So Res Inst, Birmingham, AL 35255 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6260S EP 6260S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300777 ER PT J AU Wang, H Li, M Covey, JM Stinson, S Veley, K Grossi, I Peggins, J Hill, DL Zhang, RW AF Wang, H Li, M Covey, JM Stinson, S Veley, K Grossi, I Peggins, J Hill, DL Zhang, RW TI Stability, plasma protein binding, and preclinical pharmacokinetics of adaphostin (NSC 680410), a tyrphostin analog that inhibits bcr/abl. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Univ Alabama, Birmingham, AL 35294 USA. NCI, Bethesda, MD 20892 USA. Battelle Mem Inst, Columbus, OH USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6260S EP 6261S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300779 ER PT J AU Yao, ZS Dai, WL Perry, J Brechbiel, MW Sung, C Sung, C AF Yao, ZS Dai, WL Perry, J Brechbiel, MW Sung, C Sung, C TI Effect of albumin fusion on the biodistribution of interleukin-2 SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Human Genome Sci Inc, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6260S EP 6260S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300778 ER PT J AU Gelderblom, H Marsh, S Verweij, J Obach, R Principe, P Sparreboom, A McLeod, H AF Gelderblom, H Marsh, S Verweij, J Obach, R Principe, P Sparreboom, A McLeod, H TI Diflomotecan (BN80915) pharmacokinetics in relation to ABCG2 (BCRP) genotype. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 Leiden Univ, Med Ctr, Leiden, Netherlands. Washington Univ, Sch Med, St Louis, MO 63130 USA. Dr Daniel Den Hoed Canc Ctr, Erasmus MC, NL-3008 AE Rotterdam, Netherlands. Ipsen Pharma Int, Paris, France. NCI, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008 NR 0 TC 0 Z9 0 U1 0 U2 2 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6264S EP 6265S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300795 ER PT J AU Shevach, E AF Shevach, E TI Activation and deactivation of regulatory T cell function. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6271S EP 6272S PN 2 PG 2 WC Oncology SC Oncology GA 756LU UT WOS:000187467300815 ER PT J AU Neckers, LM AF Neckers, LM TI The molecular chaperone HSP90 is a novel anticancer target. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6272S EP 6272S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300816 ER PT J AU Dennis, PA AF Dennis, PA TI Update on the development of phosphatidylinositol ether lipid analogues as rationally designed Akt inhibitors. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6277S EP 6277S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300828 ER PT J AU Grochow, LB AF Grochow, LB TI Clinical trials with pharmacodynamic goals: What's been tried, what's been proposed, and what needs to be tested. SO CLINICAL CANCER RESEARCH LA English DT Meeting Abstract CT AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics CY NOV 17-21, 2003 CL BOSTON, MASSACHUSETTS SP AACR, NCI, EORTC C1 NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 DEC 1 PY 2003 VL 9 IS 16 SU S BP 6278S EP 6278S PN 2 PG 1 WC Oncology SC Oncology GA 756LU UT WOS:000187467300832 ER PT J AU Prinz, RJ Feerick, MM AF Prinz, RJ Feerick, MM TI Children exposed to community violence or war/terrorism: Current status and research directions - Introduction SO CLINICAL CHILD AND FAMILY PSYCHOLOGY REVIEW LA English DT Editorial Material DE community violence; war; terrorism; children AB This issue of Clinical Child and Family Psychology Review, "Children Exposed to Community Violence or War/Terrorism: Current Status and Research Directions," addresses the current status of our knowledge as well as critical research needs in the area of children exposed to violence outside the family. Although much has been learned in recent years about children exposed to violence, significant research gaps remain, the identification of which may help to build a more complete and rigorous science base in this area. This journal issue represents the distillation of a 3-day workshop on children exposed to violence, held in July of 2002, that identified what is known about children exposed to violence and what this information tells us about future research directions. Although many federal agencies have supported some research in this area, there is a need for more targeted attention on the topic, particularly with regard to measurement, sampling, and interventions/services. The papers in this issue were selected with these themes in mind. Although no single issue could cover the entire field, we intend to offer a representative sample of where we are and where we need to go with the hope of stimulating additional thought, collaboration, and research in this important area. C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. Univ S Carolina, Columbia, SC 29208 USA. RP Feerick, MM (reprint author), NICHHD, Child Dev & Behav Branch, Room 4B05,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. NR 0 TC 8 Z9 8 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1096-4037 J9 CLIN CHILD FAM PSYCH JI Clin. Child Fam. Psychol. Rev. PD DEC PY 2003 VL 6 IS 4 BP 221 EP 222 DI 10.1023/B:CCFP.0000006339.77210.cb PG 2 WC Psychology, Clinical SC Psychology GA 749EM UT WOS:000186905900001 ER PT J AU Feerick, MM Prinz, RJ AF Feerick, MM Prinz, RJ TI Next steps in research on children exposed to community violence or war/terrorism SO CLINICAL CHILD AND FAMILY PSYCHOLOGY REVIEW LA English DT Editorial Material DE community violence; war; terrorism; children AB The articles in this special issue of Clinical Child and Family Psychology Review provide an overview of what is known about children's exposure to community violence and war/terrorism, and indicate significant gaps in extant research. These gaps and research needs are summarized in this conclusion. C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. Univ S Carolina, Columbia, SC 29208 USA. RP Feerick, MM (reprint author), NICHHD, Child Dev & Behav Branch, Room 4B05,6100 Execut Blvd,MSC 7510, Bethesda, MD 20892 USA. NR 0 TC 17 Z9 17 U1 0 U2 0 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1096-4037 J9 CLIN CHILD FAM PSYCH JI Clin. Child Fam. Psychol. Rev. PD DEC PY 2003 VL 6 IS 4 BP 303 EP 305 DI 10.1023/B:CCFP.0000006296.19932.c3 PG 3 WC Psychology, Clinical SC Psychology GA 749EM UT WOS:000186905900008 PM 14719641 ER PT J AU Anderson-Cohen, M Holland, SM Kuhns, DB Fleisher, TA Ding, L Brenner, S Malech, HL Roesler, J AF Anderson-Cohen, M Holland, SM Kuhns, DB Fleisher, TA Ding, L Brenner, S Malech, HL Roesler, J TI Severe phenotype of chronic granulomatous disease presenting in a female with a de novo mutation in gp91-phox and a non familial, extremely skewed X chromosome inactivation SO CLINICAL IMMUNOLOGY LA English DT Article DE NADPH-oxidase; CGD; chronic granulomatous disease; carrier; mutation; gp91-phox; X chromosome; inactivation; skewed; dihydrorhodamine ID DISCOID LUPUS-ERYTHEMATOSUS; MOLECULAR-BASIS; NADPH-OXIDASE; CYTOCHROME-B; XIST GENE; INCREASED SUSCEPTIBILITY; POINT MUTATION; CARRIER; LYONIZATION; DEFICIENCY AB Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from defects in the multienzyme complex NADPH-oxidase (phagozyte oxidase, phox), which normally produces microbicidal reactive oxygen metabolites (ROM). The reason for our patient's CGD was unusual, as revealed by the following in vitro findings in neutrophils and EBV-transformed B-cells: lack of flavocytochrome b(558) expression, restoration of significant ROM production after transduction with gp91-phox cDNA by a retrovirus vector, an 879G-->A, Trp289-->Stop mutation in one X chromosomal gp91-phox allele, a one-sided paternal X chromosome inactivation, as shown by a lyonization assay at the HUMARA locus, and the result of a dibydrorhodamine 123 flow cytometry assay revealing consistently that I in 2500 neutrophils produced ROM at normal levels. Our conclusion: A presumed autosomal form of CGD has been excluded. Instead, a spontaneous mutation in gp91-phox coinciding with an extreme X chromosome inactivation ratio resulted in X-linked CGD in this young woman. (C) 2003 Elsevier Inc. All rights reserved. C1 NIAID, Host Def Lab, Dept Lab Med, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Clin Carl Gustav Carus, Dept Pediat, Dresden, Germany. RP Roesler, J (reprint author), Univ Klinikum Carl Gustav Carus, Kinderklin, Senefelderstr 2-4, D-01307 Dresden, Germany. RI Brenner, Sebastian/D-7456-2013; OI Malech, Harry/0000-0001-5874-5775 NR 58 TC 34 Z9 35 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD DEC PY 2003 VL 109 IS 3 BP 308 EP 317 DI 10.1016/j.clim.2003.08.002 PG 10 WC Immunology SC Immunology GA 756XM UT WOS:000187511100008 PM 14697745 ER PT J AU Henn, FA Lipska, BK AF Henn, FA Lipska, BK TI Animal models for psychiatric disorders - Foreword SO CLINICAL NEUROSCIENCE RESEARCH LA English DT Editorial Material C1 Univ Mannheim, Cent Inst Mental Hlth, D-68072 Mannheim, Germany. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,IRP, Bethesda, MD 20892 USA. RP Henn, FA (reprint author), Univ Mannheim, Cent Inst Mental Hlth, Postfach 12 21 20, D-68072 Mannheim, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1566-2772 J9 CLIN NEUROSCI RES JI Clin. Neurosci. Res. PD DEC PY 2003 VL 3 IS 4-5 BP 221 EP 222 DI 10.1016/S1566-2772(03)00083-5 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 756JH UT WOS:000187461600001 ER PT J AU Lipska, BK AF Lipska, BK TI A neonatal hippocampal disconnection model; testing a neurodevelopmental hypothesis of schizophrenia SO CLINICAL NEUROSCIENCE RESEARCH LA English DT Article DE hippocarnpus; prefrontal cortex; schizophrenia; doparnine; glutamate; neurodevelopment ID MK-801-INDUCED MOTOR HYPERACTIVITY; RAT VENTRAL HIPPOCAMPUS; PREFRONTAL CORTEX; ADULT RATS; STRIATAL DOPAMINE; NUCLEUS-ACCUMBENS; PREPULSE INHIBITION; N-ACETYLASPARTATE; SOCIAL-BEHAVIOR; IBOTENIC ACID AB In a series of studies, we have shown that neonatal excitotoxic disconnection of the rat ventral hippocampus (VH) may serve as a heuristic model of schizophrenia. The model mimics a spectrum of neurobiological and behavioral features of schizophrenia. It produces functional pathology in critical brain regions implicated in schizophrenia and connected with the hippocampal formation-the striatum/nucleus accumbens and the prefrontal cortex. These brain regions are also targeted by antipsychotic drugs. Neonatal insult leads in young adulthood to the emergence of abnormalities in a number of dopamine related behaviors. It also models some of the negative aspects of schizophrenia, such as social impairments and working memory deficits. Moreover, our data show that even transient inactivation of the VH during a critical period of development that produces subtle anatomical changes in the hippocampus, may be sufficient to trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. The results of BrdU incorporation studies show that this transient disconnection in the CA1 and Ca2 area of the hippocampus may have long lasting consequences for the neurogenesis in the dentate gyrus. Our data suggest that neonatal disconnection of the VH alters development and plasticity of prefrontal cortical circuitry and produces a constellation of behavioral and cellular changes that mimic many aspects of schizophrenia. The neonatal hippocampal disconnection model represents a potential new model of schizophrenia without a gross anatomical lesion. (C) 2003 Elsevier B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,IRP, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), 10 Ctr Dr,Bldg 10,Room 4N306, Bethesda, MD 20892 USA. NR 51 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1566-2772 J9 CLIN NEUROSCI RES JI Clin. Neurosci. Res. PD DEC PY 2003 VL 3 IS 4-5 BP 283 EP 287 DI 10.1016/S1566-2772(03)00097-5 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 756JH UT WOS:000187461600009 ER PT J AU Nguyen, JD Carrasquillo, JA Little, RF Ryan, QC Wilson, W Chen, CC AF Nguyen, JD Carrasquillo, JA Little, RF Ryan, QC Wilson, W Chen, CC TI Fluorodeoxyglucose positron emission tomography in the presence of cardiac metastases SO CLINICAL NUCLEAR MEDICINE LA English DT Editorial Material DE positron emission tomography (PET); F-18 fluorodeoxyglucose (FDG); cardiac metastasis; melanoma; lymphoma ID F-18 FDG PET; PITFALLS; THROMBUS C1 Warren Grant Magnuson Clin Ctr, Dept Nucl Med 10 1C401, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Med Oncol Clin Res Unit, NIH, Bethesda, MD 20892 USA. RP Chen, CC (reprint author), Warren Grant Magnuson Clin Ctr, Dept Nucl Med 10 1C401, NIH, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 5 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0363-9762 J9 CLIN NUCL MED JI Clin. Nucl. Med. PD DEC PY 2003 VL 28 IS 12 BP 979 EP 980 DI 10.1097/01.rlu.0000099808.30653.06 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 746WR UT WOS:000186771100007 PM 14663321 ER PT J AU Miller, FG AF Miller, FG TI Ethical issues in research with healthy volunteers: Risk-benefit assessment SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID CLINICAL-RESEARCH C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 14 TC 12 Z9 12 U1 2 U2 7 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD DEC PY 2003 VL 74 IS 6 BP 513 EP 515 DI 10.1016/j.clpt.2003.08.006 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 752BC UT WOS:000187125700002 PM 14663453 ER PT J AU Gallagher-Thompson, D Haley, W Guy, D Rupert, M Arguelles, T Zeiss, LM Long, C Tennstedt, S Ory, M AF Gallagher-Thompson, D Haley, W Guy, D Rupert, M Arguelles, T Zeiss, LM Long, C Tennstedt, S Ory, M TI Tailoring psychological interventions for ethnically diverse dementia caregivers SO CLINICAL PSYCHOLOGY-SCIENCE AND PRACTICE LA English DT Review DE dementia; intervention; caregivers; caregiving; ethnicity; diversity ID CUBAN-AMERICAN ELDERS; FAMILY CAREGIVERS; ALZHEIMERS-DISEASE; AFRICAN-AMERICAN; CULTURAL-DIFFERENCES; HISPANIC CAREGIVERS; SERVICE UTILIZATION; OLDER ADULTS; WHITE; REACH AB Alzheimer's disease and other dementias are common disorders that widely, affect older adults of all races and ethnicities. Although there has been considerable research focusing on the stress experienced by family caregivers of patients with dementia, there has been little work to guide clinicians in tailoring interventions to the special needs of racially and ethnically diverse families. This paper reviews guidelines for creating culturally competent interventions, as well as reviewing the literature on racial, ethnic, and cultural differences in the stress associated with caregiving for a family member with dementia. The paper then presents three intervention programs (adapted from existing treatments) that were tailored to be sensitive to cultural issues in caregiving among African Americans, Cuban Americans, and Mexican Americans. Results and directions for future research gathered from these intervention programs are presented and implications for clinicians and researchers are discussed. C1 Stanford Univ, Sch Med, Menlo Pk, CA 94025 USA. VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. Univ S Florida, Tampa, FL 33620 USA. Univ Alabama, Birmingham, AL USA. Univ Miami, Sch Med, Coral Gables, FL 33124 USA. New England Res Inst, Watertown, MA 02172 USA. NIA, Bethesda, MD 20892 USA. RP Gallagher-Thompson, D (reprint author), Vet Affairs Med Ctr, Older Adult & Family Ctr, 795 Willow Rd 182C-MP, Menlo Pk, CA 94025 USA. NR 121 TC 29 Z9 29 U1 3 U2 13 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0969-5893 J9 CLIN PSYCHOL-SCI PR JI Clin. Psychol.-Sci. Pract. PD WIN PY 2003 VL 10 IS 4 BP 423 EP 438 DI 10.1093/clipsy/bpg042 PG 16 WC Psychology, Clinical SC Psychology GA 751HE UT WOS:000187059200003 ER PT J AU Wood, CM McDonald, MD Sundin, L Laurent, P Walsh, PJ AF Wood, CM McDonald, MD Sundin, L Laurent, P Walsh, PJ TI Pulsatile urea excretion in the gulf toadfish: mechanisms and controls SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY LA English DT Article; Proceedings Paper CT Symposium on Function of Marine Organisms: Mechanisms of Adaption to Diverse Environments CY FEB 22-23, 2003 CL TOKYO, JAPAN DE ammonia; ornithine urea cycle; glutamine; AVT; UT-A; facilitated diffusion; serotonin; 5-hydroxytryptamine; cortisol; vesicular trafficking; pavement cells ID MEDULLARY COLLECTING DUCT; MINERALOCORTICOID-LIKE RECEPTOR; CYCLE ENZYME-ACTIVITY; TELEOST OPSANUS-BETA; LAKE MAGADI TILAPIA; NITROGEN-METABOLISM; WATER PERMEABILITY; RAINBOW-TROUT; CARDIORESPIRATORY PHYSIOLOGY; MOLECULAR CHARACTERIZATION AB Opsanus beta expresses a full complement of ornithine-urea cycle (OUC) enzymes and is facultatively ureotelic, reducing ammonia-N excretion and maintaining urea-N excretion under conditions of crowding/confinement. The switch to ureotelism is keyed by a modest rise in cortisol associated with a substantial increase in cytosolic glutamine synthetase for trapping of ammonia-N and an upregulation of the capacity of the mitochondrial OUC to use glutamine-N. The entire day's urea-N production is excreted in 1 or 2 short-lasting pulses, which occur exclusively through the gills. The pulse event is not triggered by an internal urea-N threshold, is not due to pulsatile urea-N production, but reflects pulsatile activation of a specific branchial excretion mechanism that rapidly clears urea-N from the body fluids. A bidirectional facilitated diffusion transporter, with pharmacological similarity to the UT-A type transporters of the mammalian kidney, is activated in the gills, associated with an increased trafficking of dense-cored vesicles in the pavement cells. An 1814 kB cDNA ('tUT') coding for a 475-amino acid protein with approximately 62% homology to mammalian UT-A's has been cloned and facilitates phloretin-sensitive urea transport when expressed in Xenopus oocytes. tUT occurs only in gill tissue, but tUT mRNA levels do not change over the pulse cycle, suggesting that tUT regulation occurs at a level beyond mRNA. Circulating cortisol levels consistently decline prior to a pulse event and rise thereafter. When cortisol is experimentally clamped at high levels, natural pulse events are suppressed in size but not in frequency, an effect mediated through glucocorticoid receptors. The cortisol decline appears to be permissive, rather than the actual trigger of the pulse event. Fluctuations in circulating AVT levels do not correlate with pulses; and injections of AVT (at supraphysiological levels) elicit only minute urea-N pulses. However, circulating 5-hydroxytryptamine (5-HT) levels fluctuate considerably and physiological doses of 5-HT cause large urea-N pulse events. When the efferent cranial nerves to the gills are sectioned, natural urea pulse events persist, suggesting that direct motor output from the CNS to the gill is not the proximate control. (C) 2003 Elsevier Science Inc. All rights reserved. C1 McMaster Univ, Dept Biol, Hamilton, ON L8S 4K1, Canada. Univ Miami, Div Marine Biol & Fisheries, Rosenstiel Sch Marine & Atmospher Sci, NIEHS,Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Univ Gothenburg, Dept Zoophysiol, SE-40530 Gothenburg, Sweden. CNRS, Dept Morphol Fonct & Ultrastruct Adaptat, F-67087 Strasbourg, France. RP Wood, CM (reprint author), McMaster Univ, Dept Biol, 1280 Main St W, Hamilton, ON L8S 4K1, Canada. NR 100 TC 40 Z9 40 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1096-4959 J9 COMP BIOCHEM PHYS B JI Comp. Biochem. Physiol. B-Biochem. Mol. Biol. PD DEC PY 2003 VL 136 IS 4 BP 667 EP 684 DI 10.1016/S1096-4959(03)00169-6 PG 18 WC Biochemistry & Molecular Biology; Zoology SC Biochemistry & Molecular Biology; Zoology GA 755AV UT WOS:000187366400008 PM 14662293 ER PT J AU Thigpen, JE Haseman, JK Saunders, HE Setchell, KDR Grant, MG Forsythe, DB AF Thigpen, JE Haseman, JK Saunders, HE Setchell, KDR Grant, MG Forsythe, DB TI Dietary phytoestrogens accelerate the time of vaginal opening in immature CD-1 mice SO COMPARATIVE MEDICINE LA English DT Article ID ENDOCRINE-DISRUPTING CHEMICALS; MOUSE UTEROTROPHIC ASSAY; RODENT DIETS; ESTROGENIC ACTIVITY; MAMMARY-CANCER; EDSTAC RECOMMENDATIONS; PREPUBERTAL EXPOSURES; SEXUAL DEVELOPMENT; BISPHENOL-A; GENISTEIN AB The purpose of the study reported here was to determine the effects of dietary phytoestrogens on the time of vaginal opening (VO) in immature CD-1 mice, and to correlate it with phytoestrogen and total metabolizable energy (ME) contents of the diet in an effort to determine the most appropriate diets(s) for comparing or evaluating the estrogenic or antiestrogenic activity of endocrine disruptor compounds (EDC). Mice were weaned at postnatal day (PND) 15 and fed the test diets from PND 15 to 30. Vaginal opening was recorded from PND 20 to 30. The phytoestrogen content of the diet was highly predictive (P < 0.0001) of the proportion of mice with VO at PND 24. Total ME content also was significantly (P < 0.01) correlated with time of VO, although this variable was somewhat less predictive than was phytoestrogen content. Time of VO in mice was significantly (P < 0.05) accelerated in mice fed diets high in phytoestrogens, compared with those containing low phytoestrogen content. It was concluded that: dietary daidzein and genistein can significantly (P < 0.01) accelerate the time of VO in CD-1 mice; the advancement in time of VO is more highly correlated with daidzein and genistein contents of the diets than with total ME content; advancement in the time of VO is a sensitive end point for evaluating the estrogenic activity of EDCs, and should be part of the standard protocol for evaluating EDCs. Phytoestrogen-free diet(s) containing the same amount of ME should be used in bioassays that compare the time of VO, or increases in uterine weight as end points for evaluating the estrogenic activity of an EDC. C1 NIEHS, Qual Assurance Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. RP Thigpen, JE (reprint author), NIEHS, Qual Assurance Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 52 TC 42 Z9 44 U1 0 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD DEC PY 2003 VL 53 IS 6 BP 607 EP 615 PG 9 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 763DF UT WOS:000188057800004 PM 14727808 ER PT J AU Oh, CK Jo, JH Jang, HS Kim, MB Kwon, YW Kwon, KS AF Oh, CK Jo, JH Jang, HS Kim, MB Kwon, YW Kwon, KS TI An unusual case of mercurial baboon syndrome from metallic mercury in a broken industrial barometer SO CONTACT DERMATITIS LA English DT Editorial Material DE baboon syndrome; barometer; mercury; patch test ID EXANTHEM C1 Pusan Natl Univ, Coll Med, Dept Dermatol, Pusan 602739, South Korea. NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Oh, CK (reprint author), Pusan Natl Univ, Coll Med, Dept Dermatol, 1-10 Ami Dong, Pusan 602739, South Korea. EM ckoh@pusan.ac.kr NR 12 TC 4 Z9 5 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-1873 J9 CONTACT DERMATITIS JI Contact Dermatitis PD DEC PY 2003 VL 49 IS 6 BP 309 EP 310 DI 10.1111/j.0105-1873.2003.0251e.x PG 2 WC Allergy; Dermatology SC Allergy; Dermatology GA 810YX UT WOS:000220740700013 PM 15025708 ER PT J AU Collins, JF Egan, D Yusuf, S Garg, R Williford, WO Geller, N AF Collins, JF Egan, D Yusuf, S Garg, R Williford, WO Geller, N CA DIG Investigators TI Overview of the DIG trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE large simple trial; digoxin; heart failure; randomized clinical trial ID CONGESTIVE-HEART-FAILURE; DIGOXIN; WITHDRAWAL; DIGITALIS AB Congestive heart failure is a major public health problem in the United States, Canada, and other Western countries. The Digitalis Investigation Group (DIG) trial was a randomized, double-blind placebo-controlled trial that evaluated the effects of digoxin on all-cause mortality and on hospitalization for heart failure in patients with heart failure and left ventricular ejection fraction less than or equal to0.45 with normal sinus rhythm. It was designed as a large simple trial. There were 6800 patients entered into the main study over a 31.5-month recruitment period at 302 participating centers in the United States and Canada. All patients were followed for a minimum of 28 months. In order for this study to succeed, many groups had to work together successfully. In this supplement, we present practical aspects of organizing and conducting a large simple trial such as DIG. (C) 2003 Elsevier Inc. All rights reserved. C1 Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, Perry Point, MD 21902 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. NHLBI, Bethesda, MD 20892 USA. Hamilton Gen Hosp, Hamilton, ON, Canada. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Collins, JF (reprint author), Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, POB 1010, Perry Point, MD 21902 USA. NR 13 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 269S EP 276S DI 10.1016/S0197-2456(03)00104-1 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100001 PM 14643073 ER PT J AU Williford, WO Collins, JF Homey, A Kirk, G McSherry, F Spence, E Stinnett, S Howell, CL Garg, R Egan, D Yusuf, S AF Williford, WO Collins, JF Homey, A Kirk, G McSherry, F Spence, E Stinnett, S Howell, CL Garg, R Egan, D Yusuf, S CA DIG Investigators TI The role of the data coordinating center in the DIG trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE data coordinating center; large simple trial; digoxin; heart failure; randomized clinical trial ID DIGOXIN AB The Digitalis Investigation Group (DIG) trial was a large simple trial (LST) begun in 1990 as a collaboration between the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP). Its primary objective was to determine whether digitalis had beneficial, harmful, or no effect on total mortality in patients with congestive heart failure and an ejection fraction less than or equal to0.45. The Perry Point VA CSP Coordinating Center served as the trial's data coordinating center (DCC). The DCC was involved in all phases of the study from planning and design, organization and start-up, and patient recruitment and follow-up through closeout, final analyses, and manuscript preparation. While DCC responsibilities for an LST are basically the same as for other multicenter randomized clinical trials, their size and the inclusion of many inexperienced research sites can add a complexity that the DCC must be prepared to handle from the beginning. This paper describes the role of the DCC in the DIG trial. (C) 2003 Elsevier Inc. All rights reserved. C1 Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, VA Med Ctr, Perry Point, MD 21902 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. NHLBI, Bethesda, MD 20892 USA. Hamilton Gen Hosp, Div Cardiol, Hamilton, ON, Canada. RP Williford, WO (reprint author), Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, VA Med Ctr, POB 1010, Perry Point, MD 21902 USA. NR 7 TC 3 Z9 3 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 277S EP 288S DI 10.1016/S0197-2456(03)00103-X PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100002 PM 14643074 ER PT J AU Fye, CL Gagne, WH Raisch, DW Jones, MS Sather, MR Buchanan, SL Chacon, FR Garg, R Yusuf, S Williford, WO AF Fye, CL Gagne, WH Raisch, DW Jones, MS Sather, MR Buchanan, SL Chacon, FR Garg, R Yusuf, S Williford, WO CA DIG Investigators TI The role of the pharmacy coordinating center in the DIG trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE large simple trial; randomized clinical trial; digoxin; heart failure; pharmacy coordinating center AB Large simple trials (LSTs) emerged in response to the need for large sample sizes to answer important clinical questions in which treatments have a moderate effect on clinical endpoints. Between 1991 and 1996 the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs (VA) Cooperative Studies Program conducted an LST entitled "Digitalis Investigation Group (DIG): Trial to Evaluate the Effect of Digitalis on Mortality in Heart Failure." The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center served as the DIG pharmacy coordinating center (PCC). As a direct result of involvement in the DIG trial, the PCC identified the need for an increased emphasis on computerization and automated support of clinical trials, especially LSTs. (C) 2003 Elsevier Inc. All rights reserved. C1 Clin Res Pharm Coordinat Ctr, VA Cooperat Studies Program, Albuquerque, NM 87106 USA. NHLBI, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. McMaster Clin, Hamilton, ON, Canada. VA Med Ctr, Cooperat Studies Program Coordinating Ctr, Perry Point, MD USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Fye, CL (reprint author), Clin Res Pharm Coordinat Ctr, VA Cooperat Studies Program, 2401 Ctr Ave SE, Albuquerque, NM 87106 USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 289S EP 297S DI 10.1016/S0197-2456(03)00102-8 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100003 PM 14643075 ER PT J AU Collins, JE Martin, S Kent, E Liuni, C Garg, R Egan, D AF Collins, JE Martin, S Kent, E Liuni, C Garg, R Egan, D CA DIG Investigators TI The use of regional coordinating centers in large clinical trials: the DIG trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE randomized clinical trials; large simple trial; heart failure; digoxin; regional coordinating centers AB The Digitalis Investigation Group (DIG) trial was a large simple clinical trial that involved 302 participating centers in the United States and Canada. In order to encourage participation by Canadian investigators, to provide additional help to what were expected to be largely research-inexperienced investigators in Canada, and to provide the study's data coordinating center with resources in Canada to deal with potentially different rules, regulations, and cultural differences, regional coordinating centers were established in four regions of Canada: the maritime provinces, Quebec, Ontario, and western Canada. Canadian centers recruited significantly better than their U.S. counterparts and had slightly better retention and follow-up. While it is not possible to declare that the regional coordinating centers were responsible for this improvement, it is believed that these regional centers did play a role. This role included being able to identify investigators who could be expected to do well, providing one-on-one training and instruction to investigators, and being able to solve problems and implement change in the relatively fewer centers in their regions. The regional coordinating center also reduced the intensity of the workload on the data coordinating center by serving as the primary point of contact for Canadian investigators. The use of regional coordinating centers in studies with a large number of participating centers is highly recommended. (C) 2003 Elsevier Inc. All rights reserved. C1 Cooperat Studies Program Coordinating Ctr, VA Maryland Hlth Care Syst, Dept Vet Affairs, Perry Point, MD 21902 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ Alberta, Edmonton, AB, Canada. St Josephs Hosp, Hamilton, ON, Canada. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. Eli Lilly & Co, Indianapolis, IN 46285 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Collins, JE (reprint author), Cooperat Studies Program Coordinating Ctr, VA Maryland Hlth Care Syst, Dept Vet Affairs, POB 1010, Perry Point, MD 21902 USA. NR 3 TC 9 Z9 9 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 298S EP 305S DI 10.1016/S0197-2456(03)00101-6 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100004 PM 14643076 ER PT J AU Collins, JF Garg, R Teo, KK Williford, WO Howell, CL AF Collins, JF Garg, R Teo, KK Williford, WO Howell, CL CA DIG Investigators TI The role of the data coordinating center in the IRB review and approval process: the DIG trial experience SO CONTROLLED CLINICAL TRIALS LA English DT Article DE data coordinating center responsibilities; institutional review boards; OHRP; patient rights; patient safety AB Before any clinical trial can begin to recruit patients, participating clinical centers must obtain approval from their institutional review board (IRB). When studies are federally funded, such as by the U.S. Department of Health and Human Services (DHHS), centers must also have or obtain a federal compliance agreement from the Office of Human Research Protections (formerly the Office for Protection from Research Risks [OPRR]). The Digitalis Investigation Group trial was a large, international, double-blind, DHHS-funded randomized trial on the effect of digoxin on mortality in heart failure. Due to the anticipated number of centers (>200), the study's data coordinating center (DCC) was requested to assume additional responsibilities that included: (1) acting as a liaison between the OPRR and all study centers; (2) reviewing and correcting all assurance statements before submission to the OPRR; (3) reviewing and approving all centers' informed consent forms; and (4) helping the many research-inexperienced centers to establish IRBs or to locate an IRB in their region that would accept IRB responsibility for them. Although a heavy burden was placed on the DCC, the IRB and OPRR approval process was probably shortened by many weeks at those centers not already possessing a federal compliance agreement. This enabled the study to be completed on schedule and within budget. (C) 2003 Elsevier Inc. All rights reserved. C1 Cooperat Studies Program Coordinat Ctr, Dept Vet Affairs, Perry Point, MD USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. NHLBI, Rockville, MD USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Alberta Hosp, Edmonton, AB T6G 2B7, Canada. RP Collins, JF (reprint author), Cooperat Studies Program Coordinat Ctr, Dept Vet Affairs, POB 1010, Perry Point, MD USA. NR 10 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 306S EP 315S DI 10.1016/S0197-2456(03)00100-4 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100005 PM 14643077 ER PT J AU Egan, D Geller, N Yusuf, S Garg, R Collins, JF Mathew, J Philbin, E AF Egan, D Geller, N Yusuf, S Garg, R Collins, JF Mathew, J Philbin, E CA DIG Investigators TI Lessons learned from the DIG trial SO CONTROLLED CLINICAL TRIALS LA English DT Article DE large simple trial; digitalis; trial conduct; lessons learned; clinical trial organizational structures ID HEART-FAILURE; MORTALITY AB The Digitalis Investigation Group (DIG) trial was the first large simple trial conducted by the National Heart, Lung, and Blood Institute in conjunction with the Department of Veterans Affairs. A large simple trial is a major undertaking. Simplification at the sites requires careful planning and discipline. Lessons learned from the DIG trial were: (1) keep a large simple trial very simple and keep all study procedures very simple; (2) ancillary studies are important and can complement a large simple trial but require careful advanced planning; (3) anticipate special needs when shipping study drugs internationally; (4) regional coordinating centers can be very useful; (5) recruit as many capable sites as possible; (6) provide research-inexperienced sites/investigators with extra help to obtain federalwide assurance statements from the Office for Human Research Protections and institutional review board approvals; (7) adequately reimburse sites for the work completed; (8) maintain investigator enthusiasm; (9) monitor the slow performers and sites with numerous personnel changes; (10) choose an endpoint that is easy to ascertain; (11) keep the trial simple for participants; and (12) plan early for closeout and for activities between the end of the trial and publication of results. (C) 2003 Elsevier Inc. All rights reserved. C1 NHLBI, Bethesda, MD 20892 USA. Hamilton Gen Hosp, Hamilton, ON, Canada. Eli Lilly & Co, Indianapolis, IN 46285 USA. Cooperat Studies Program, Dept Vet Affairs, Perry Point, MD USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Univ Iowa, Coll Med, Dept Med, Iowa City, IA 52242 USA. Wissonsin Heart & Vasc Clin, Milwaukee, WI USA. Albany Med Coll, Div Cardiol, Albany, NY 12208 USA. RP Egan, D (reprint author), 4400 Everett St, Kensington, MD 20895 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 2003 VL 24 IS 6 SU S BP 316S EP 326S DI 10.1016/S0197-2456(03)00099-0 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 754HY UT WOS:000187311100006 PM 14643078 ER PT J AU Minneci, PC Deans, KJ Banks, SM Gerstenberger, E Danner, RL Eichacker, PQ Natanson, C Solomon, SB AF Minneci, PC Deans, KJ Banks, SM Gerstenberger, E Danner, RL Eichacker, PQ Natanson, C Solomon, SB TI Effects of epinephrine, norepinephrine, and vasopressin on survival rates in a canine model of septic shock SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 33rd Critical Care Congress of the Society-of-Critical-Care-Medicine CY FEB 20-25, 2004 CL ORLANDO, FLORIDA SP Soc Critical Care Med C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. MGH, Dept Surg, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2003 VL 31 IS 12 SU S MA 179 BP A47 EP A47 PN 2 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 758LW UT WOS:000187636500169 ER PT J AU Minneci, PC Deans, KJ Banks, SM Eichacker, PQ Natanson, C AF Minneci, PC Deans, KJ Banks, SM Eichacker, PQ Natanson, C TI Dose dependent effects of steroids on survival rates and shock during sepsis: A meta-analysis SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 33rd Critical Care Congress of the Society-of-Critical-Care-Medicine CY FEB 20-25, 2004 CL ORLANDO, FLORIDA SP Soc Critical Care Med C1 MGH, Dept Surg, Boston, MA USA. NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2003 VL 31 IS 12 SU S MA 77 BP A20 EP A20 PN 2 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 758LW UT WOS:000187636500075 ER PT J AU Umbarger, LA Ognibene, FP Slonim, AD Johnson, CW Miyasaki, AY Leduc, JR AF Umbarger, LA Ognibene, FP Slonim, AD Johnson, CW Miyasaki, AY Leduc, JR TI Does transfusion in the adult ICU affect longterm mortality? SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 33rd Critical Care Congress of the Society-of-Critical-Care-Medicine CY FEB 20-25, 2004 CL ORLANDO, FLORIDA SP Soc Critical Care Med C1 NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Kaiser Permanente, Crit Care Unit, Honolulu, HI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2003 VL 31 IS 12 SU S MA 256 BP A70 EP A70 PN 2 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 758LW UT WOS:000187636500248 ER PT J AU Miranda, J Nakamura, R Bernal, G AF Miranda, J Nakamura, R Bernal, G TI Including ethnic minorities in mental health intervention research: A practical approach to a long-standing problem SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE mental health treatments; minority mental health ID CROSS-NATIONAL EPIDEMIOLOGY; RANDOMIZED CONTROLLED-TRIAL; UNITED-STATES; PERCEIVED DISCRIMINATION; PSYCHIATRIC-DISORDERS; INFANT-MORTALITY; PRIMARY-CARE; DEPRESSION; COMMUNITY; PREVALENCE AB This paper examines a controversy that arose while developing a supplement to Mental Health: A Report of the Surgeon General that was focused on ethnic minority mental health. The controversy involved whether and how to make recommendations about ethnic minorities seeking mental health care. We found that few studies provided information on outcomes of mental health care for ethnic minorities. In this paper, we discuss outcomes of mental health care for ethnic minorities and how to proceed in developing an evidence base for understanding mental health care and minorities. We conclude that entering representative (based on population) numbers of ethnic minorities in efficacy trials is unlikely to produce useful information on outcomes of care because the numbers will be too small to produce reliable findings. We also conclude that while conducting randomized efficacy trials for all mental health interventions for each ethnic group would be impractical, innovative and theoretically informed studies that focus on specific cultural groups are needed to advance the knowledge base. We call for theory-driven research focused on mental health disparities that has the potential for understanding disparities and improving outcomes for ethnic minority populations. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. NIMH, Bethesda, MD 20892 USA. Univ Puerto Rico, Dept Psychol, San Juan, PR 00931 USA. RP Miranda, J (reprint author), Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RI Bernal, Guillermo/E-6360-2010 OI Bernal, Guillermo/0000-0001-8855-1314 FU AHRQ HHS [5P01-HS1-0858:03]; NIA NIH HHS [AG-02-004]; NIMH NIH HHS [MH546230-06, MH59876] NR 67 TC 60 Z9 60 U1 2 U2 13 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD DEC PY 2003 VL 27 IS 4 BP 467 EP 486 DI 10.1023/B:MEDI.0000005484.26741.79 PG 20 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 748AU UT WOS:000186840000011 PM 14727681 ER PT J AU Lakhani, NJ Venitz, J Figg, WD Sparreboom, A AF Lakhani, NJ Venitz, J Figg, WD Sparreboom, A TI Pharmacogenetics of estrogen metabolism and transport in relation to cancer SO CURRENT DRUG METABOLISM LA English DT Review DE estrogen; metabolism; transport; cancer; pharmacogenetics ID CATECHOL-O-METHYLTRANSFERASE; S-TRANSFERASE M1; PREMENOPAUSAL BREAST-CANCER; PRIMARY CONGENITAL GLAUCOMA; RESISTANCE PROTEIN; GENETIC POLYMORPHISMS; LUNG-CANCER; CYTOCHROME P4501B1; DRUG-RESISTANCE; OVARIAN-CANCER AB Exposure to estrogens has been long associated with the genesis of human malignancies, including breast, ovarian, and endometrial cancer. A variety of phase I and II enzymes are involved in the metabolic activation and deactivation of estrogens, including cytochrome P450 isoforms, estrone sulfatase, sulfotransferases, catechol-o-methyltransferase, and uridine-5'-diphosphate glucuronosyltransferase. In addition, at least one ATP-binding cassette gene (i.e., ABCG2) is involved in estrogen transport. Variability in the expression levels of these proteins may have important consequences for an individual's susceptibility to certain malignancies. Naturally occurring variants in the genes involved in estrogen exposure levels have been identified that might affect protein function and expression. This review focuses on recent advances in the pharmacogenetics of these proteins, and discusses potential clinical ramifications of these genetic variants. C1 NCI, Ctr Canc Res, Clin Pharmacol Res Core, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Richmond, VA USA. RP Figg, WD (reprint author), NCI, Ctr Canc Res, Clin Pharmacol Res Core, NIH, Bldg 10,Rm 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 137 TC 14 Z9 14 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD DEC PY 2003 VL 4 IS 6 BP 505 EP 513 DI 10.2174/1389200033489244 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 751LD UT WOS:000187067800004 PM 14683478 ER PT J AU Wang, HB Negishi, M AF Wang, HB Negishi, M TI Transcriptional regulation of cytochrome P4502B genes by nuclear receptors SO CURRENT DRUG METABOLISM LA English DT Review DE CYP2B; nuclear receptor; CAR; PXR; liver; induction; regulation ID CONSTITUTIVE ANDROSTANE RECEPTOR; PREGNANE-X-RECEPTOR; RESPONSIVE ENHANCER MODULE; HUMAN CYP2B6 GENE; PHENOBARBITAL-INDUCIBLE CYTOCHROME-P-450; ANION-TRANSPORTING POLYPEPTIDE-2; PRIMARY HUMAN HEPATOCYTES; RAT-LIVER; XENOBIOTIC RESPONSE; 5'-FLANKING REGION AB Cytochrome P450 2B genes have been used extensively as prototypical models to study phenobarbital induction of P450 enzymes. Although its basal hepatic abundance is relatively low, CYP2B is highly inducible by various chemicals. Cross regulation and shared substrate specificity of CYP2B with CYP3A and other drug metabolizing enzymes lend support to the pharmacological and toxicological significance of CYP2B induction. The constitutive androstane receptor (CAR) appears to be one of the main regulators involved in transcriptional activation of CYP2B genes, although pregnane X receptor (PXR), glucocorticoids receptor (GR), and other nuclear receptors may be required for their optimal activation. In this article, we review current advances in the mechanisms of species-specific activation of CYP2B genes by CAR, with the human CYP2B6 gene being a main focus. Several recent findings, including discovery of a human CAR specific activator 6-(4-chlorophenyl:imidazo[2,1-b]thiazole- 5carbaidehyde O-(3,4-dichlorobenzyl)oxime (CITCO), identification of a far-distal xenobiotic-responsive enhancer module (XREM) in the CYP2B6 gene promoter, and generation of CAR-null mice as a model of characterizing CAR target gene expression, will also be discussed. These findings should provide greater insight into the mechanisms and species-specific differences of CAR regulation of CYP2B and other target genes. C1 NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 118 TC 76 Z9 78 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD DEC PY 2003 VL 4 IS 6 BP 515 EP 525 DI 10.2174/1389200033489262 PG 11 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 751LD UT WOS:000187067800005 PM 14683479 ER PT J AU Segre, J AF Segre, J TI Complex redundancy to build a simple epidermal permeability barrier SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID CORNIFIED ENVELOPE; FETAL MATURATION; MICE; SKIN; DIFFERENTIATION; EXPRESSION; INVOLUCRIN; PRECURSOR; PROTEINS; CLONING AB To survive the transition from an aqueous in utero to a terrestrial ex utero environment, mice and humans must construct an epidermal permeability barrier in utero. Terminally differentiated epidermal cells, lipids and tight junctions are all essential to achieve this barrier. Recent analyses of mouse mutants with defects in structural components of the terminally differentiated epidermal cell, catalyzing enzymes, lipid processing, transcriptional regulators and the intercellular junctions have highlighted their essential function in establishing the epidermal permeability barrier. Particularly interesting examples include modulation of the expression of transglutaminase 1 enzyme, the transcription factor Klf4 and the claudin tight junction proteins. However, careful analysis of the various mutant phenotypes during embryonic development, as neonates and either as adults or transplanted skin, has revealed much more about the redundancy and compensatory mechanisms of the system. Molecular analysis of the various mouse mutants has demonstrated common pathways to compensate for loss of the epidermal barrier. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Segre, J (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A26,MSC 4442, Bethesda, MD 20892 USA. NR 29 TC 5 Z9 5 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2003 VL 15 IS 6 BP 778 EP 784 DI 10.1016/j.ceb.2003.10.001 PG 7 WC Cell Biology SC Cell Biology GA 751VF UT WOS:000187109200019 ER PT J AU Siraganian, RP AF Siraganian, RP TI Mast cell signal transduction from the high-affinity IgE receptor SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID FC-EPSILON-RI; OPERATED CALCIUM CURRENT/(CRAC); FUNCTION-ASSOCIATED ANTIGEN; IMMUNOGLOBULIN-E RECEPTOR; SYK TYROSINE KINASE; MEDIATED DEGRANULATION; ADAPTER MOLECULE; RBL-2H3 CELLS; ACTIVATION; PROTEIN AB Antigen-mediated aggregation of IgE bound to its high-affinity receptor on mast cells or basophils initiates a complex series of biochemical events, resulting in the release of mediators that cause allergic inflammation and anaphylactic reactions. Recent progress has defined the molecular pathways that are involved in stimulating these cells and has shown the importance of protein tyrosine kinases in the subsequent reactions. The activation pathways are regulated both positively and negatively by the interactions of numerous signaling molecules. C1 NIDCR, Oral Infect & Immun, Receptors & Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), NIDCR, Oral Infect & Immun, Receptors & Signal Transduct Sect, NIH, Bldg 10 Room 1N-106, Bethesda, MD 20892 USA. NR 55 TC 155 Z9 156 U1 3 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD DEC PY 2003 VL 15 IS 6 BP 639 EP 646 DI 10.1016/j.coi.2003.09.010 PG 8 WC Immunology SC Immunology GA 748LB UT WOS:000186862400008 PM 14630197 ER PT J AU Veenstra, TD Conrads, TP AF Veenstra, TD Conrads, TP TI Serum protein fingerprinting SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Article DE biomarkers; cancer; early diagnosis; mass spectrometry; proteomic patterns; serum fingerprinting ID HUMAN PLASMA PROTEOME; OVARIAN-CANCER; PROSTATE-CANCER; MASS-SPECTROMETRY; PATTERNS; IDENTIFICATION; STRATEGIES; BIOMARKERS; PATHWAYS; MEN AB The core technologies in the rapidly expanding field of proteomics have matured to the point where quantitative measurements of thousands of proteins can be conducted, enabling truly global measurements of protein expression. This advent has brought with it the hope of discovering novel biomarkers that promise a renaissance in clinical medicine. To meet this need, many proteomic studies have focused on the identification and subsequent comparative analysis of the thousands of proteins that populate complex biological systems such as serum and tissues. A novel application of mass spectrometry has been in proteomic pattern analysis, which has emerged as an effective method for the early diagnosis of diseases. In stark contrast to 'classical' proteomics, proteomic pattern analysis relies on the pattern of proteins observed, rather than on the discrete identification of a protein. Proteomic pattern technology allows hundreds of clinical samples to be analyzed per day and promises to be a novel, highly sensitive predictive clinical tool to improve diagnostic and prognostic medicine. C1 SAIC Frederick Inc, Natl Canc Inst, Frederick, MD 21702 USA. RP Conrads, TP (reprint author), SAIC Frederick Inc, Natl Canc Inst, POB B, Frederick, MD 21702 USA. EM conrads@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 39 TC 7 Z9 7 U1 1 U2 1 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD DEC PY 2003 VL 5 IS 6 BP 584 EP 593 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 763MP UT WOS:000188090000003 PM 14755884 ER PT J AU Donoghue, JP Hikosaka, O AF Donoghue, JP Hikosaka, O TI Motor systems - Editorial overview. SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Editorial Material C1 Brown Med Sch, Dept Neurosci, Providence, RI 02912 USA. NEI, Sect Neuronal Networks, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Donoghue, JP (reprint author), Brown Med Sch, Dept Neurosci, Box 1953, Providence, RI 02912 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD DEC PY 2003 VL 13 IS 6 BP 643 EP 646 DI 10.1016/j.conb.2003.11.002 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 756LT UT WOS:000187467100001 ER PT J AU Sommer, MA AF Sommer, MA TI The role of the thalamus in motor control SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID DEEP BRAIN-STIMULATION; GENERATED LIMB MOVEMENTS; BASAL GANGLIA; NEURONAL-ACTIVITY; EYE-MOVEMENTS; TRANSNEURONAL TRANSPORT; VISUOMOTOR FUNCTIONS; SUBSTANTIA-NIGRA; CEREBELLAR LOOPS; EFFERENCE COPY AB Two characteristics of the thalamus - its apparently simple relay function and its daunting multinuclear structure - have been customarily viewed as good reasons to study something else. Yet, now that many other brain regions have been explored and neurophysiologists are turning to questions of how larger circuits operate, these two characteristics are starting to seem more attractive. First, the relay nature of thalamic neurons means that recording from them, like tapping into a wire, can reveal the signals carried by specific circuits. Second, the concentration of like relay neurons into nuclei means that inactivating or stimulating them can efficiently test the functions of the circuits. Recent studies implementing these principles have revealed pathways through the thalamus that contribute to generating movements and to monitoring one's own actions (corollary discharge). C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sommer, MA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 70 TC 63 Z9 65 U1 0 U2 13 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD DEC PY 2003 VL 13 IS 6 BP 663 EP 670 DI 10.1016/j.conb.2003.10.014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 756LT UT WOS:000187467100004 PM 14662366 ER PT J AU Porter, FD AF Porter, FD TI Human malformation syndromes due to inborn errors of cholesterol synthesis SO CURRENT OPINION IN PEDIATRICS LA English DT Review DE cholesterol synthesis; Smith-Lemli-Opitz syndrome; human malformation syndromes ID LEMLI-OPITZ-SYNDROME; DOMINANT CHONDRODYSPLASIA PUNCTATA; 7-DEHYDROCHOLESTEROL REDUCTASE GENE; UNCONJUGATED ESTRIOL; CARRIER FREQUENCY; SONIC-HEDGEHOG; CHILD SYNDROME; OPTIZ-SYNDROME; RSH SYNDROME; MUTATIONS AB Purpose of review This review covers a group of human malformation syndromes, which are caused by inborn errors of cholesterol synthesis. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation, and mental retardation syndrome that is the prototypical example of this group of disorders, In the 10 years since the biochemical cause of SLOS was identified, other malformation syndromes have been shown to result from defects in this pathway. These include desmosterolosis, lathosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM dysplasia), and some cases of Antley-Bixler syndrome. These disorders represent the first true merging of dysmorphology with biochemical genetics. Recent findings Recent studies report the identification of human lathosterolosis patients, indicate that SLOS is a relatively common genetic disorder that may be a major unrecognized cause of fetal loss, suggest that correction of the biochemical defect can improve central nervous system function, and show that perturbed sonic hedgehog signaling due to decreased sterol levels likely underlies some of the malformations in SLOS and lathosterolosis. Summary Recognition of the biochemical defect in these syndromes has given insight into the role that cholesterol plays during normal development, into understanding the pathophysiological processes that underlie the clinical problems found in these disorders, and into developing therapeutic interventions. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHD, NIH, Bldg 10,Room 9S241,10 Ctr Dr, Bethesda, MD 20892 USA. NR 65 TC 78 Z9 80 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8703 J9 CURR OPIN PEDIATR JI CURR. OPIN. PEDIATR. PD DEC PY 2003 VL 15 IS 6 BP 607 EP 613 DI 10.1097/00008480-200312000-00011 PG 7 WC Pediatrics SC Pediatrics GA 748XX UT WOS:000186887200011 PM 14631207 ER PT J AU Gorden, P Gavrilova, O AF Gorden, P Gavrilova, O TI The clinical uses of leptin SO CURRENT OPINION IN PHARMACOLOGY LA English DT Review ID REVERSES INSULIN-RESISTANCE; NORMAL FEMALE MICE; RECOMBINANT LEPTIN; DIABETES-MELLITUS; OBESE GENE; GENERALIZED LIPODYSTROPHY; REPLACEMENT THERAPY; LIPOATROPHIC MICE; ADIPOSE-TISSUE; BODY-WEIGHT AB Leptin is the first of a group of adipocyte-secreted hormones to be used clinically to treat hypoleptinemic states. In children with congenital leptin deficiency and extreme obesity, leptin induces satiety and a dramatic loss of weight. In hypoleptinemic patients with extreme insulin resistance and lipodystrophy, leptin ameliorates insulin resistance, hyperglycemia, hyperinsulinemia, dyslipidemia and hepatic steatosis. In both these leptin-deficient states, leptin therapy restores gonadotrophin secretion, as well as luteinizing hormone and thyroid-stimulating hormone pulsitility. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gorden, P (reprint author), NIDDKD, NIH, 9000 Rockville Pike,Bldg 10,Room 8S-235S, Bethesda, MD 20892 USA. NR 54 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD DEC PY 2003 VL 3 IS 6 BP 655 EP 659 DI 10.1016/j.coph.2003.06.006 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 753UE UT WOS:000187248300013 PM 14644019 ER PT J AU Schmid, I Merlin, S Perfetto, SP AF Schmid, I Merlin, S Perfetto, SP TI Biosafety concerns for shared flow cytometry core facilities SO CYTOMETRY PART A LA English DT Article DE flow cytometry; occupational health; biohazard; biosafety; cell sorting ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTED H9 CELLS; WHOLE-BLOOD; POSTEXPOSURE PROPHYLAXIS; INACTIVATION; MYCOPLASMA; EXPOSURES; REAGENTS; CONTAMINATION; CONTAINMENT AB Many researchers who need How cytometry for their projects have neither sufficient funds nor the work volume to justify the purchase of an analytic cytometer or cell sorter. in shared How cytometry facilities, costs for instrument purchases, cytometer maintenance, and personnel are pooled to provide economic services for a multitude of users when they are required. Owing to the diverse nature of the samples that are submitted to core facilities, the biohazard potential of the samples can vary dramatically. For the safety of facility personnel and users, it is critical that information about hazards contained in the samples be transmitted to instrument operators before flow cytometry experiments are started. During 1999 the former Biosafety Committee of the international Society for Analytical Cytology formulated a framework biosafety questionnaire for shared facilities designed to request information about the hazard potential of experimental samples from investigators who wish to use the facility. In this report we review safety issues that are pertinent to flow cytometry core facilities by discussing the individual components of this biosafety questionnaire. (C) 2003 Wiley-Liss, Inc. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Hematol Oncol, Los Angeles, CA 90095 USA. Becton Dickinson Immunocytometry Syst, San Jose, CA USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD USA. RP Schmid, I (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Hematol Oncol, 12-236 Factor Bldg, Los Angeles, CA 90095 USA. FU NCI NIH HHS [CA-16042]; NIAID NIH HHS [AI-28697] NR 59 TC 9 Z9 9 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD DEC PY 2003 VL 56A IS 2 BP 113 EP 119 DI 10.1002/cyto.a.10085 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 748YK UT WOS:000186888600007 PM 14608639 ER PT J AU Joshi, SS Bishop, MR Lynch, JC Tarantolo, SR Abhyankar, S Bierman, PJ Vose, JM Geller, RB McGuirk, J Foran, J Bociek, RG Hadi, A Day, SD Armitage, JO Kessinger, A Pavletic, ZS AF Joshi, SS Bishop, MR Lynch, JC Tarantolo, SR Abhyankar, S Bierman, PJ Vose, JM Geller, RB McGuirk, J Foran, J Bociek, RG Hadi, A Day, SD Armitage, JO Kessinger, A Pavletic, ZS TI Immunological and clinical effects of post-transplant G-CSF versus placebo in T-cell replete allogeneic blood transplant patients: results from a randomized double-blind study SO CYTOTHERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; BONE-MARROW TRANSPLANTATION; STEM-CELL; IMMUNE RECONSTITUTION; HEMATOLOGIC MALIGNANCIES; FILGRASTIM; TRIAL; LEUKEMIA; RECOVERY; DONORS AB Background Immunological and clinical effects of post-transplant growth factor administration have not been well studied. This report describes the outcome and immune functions of a total of 50 HLA-matched related donor allogeneic blood stem-cell transplantation patients who received post-transplant G-CSF (10 mug/kg) or placebo. Methods Immune status, including number of lymphocyte subsets and their functions, and serum immunoglobulin levels and clinical status - including GvHD, rate of relapse, event-free survival, and overall survival - were determined in the patients enrolled in this study. Results Twenty-eight patients survived 1 year after transplant, and 15 patients had available results to compare immune function by randomization assignment. At 12 months post-transplant, immune parameters in G-CSF versus placebo groups showed no statistically significant differences in number of circulating lymphocyte subsets CD3, CD4, CD8, CD19 and CD56 in the two groups. There was no significant (NS) difference in immunoglobulin IgG, IgA and IgM levels, NK or LAK cell-mediated cytotoxicity levels, and mitogen-induced proliferation between post-transplant G-CSF and placebo group. In addition, the analyses of immune parameters at earlier time-points on Days 28, 100, 180, and 270 revealed that, except for LAK cytotoxicity at Day 100, there was no differences between the two groups. Fourteen of 26 patients are alive in the G-CSF arm and nine of 24 in the placebo arm. Median follow-up of surviving patients is 43 months. Four year overall and event-free survival in the G-CSF and the placebo group were 53% and 35% (NS), and 44% and 36% (NS) respectively. Bacterial or fungal infections were the cause of six of 12 deaths in the G-CSF arm (all bacterial) and of four of 15 deaths in the placebo arm (two deaths from Aspergillus) (P = 0.26). Two patients relapsed in the G-CSF arm and three in the placebo arm. Four year cumulative incidences of relapse were 8% versus 13% in G-CSF versus placebo arms, respectively, (NS). Chronic GvHD developed in 14 of 19 100-day survivors after G-CSF (11 extensive stage), and in 17 of 20 (14 extensive stage) in the placebo arm. The 4-year cumulative incidence of chronic GvHD was 56% [95% confidence interval (CI) 24-88%] after G-CSF and 71% (95% CI 48-94%) after placebo; this difference was not statistically significant (log rank P-0.41). Conclusion In summary, there were no significant immunological or alterations in clinical benefit of post-transplant G-CSF administration in T-replete allotransplant recipients. C1 Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. St Lukes Hosp, Kansas City, MO 64111 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Joshi, SS (reprint author), Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, 986395 Nebraska Med Ctr, Omaha, NE 68198 USA. NR 21 TC 5 Z9 5 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 1465-3249 J9 CYTOTHERAPY JI Cytotherapy PD DEC PY 2003 VL 5 IS 6 BP 542 EP 552 DI 10.1080/14653240310003648 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology; Hematology; Medicine, Research & Experimental SC Cell Biology; Biotechnology & Applied Microbiology; Hematology; Research & Experimental Medicine GA 751EL UT WOS:000187039800008 PM 14660050 ER PT J AU Li, WM Qiao, WH Chen, L Xu, XL Yang, X Li, D Li, CL Brodie, SG Meguid, MM Hennighausen, L Deng, CX AF Li, WM Qiao, WH Chen, L Xu, XL Yang, X Li, D Li, CL Brodie, SG Meguid, MM Hennighausen, L Deng, CX TI Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice SO DEVELOPMENT LA English DT Article DE Smad4/Dpc4; TGF beta; transdifferentiation; keratinocytes; neoplasia ID GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR GENE; TGF-BETA; TRANSGENIC MICE; BREAST-CANCER; GLAND DEVELOPMENT; II RECEPTOR; MESENCHYMAL TRANSDIFFERENTIATION; JUVENILE POLYPOSIS; PANCREATIC-CANCER AB Smad4 is a central mediator for TGFbeta signals, which play important functions in many biological processes. To study the role of Smad4 in mammary gland development and neoplasia, we disrupted this gene in mammary epithelium using a Cre-loxP approach. Smad4 is expressed in the mammary gland throughout development; however, its inactivation did not cause abnormal development of the gland during the first three pregnancies. Instead, lack of Smad4 gradually induced cell proliferation, alveolar hyperplasia and transdifferentiation of mammary epithelial cells into squamous epithelial cells. Consequently, all mutant mice developed squamous cell carcinoma and/or mammary abscesses between 5 and 16 months of age. We demonstrated that absence of Smad4 resulted in beta-catenin accumulation at onset and throughout the process of transdifferentiation, implicating beta-catenin, a key component of the Writ signaling pathway, in the development of squamous metaplasia in Smad4-null mammary glands. We further demonstrated that TGFbeta1 treatment degraded beta-catenin and induced epithelial-mesenchymal transformation in cultured mammary epithelial cells. However, such actions were blocked in the absence of Smad4. These findings indicate that TGFbeta/Smad4 signals play a role in cell fate maintenance during mammary gland development and neoplasia. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Upstate Med Univ, Program Neurosci, Dept Surg, Syracuse, NY 13210 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 57 TC 62 Z9 72 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC PY 2003 VL 130 IS 24 BP 6143 EP 6153 DI 10.1242/dev.00820 PG 11 WC Developmental Biology SC Developmental Biology GA 755JQ UT WOS:000187400100025 PM 14597578 ER PT J AU Suzuki, K Bachiller, D Chen, YPP Kamikawa, M Ogi, H Haraguchi, R Ogino, Y Minami, Y Mishina, Y Ahn, K Crenshaw, EB Yamada, G AF Suzuki, K Bachiller, D Chen, YPP Kamikawa, M Ogi, H Haraguchi, R Ogino, Y Minami, Y Mishina, Y Ahn, K Crenshaw, EB Yamada, G TI Regulation of outgrowth and apoptosis for the terminal appendage: external genitalia: development by concerted actions of BMP signaling SO DEVELOPMENT LA English DT Review DE external genitalia; genital tubercle; BMP; FGF8; noggin; WNT5A; apoptosis; cell proliferation; distal urethral epithelium ID APICAL ECTODERMAL RIDGE; BONE-MORPHOGENETIC PROTEIN-4; PROGRAMMED CELL-DEATH; EPITHELIAL-MESENCHYMAL INTERACTIONS; VERTEBRATE LIMB DEVELOPMENT; FIBROBLAST-GROWTH-FACTOR; TGF-BETA-S; SONIC-HEDGEHOG; FEEDBACK LOOP; MOUSE TOOTH AB Extra-corporal fertilization depends on the formation of copulatory organs: the external genitalia. Coordinated growth and differentiation of the genital tubercle (GT), an embryonic anlage of external genitalia, generates a proximodistally elongated structure suitable for copulation, erection, uresis and ejaculation. Despite recent progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes of external genitalia formation. Bone morphogenetic protein genes (Bmp genes) and their antagonists were spatiotemporally expressed during GT development. Exogenously applied BMP increased apoptosis of GT and inhibited its outgrowth. It has been shown that the distal urethral epithelium (DUE), distal epithelia marked by the Fgf8 expression, may control the initial GT outgrowth. Exogenously applied BMP4 downregulated the expression of Fgf8 and Wnt5a, concomitant with increased apoptosis and decreased cell proliferation of the GT mesenchyme. Furthermore, noggin mutants and Bmpr1a conditional mutant mice displayed hypoplasia and hyperplasia of the external genitalia respectively. noggin mutant mice exhibited downregulation of Wnt5a and Fgf8 expression with decreased cell proliferation. Consistent with such findings; Wnt5a mutant mice displayed GT agenesis with decreased cell proliferation. By contrast, Bmpr1a mutant mice displayed decreased apoptosis and augmented Fgf8 expression in the DUE associated with GT hyperplasia. These results suggest that some of the Bmp genes could negatively affect proximodistally oriented outgrowth of GT with regulatory functions on cell proliferation and apoptosis. The DUE region can be marked only until 14.0 dpc (days post coitum) in mouse development, while GT outgrowth continues thereafter. Possible signaling crosstalk among the whole distal GT regions were also investigated. C1 Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, CARD, Kumamoto 8600811, Japan. Univ Calif Los Angeles, Sch Med, Div Head & Neck Surg, Genet Mol Lab, Los Angeles, CA 90095 USA. Tulane Univ, Dept Cell & Mol Biol, New Orleans, LA 70118 USA. Kobe Univ, Grad Sch Med, Dept Genome Sci, Kobe, Hyogo, Japan. NIEHS, Mol Dev Biol Grp, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. Childrens Hosp Philadelphia, Ctr Childhood Commun, Mammalian Neurogenet Grp, Philadelphia, PA 19104 USA. RP Yamada, G (reprint author), Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, CARD, Honjo 2-2-1, Kumamoto 8600811, Japan. NR 102 TC 81 Z9 87 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC PY 2003 VL 130 IS 25 BP 6209 EP 6220 DI 10.1242/dev.00846 PG 12 WC Developmental Biology SC Developmental Biology GA 755JT UT WOS:000187400300006 PM 14602679 ER PT J AU Cole, PM Teti, LO Zahn-Waxler, C AF Cole, PM Teti, LO Zahn-Waxler, C TI Mutual emotion regulation and the stability of conduct problems between preschool and early school age SO DEVELOPMENT AND PSYCHOPATHOLOGY LA English DT Article ID BEHAVIOR PROBLEMS; CHILDREN AB Mutual regulation of anger plays a role in both healthy adjustment and mental health problems. This study of 85 preschooler boys and girls examined mother-preschooler anger regulation during a frustration in relation to the child's preschool and school age problem status. Less mutual positive emotion, more mutual anger, and more emotional mismatches than other dyads characterized dyads with a stable conduct problem child. Maternal emotion predicted school age conduct problems, particularly for boys. Maternal emotion also predicted stability versus improvement of symptoms. The emotional dynamics of mother-preschooler angry exchanges may redirect girls' conduct problems and may contribute to the stability of boys' conduct problems. C1 Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. NIMH, Bethesda, MD 20892 USA. Pacific Inst Res & Evaluat, Bethesda, MD 20814 USA. RP Cole, PM (reprint author), Penn State Univ, Dept Psychol, 417 Moore Bldg, University Pk, PA 16802 USA. NR 44 TC 108 Z9 108 U1 4 U2 21 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-5794 J9 DEV PSYCHOPATHOL JI Dev. Psychopathol. PD WIN PY 2003 VL 15 IS 1 BP 1 EP 18 DI 10.1017/S0954579403000014 PG 18 WC Psychology, Developmental SC Psychology GA 692TD UT WOS:000183675600001 PM 12848432 ER PT J AU Huang, CC Lawson, ND Weinstein, BM Johnson, SL AF Huang, CC Lawson, ND Weinstein, BM Johnson, SL TI reg6 is required for branching morphogenesis during blood vessel regeneration in zebrafish caudal fins SO DEVELOPMENTAL BIOLOGY LA English DT Article DE zebrafish; regeneration; angiogenesis; plexus; branching; anastomosis ID ENDOTHELIAL-CELLS; GROWTH-CONTROL; MECHANISMS; ANGIOGENESIS AB Postnatal neovascularization is essential for wound healing, cancer progression, and many other physiological functions. However, its genetic mechanism is largely unknown. In this report, we study neovascularization in regenerating adult zebrafish fins using transgenic fish that express EGFP in blood vessel endothelial cells. We first describe the morphogenesis of regenerating vessels in wild-type animals and then the phenotypic analysis of a genetic mutation that disrupts blood vessel regeneration. In wild-type zebrafish caudal fins, amputated blood vessels heal their ends by 24 h postamputation (hpa) and then reconnect arteries and veins via anastomosis, to resume blood flow at wound sites by 48 hpa. The truncated vessels regenerate by first growing excess vessels to form unstructured plexuses, resembling the primary capillary plexuses formed during embryonic vasculogenesis. Interestingly, this mode of vessel growth switches by 8 days postamputation (dpa) to growth without a plexus intermediate. During blood vessel regeneration, vessel remodeling begins during early plexus formation and continues until the original vasculature pattern is reestablished at similar to35 dpa. Temperature-sensitive mutants for reg6 have profound defects in blood vessel regeneration. At the restrictive temperature, reg6 regenerating blood vessels first fail to make reconnections between severed arteries and veins, and then form enlarged vascular sinuses rather than branched vascular plexuses. Reciprocal temperature-shift experiments show that reg6 function is required throughout plexus formation, but not during later growth. Our results suggest that the reg6 mutation causes defects in branch formation and/or angiogenic sprouting. (C) 2003 Elsevier Inc. All rights reserved. C1 Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. NIH, Unit Vertebrate Organogenesis, Bethesda, MD 20892 USA. RP Johnson, SL (reprint author), Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. EM sjohnson@genetics.wustl.edu FU NICHD NIH HHS [P01 HD039952, HD39952]; NIGMS NIH HHS [R01 GM056988] NR 24 TC 52 Z9 52 U1 2 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD DEC 1 PY 2003 VL 264 IS 1 BP 263 EP 274 DI 10.1016/j.ydbio.2003.08.016 PG 12 WC Developmental Biology SC Developmental Biology GA 746AF UT WOS:000186723300020 PM 14623247 ER PT J AU Darland, DC Massingham, LJ Smith, SR Piek, E St-Geniez, M D'Amore, PA AF Darland, DC Massingham, LJ Smith, SR Piek, E St-Geniez, M D'Amore, PA TI Pericyte production of cell-associated VEGF is differentiation-dependent and is associated with endothelial survival SO DEVELOPMENTAL BIOLOGY LA English DT Article ID SMOOTH-MUSCLE CELLS; GROWTH-FACTOR-BETA; TGF-BETA; MURAL CELLS; PDGF-B; NG2 PROTEOGLYCAN; BLOOD-VESSELS; MICE; ANGIOPOIETIN-1; TUMORS AB Pericytes have been suggested to play a role in regulation of vessel stability; one mechanism for this stabilization may be via pericyte-derived vascular endothelial growth factor (VEGF). To test the hypothesis that differentiation of mesenchymal cells to pericytes/smooth muscle cells (SMC) is accompanied by VEGF expression, we used endothelial cell (EC) and mesenchymal cell cocultures to model cell-cell interactions that occur during vessel development. Coculture of EC and 10T1/2 cells, multipotent mesenchymal cells, led to induction of VEGF expression by 10T1/2 cells. Increased VEGF expression was dependent on contact between EC-10T1/2 and was mediated by transforming growth factorbeta (TGFbeta). A majority of VEGF produced in coculture was cell- and/or matrix-associated. Treatment of cells with high salt, prolamine, heparin, or suramin released significant VEGF, suggesting that heparan sulfate proteoglycan might be sequestering some of the VEGF. Inhibition of VEGF in cocultures led to a 75% increase in EC apoptosis, indicating that EC survival in cocultures is dependent on 10T1/2-derived VEGF. VEGF gene expression in developing retinal vasculature was observed in pericytes contacting newly formed nucrovessels. Our observations indicate that differentiated pericytes produce VEGF that may act in a juxtacrine/paracrine manner as a survival and/or stabilizing factor for EC in microvessels. (C) 2003 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP D'Amore, PA (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. FU NEI NIH HHS [NEI EY05318]; NHLBI NIH HHS [NHLBI10157-02] NR 43 TC 208 Z9 217 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD DEC 1 PY 2003 VL 264 IS 1 BP 275 EP 288 DI 10.1016/S0012-1606(03)00492-5 PG 14 WC Developmental Biology SC Developmental Biology GA 746AF UT WOS:000186723300021 PM 14623248 ER PT J AU Petukhova, GV Romanienko, PJ Camerini-Otero, RD AF Petukhova, GV Romanienko, PJ Camerini-Otero, RD TI The Hop2 protein has a direct role in promoting interhomolog interactions during mouse meiosis SO DEVELOPMENTAL CELL LA English DT Article ID HOMOLOGOUS CHROMOSOME SYNAPSIS; DNA STRAND EXCHANGE; SACCHAROMYCES-CEREVISIAE; MEIOTIC RECOMBINATION; SYNAPTONEMAL COMPLEX; IONIZING-RADIATION; FISSION YEAST; C-ELEGANS; MICE; GENE AB The S. cerevisiae Hop2 protein and its fission yeast homolog Meu13 are required for proper homologous chromosome pairing and recombination during meiosis. The mechanism of this requirement is, however, not understood. The previous studies in Saccharomyces suggested that Hop2 is a guardian of meiotic chromosome synapsis with the ability to prevent or resolve deleterious associations between nonhomologous chromosomes. We have generated a Hop2 knockout mouse that shows profound meiotic defects with a distinct and novel phenotype. Hop2(-/-) spermatocytes arrest at the stage of pachytene-like chromosome condensation. Axial elements are fully developed, but synapsis of any kind is very limited. Immunofluorescence analysis of meiotic chromosome spreads indicates that while meiotic double-stranded breaks are formed and processed in the Hop2 knockout, they fail to be repaired. In aggregate, the Hop2 phenotype is consistent with a direct role for the mouse Hop2 protein in promoting homologous chromosome synapsis. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 67 TC 86 Z9 88 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD DEC PY 2003 VL 5 IS 6 BP 927 EP 936 DI 10.1016/S1534-5807(03)00369-1 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 757BE UT WOS:000187528300013 PM 14667414 ER PT J AU Monk, CS Grillon, C Baas, JMP McClure, EB Nelson, EE Zarahn, E Charney, DS Ernst, M Pine, DS AF Monk, CS Grillon, C Baas, JMP McClure, EB Nelson, EE Zarahn, E Charney, DS Ernst, M Pine, DS TI A neuroimaging method for the study of threat in adolescents SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE functional magnetic resonance imaging; fMRI; amygdala; fear; anxiety ID FEAR-POTENTIATED STARTLE; POSTTRAUMATIC-STRESS-DISORDER; CEREBRAL-BLOOD-FLOW; EMOTIONAL FACIAL EXPRESSIONS; MEDIAL PREFRONTAL CORTEX; AMYGDALA RESPONSE; ANXIETY DISORDERS; CONDITIONED FEAR; HEMISPHERIC-ASYMMETRY; ANTICIPATORY ANXIETY AB Little is understood about the brain basis of anxiety, particularly among youth. However, threat paradigms with animals are delineating the relationship between anxietylike behaviors and brain function. We adapted a threat paradigm for adolescents using functional magnetic resonance imaging. The aim was to examine amygdala activation to fear. The threat was an aversive air blast directed to the larynx. Participants were explicitly informed that they might receive the air blast when viewing one stimulus (threat condition) and would not receive the blast when viewing the other stimulus (safe condition). Participants provided fear ratings immediately after each trial. Based on the relatively mild nature of the air blast, we expected participants to report varying degrees of fear Those who reported increased fear showed right amygdala activation during the threat condition and left amygdala activation in the safe condition. These procedures offer a promising tool for studying youth with anxiety disorders. (C) 2003 Wiley Periodicals, Inc. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Columbia Univ, Dept Psychiat, New York, NY 10032 USA. RP Monk, CS (reprint author), 15K N Dr,Room 204,MSC 2670, Bethesda, MD 20892 USA. RI Nelson, Eric/B-8980-2008; Monk, Christopher/J-1805-2014; OI Nelson, Eric/0000-0002-3376-2453; Baas, Johanna/0000-0001-6267-8712 NR 60 TC 18 Z9 18 U1 9 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD DEC PY 2003 VL 43 IS 4 BP 359 EP 366 DI 10.1002/dev.10146 PG 8 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 751AP UT WOS:000187030900009 PM 15027419 ER PT J AU Kovacs, P Hanson, RL Lee, YH Yang, XL Kobes, SY Permana, PA Bogardus, C Baier, LJ AF Kovacs, P Hanson, RL Lee, YH Yang, XL Kobes, SY Permana, PA Bogardus, C Baier, LJ TI The role of insulin receptor substrate-1 gene (IRS1) in type 2 diabetes in Pima Indians SO DIABETES LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; AUTOSOMAL GENOMIC SCAN; SKELETAL-MUSCLE; RESISTANCE; MELLITUS; NIDDM; PHOSPHORYLATION; POLYMORPHISM; HNF-4-ALPHA; PATHWAY AB The insulin receptor substrate-1 (IRS1) is a critical element in insulin-signaling pathways, and mutations in the IRS1 gene have been reported to have a role in determining susceptibility to traits related to type 2 diabetes. In gene expression studies of tissue biopsies from nondiabetic Pima Indians, IRS1 mRNA levels were reduced in adipocytes from obese subjects compared with lean subjects, and IRS1 mRNA levels were also reduced in skeletal muscle from insulin-resistant subjects compared with insulin-sensitive subjects (all P < 0.05). Based on these expression differences and the known physiologic role of IRS1, this gene was investigated as a candidate gene for susceptibility to type 2 diabetes in Pima Indians, a population with an extremely high incidence and prevalence of type 2 diabetes. Thirteen variants were identified, and among these variants, several were in complete linkage disequilibrium. Four genotypically unique variants were further genotyped in 937 DNA samples from full-heritage Pima Indians. Three of the variants were modestly associated with type 2 diabetes (P < 0.05), one of which was additionally associated with 2-h plasma insulin and glucose as well as insulin action at physiologic and maximally stimulating insulin concentrations (all P < 0.05). The association of variants in IRS1 with type 2 diabetes and type 2 diabetes-related phenotypes and the differential expression of IRS1 in adipocytes and skeletal muscle suggest a role of this gene in the pathogenesis of type 2 diabetes in Pima Indians. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ 85016 USA. RP Baier, LJ (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, Phoenix Epidemiol & Clin Res Branch, 4212 N 16Th St, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 24 TC 30 Z9 30 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD DEC PY 2003 VL 52 IS 12 BP 3005 EP 3009 DI 10.2337/diabetes.52.12.3005 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746AH UT WOS:000186723600020 PM 14633864 ER PT J AU De Rekeneire, N Resnick, HE Schwartz, AV Shorr, RI Kuller, LH Simonsick, EM Vellas, B Harris, TB AF De Rekeneire, N Resnick, HE Schwartz, AV Shorr, RI Kuller, LH Simonsick, EM Vellas, B Harris, TB TI Diabetes is associated with subclinical functional limitation in nondisabled older individuals: The Health, Aging, and Body Composition study SO DIABETES CARE LA English DT Article ID LOWER-EXTREMITY FUNCTION; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; GLYCEMIC CONTROL; PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; US ADULTS; WOMEN; RISK; COMPLICATIONS AB OBJECTIVE - The aim of this study was to examine the role of comorbid conditions and body composition in the association between diabetes and subclinical Functional limitation, an indication of early functional decline, in well-functioning older individuals. RESEARCH DESIGN AND METHODS - This was a cross-sectional analysis of 3,075 well-functioning black and white men and women aged 70-79 years, enrolled in the Health, Aging, and Body Composition Study. Diabetes was defined by self-report and/or hypoglycemic medication use or fasting glucose greater than or equal to126 mg/dl. Subclinical functional limitation was defined using self-report of capacity and objective performance measures. Comorbid conditions were identified by self-reported diagnoses, medication use, and clinical measures. Body composition measures included anthropometry and total fat (dual X-ray absorptiometry). RESULTS - Of 2, 926 participants, 1,252 (42.8%) had subclinical functional limitation at baseline. Among 2,370 individuals without diabetes, 40% had subclinical functional limitation, whereas the prevalence was 53% among the 556 diabetic participants with an age/sex/race-adjusted odds ratio (OR) 1.70 (95% Cl 1.40-2.06). This Association remained significant when adjusted for body Composition measures (OR 1.54 [1.26-1.88]), diabetes-related comorbidities, and other potential confounders (OR 1.40 [1.14-1.73]). In the fully adjusted model, consideration of HbA(1c) (< or greater than or equal to7%) and diabetes duration showed that poor glycemic control in diabetic individuals explained the association with subclinical functional limitation. CONCLUSIONS- In a well-functioning older population, diabetes is associated with early indicators of functional decline, even after accounting for body Composition and diabetes-related comorbidities. Poor glycemic control Contributes to this relationship. Whether improvement in glycemic control in older people with diabetes would change this association should be tested. C1 NIA, Lab Eipidemiol Demog & Biometry, Bethesda, MD 20892 USA. MedStar Res Inst, Washington, DC USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15260 USA. NIA, Ctr Gerontol Res, Bethesda, MD 20892 USA. Univ Toulouse 1, Dept Geriatr Med, F-31042 Toulouse, France. RP De Rekeneire, N (reprint author), NIA, Lab Eipidemiol Demog & Biometry, Gateway Bldg,Suite 3C-309,7201, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 35 TC 79 Z9 79 U1 0 U2 2 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 DEC PY 2003 VL 26 IS 12 BP 3257 EP 3263 DI 10.2337/diacare.26.12.3257 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746AM UT WOS:000186724000009 PM 14633811 ER PT J AU Hirshberg, B Rother, KI Digon, BJ Lee, J Gaglia, JL Hines, K Read, EJ Chang, R Wood, BJ Harlan, DM AF Hirshberg, B Rother, KI Digon, BJ Lee, J Gaglia, JL Hines, K Read, EJ Chang, R Wood, BJ Harlan, DM TI Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression SO DIABETES CARE LA English DT Article ID LONG-TERM SURVIVAL; PANCREATIC-ISLETS; HUMANIZED ANTI-CD154; GLYCEMIC CONTROL; HEART-FAILURE; ALLOGRAFTS; MORTALITY; OUTCOMES; MELLITUS; RESERVE AB OBJECTIVE - The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned. RESEARCH DESIGN AND METHODS - Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus. RESULTS - All patients noted less frequent and less severe hypoglycemia and one-half were, insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdomin. at hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function. CONCLUSIONS - We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and toss of function over time. C1 NIDDK, Transplantat & Autoimmun Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, US Dept HHS, Bethesda, MD 20892 USA. NIH, Special Procedures Diagnost Radiol Dept, Dept Transfus Med, US Dept HHS, Bethesda, MD 20892 USA. RP Harlan, DM (reprint author), NIDDK, Transplantat & Autoimmun Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Room BN307, Bethesda, MD 20892 USA. NR 30 TC 83 Z9 84 U1 0 U2 2 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 DEC PY 2003 VL 26 IS 12 BP 3288 EP 3295 DI 10.2337/diacare.26.12.3288 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746AM UT WOS:000186724000014 PM 14633816 ER PT J AU Stefan, N Stumvoll, M Vozarova, B Weyer, C Funahashi, T Matsuzawa, Y Bogardus, C Tataranni, PA AF Stefan, N Stumvoll, M Vozarova, B Weyer, C Funahashi, T Matsuzawa, Y Bogardus, C Tataranni, PA TI Plasma adiponectin and endogenous glucose production in humans SO DIABETES CARE LA English DT Article ID INSULIN SECRETORY DYSFUNCTION; ADIPOSE-SPECIFIC PROTEIN; X-RAY ABSORPTIOMETRY; DIABETES-MELLITUS; LIPID-METABOLISM; RESISTANCE; ACRP30; SENSITIVITY; DECREASE; OBESITY AB OBJECTIVE - High plasma adiponectin is associated with reduced risk of type 2 diabetes, probably a consequence of its insulin-sensitizing properties. In vivo data in rodents Suggest that the insulin-sensitization responsible for improvement of glycemia occurs in muscle and liver. Whereas associations of plasma adiponectin with muscle insulin sensitivity in humans have been examined, this has not been done for the liver. RESEARCH DESIGN AND METHODS - We therefore analyzed the relationship between fasting plasma adiponectin and basal endogenous glucose production [EGP]-basal) and insulin-suppressed EGP (EGP-insulin, isotope dilution technique) in 143 Pima Indians (94 with normal glucose tolerance, 36 with impaired glucose tolerance, and 16 with type 2 diabetes). RESULTS - Fasting plasma adiponectin concentrations were negatively correlated with EGP-basal and EGP-insulin before (P = 0.006 and P < 0.0001, respectively) as Well as after adjustment for age, sex, percent body fat, and insulin-stimulated whole-body glucose uptake (P = 0.007 and P = 0.0005, respectively). CONCLUSIONS - These findings are compatible with the hypothesis that adiponectin increases hepatic insulin sensitivity. Consistent with data in animals, adiponectin may have generalized insulin-sensitizing effects in humans. C1 Div Endocrinol Metab & Pathobiochem, Dept Internal Med, D-72076 Tubingen, Germany. NIDDKD, Clin Diabet & Nutr Sect, Dept Hlth & Human Serv, NIH, Phoenix, AZ USA. Osaka Univ, Grad Sch Med, Dept Internal Med & Mol Sci, Suita, Osaka 565, Japan. RP Stefan, N (reprint author), Div Endocrinol Metab & Pathobiochem, Dept Internal Med, Otfried Muller Str 10, D-72076 Tubingen, Germany. OI de Courten, Barbora/0000-0001-8760-2511 NR 30 TC 74 Z9 87 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 DEC PY 2003 VL 26 IS 12 BP 3315 EP 3319 DI 10.2337/diacare.26.12.3315 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746AM UT WOS:000186724000018 PM 14633820 ER PT J AU Putnam, SD Frenck, RW Riddle, MS El-Gendy, A Taha, NN Pittner, BT Abu-Elyazeed, R Wierzba, TF Rao, MR Savarino, SJ Clemens, JD AF Putnam, SD Frenck, RW Riddle, MS El-Gendy, A Taha, NN Pittner, BT Abu-Elyazeed, R Wierzba, TF Rao, MR Savarino, SJ Clemens, JD TI Antimicrobial susceptibility trends in Campylobacter jejuni and Campylobacter coli isolated from a rural Egyptian pediatric population with diarrhea SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article ID ANTIBIOTIC-RESISTANCE; HAEMOPHILUS-INFLUENZAE; INFECTIONS; QUINOLONE; AZITHROMYCIN; THAILAND; BACTERIA; ANIMALS AB Comparative and trend analysis was conducted on annual prevalence of antimicrobial susceptibility among Campylobacter jejuni and Campylobacter coli recovered from rural Egyptian children from 1995 through 2000. C jejuni and C coli demonstrated significant decreasing trends in ciprofloxacin susceptibility over the study period (p < 0.001 for both). In general, C coli demonstrated a higher degree of susceptibility than C. jejuni, however, there was no statistical difference (p = 0.2) comparing the linear trends over the duration of the study. There was no indication of frank macrolide (erythromycin or azithromycin) resistance among any Campylobacter. Moreover, there were statistically significant positive trends in both the MIC50 and MIC90 values for the erythromycin and azithromycin during the study period, suggesting a possible decreasing trend in susceptibility among Campylobacter. This study demonstrated that antimicrobial susceptibility in Campylobacter has significantly decreased from 1995 through 2000 among pediatric diarrhea cases in rural Egypt. (C) 2003 Elsevier Inc. All rights reserved. C1 USN, Med Res Ctr, Enter Dis Res Program, Silver Spring, MD USA. Naval Med Res Unit 3, Enter Dis Res Program, Cairo, Egypt. Mayo Clin, Dept Immunol, Rochester, MN USA. NICHHD, Epidemiol Branch, Bethesda, MD 20892 USA. Int Vaccine Inst, Seoul, South Korea. RP Putnam, SD (reprint author), USN, Med Res Ctr, Enter Dis Res Program, Silver Spring, MD USA. EM putnams@nmrc.navy.mil RI Riddle, Mark/A-8029-2011 FU NICHD NIH HHS [Y1-HD-0026-01] NR 19 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD DEC PY 2003 VL 47 IS 4 BP 601 EP 608 DI 10.1016/S0732-8893(03)00154-8 PG 8 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 761JJ UT WOS:000187897500009 PM 14711482 ER PT J AU Franks, ME Macpherson, GR Lepper, ER Figg, WD Sparreboom, A AF Franks, ME Macpherson, GR Lepper, ER Figg, WD Sparreboom, A TI New directions in cancer research 2003: technological advances in biology, drug resistance, and molecular pharmacology SO DRUG RESISTANCE UPDATES LA English DT Review DE array-technology; drug resistance; prostate cancer; novel targets; chemotherapy ID COPPER TRANSPORTER CTR1; PROSTATE-CANCER; SACCHAROMYCES-CEREVISIAE; CISPLATIN RESISTANCE; HUMAN OVARIAN; INHIBITORS; CELLS; OXALIPLATIN; ANTAGONIST; ATRASENTAN AB The 94th Annual Meeting of the American Association for Cancer Research (AACR) was held from July 11 to 14, 2003 in Washington, DC, and provided an overview of the latest developments in the field of cancer. This report provides highlights of presentations on array-based and RNA-interference technologies to study cancer biology and molecular pharmacology of anticancer drugs, mechanisms and modulation of drug resistance patterns, recent developments in the treatment of prostate cancer, and the medicinal chemistry of established and novel anticancer drugs. Published by Elsevier Ltd. C1 NCI, Clin Pharmacol Res Core, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Ctr Canc Res, Bldg 10,Room 5A01,9000 Rockvill Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 103 TC 8 Z9 8 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD DEC PY 2003 VL 6 IS 6 BP 301 EP 312 DI 10.1016/j.drup.2003.09.002 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 774RY UT WOS:000188999600001 PM 14744494 ER PT J AU Lorenzo, PS Dennis, PA AF Lorenzo, PS Dennis, PA TI Modulating protein kinase C (PKC) to increase the efficacy of chemotherapy: stepping into darkness SO DRUG RESISTANCE UPDATES LA English DT Review DE PKC; kinase; apoptosis; chemotherapy ID HUMAN-BREAST-CANCER; HUMAN LEUKEMIA-CELLS; CHRONIC LYMPHOCYTIC-LEUKEMIA; CYCLIN-DEPENDENT KINASES; DRUG-INDUCED APOPTOSIS; ESTER TUMOR PROMOTERS; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; SIGNAL-TRANSDUCTION; PHORBOL ESTERS AB The identification of molecules that promote chemotherapeutic resistance would allow rationally designed approaches to abrogate this resistance, thereby possibly improving clinical outcomes for patients with cancer. In this regard, the PKC family is attractive for targeting, because it is comprised of a family of isoforms that play key roles in multiple cellular processes and can contribute to cellular transformation. Encouraging in vitro data originally showed that approaches to modulate PKC activity through small-molecule inhibitors or genetic manipulation could affect tumor cell survival. Recently, some of these approaches have begun clinical testing. Early-stage clinical trials revealed scattered clinical responses to these agents, but the most recent clinical trials have shown that combining modulators of PKC with standard chemotherapy does not improve outcome over chemotherapy alone. In this review, we will trace the development of these approaches, and discuss possible explanations for the recent negative results. Importantly, we will suggest guidelines for the clinical evaluation of PKC modulators. Published by Elsevier Ltd. C1 USN, NCI, Canc Therapeut Branch, Bethesda, MD 20889 USA. Canc Res Ctr Hawaii, Na Prod Program, Honolulu, HI 96813 USA. RP Dennis, PA (reprint author), USN, NCI, Canc Therapeut Branch, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. EM pd85f@nih.gov NR 119 TC 11 Z9 11 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD DEC PY 2003 VL 6 IS 6 BP 329 EP 339 DI 10.1016/j.drup.2003.10.003 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 774RY UT WOS:000188999600004 PM 14744497 ER PT J AU Shotland, LI Mastrioanni, MA Choo, DL Szymko-Bennett, YM Dally, LG Pikus, AT Sledjeski, K Marques, A AF Shotland, LI Mastrioanni, MA Choo, DL Szymko-Bennett, YM Dally, LG Pikus, AT Sledjeski, K Marques, A TI Audiologic manifestations of patients with post-treatment Lyme disease syndrome SO EAR AND HEARING LA English DT Article AB Objective: The purpose of this study was to characterize auditory function in patients diagnosed with post-treatment Lyme disease syndrome (PTLDS). Design: Eighteen patients with PTLDS were evaluated and compared to a normal population. Evaluations consisted of pure tone and speech thresholds, word recognition (WRS), acoustic immittance battery, auditory brain stem response (ABR), and loudness discomfort level (LDL). Both seropositive and seronegative patients were evaluated. Audiologists were blinded to patient status. Results: Forty four percent of the patients had one or more abnormal pure tone thresholds compared to gender- and age-adjusted norms. Thirty-one percent showed abnormally reduced LDLs, and 17% had abnormal acoustic reflexes at one or more frequencies. Conclusions: This paper catalogs previously unstudied long-term auditory system sequelae resulting from PTLDS. Our most significant finding was the dramatically reduced loudness tolerance in the presence of either normal or minimally impaired hearing. The clinician is encouraged to consider PTLDS when confronted with these or similar findings in patients having history of Borrelia burgdorferi infection and continued complaints. C1 Natl Inst Deafness & Other Commun Disorders, Hearing Sect, Neurootol Branch, NIH, Bethesda, MD USA. Childrens Hosp, Dept Otolaryngol, Cincinnati, OH 45229 USA. EMMES Corp, Bethesda, MD USA. Zebra Syst Int, Bethesda, MD USA. Kirksville Sch Osteopathy, Kirksville, MO USA. NIAID, Clin Invest Lab, Bethesda, MD 20892 USA. RP Shotland, LI (reprint author), James H Quillen VAMC, Audiol 126, Mountain Home, TN 37684 USA. NR 38 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0196-0202 J9 EAR HEARING JI Ear Hear. PD DEC PY 2003 VL 24 IS 6 BP 508 EP 517 DI 10.1097/01.AUD.0000100205.25774.5F PG 10 WC Audiology & Speech-Language Pathology; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Otorhinolaryngology GA 752LY UT WOS:000187163400005 PM 14663350 ER PT J AU Bickham, JW Matson, CW Islamzadeh, A Rowe, GT Donnelly, KC Swartz, CD Rogers, WJ Wickliffe, JK Autenrieth, RL Mcdonald, TJ Politov, D Palatnikov, G Mekhtiev, AA Kasimov, R AF Bickham, JW Matson, CW Islamzadeh, A Rowe, GT Donnelly, KC Swartz, CD Rogers, WJ Wickliffe, JK Autenrieth, RL Mcdonald, TJ Politov, D Palatnikov, G Mekhtiev, AA Kasimov, R TI Editorial: The unknown environmental tragedy in Sumgayit, Azerbaijan SO ECOTOXICOLOGY LA English DT Editorial Material DE Azerbaijan; Sumgayit; environmental pollution; social and economic factors ID CASPIAN SEA C1 Texas A&M Univ, Dept Wildlife & Fisheries Sci, College Stn, TX 77843 USA. Sumgayit Ctr Environm Rehabil, Sumgayit 373200, Azerbaijan. Texas A&M Univ, Dept Marine Biol, Galveston, TX 77553 USA. Texas A&M Univ, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. W Texas A&M Univ, Dept Life Earth & Environm Sci, Canyon, TX 79601 USA. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. Texas A&M Univ, Dept Civil Engn, College Stn, TX 77843 USA. Texas A&M Univ Syst Hlth Sci Ctr, Sch Rural Publ Hlth, College Stn, TX 77802 USA. NI Vavilov Gen Genet Res Inst, Moscow 119991, Russia. Acad Sci Azerbaijan Republ, Karaev Inst Physiol, Baku 307100, Azerbaijan. RP Bickham, JW (reprint author), Texas A&M Univ, Dept Wildlife & Fisheries Sci, College Stn, TX 77843 USA. RI Matson, Cole/F-7992-2010 OI Matson, Cole/0000-0002-6472-9357 NR 6 TC 9 Z9 9 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0963-9292 J9 ECOTOXICOLOGY JI Ecotoxicology PD DEC PY 2003 VL 12 IS 6 BP 505 EP 508 DI 10.1023/B:ECTX.0000003037.55253.c5 PG 4 WC Ecology; Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 742MG UT WOS:000186521000010 PM 14680331 ER PT J AU Swartz, CD Donnelly, KC Islamzadeh, A Rowe, GT Rogers, WJ Palatnikov, GM Mekhtiev, AA Kasimov, M Mcdonald, TJ Wickliffe, JK Presley, BJ Bickham, JW AF Swartz, CD Donnelly, KC Islamzadeh, A Rowe, GT Rogers, WJ Palatnikov, GM Mekhtiev, AA Kasimov, M Mcdonald, TJ Wickliffe, JK Presley, BJ Bickham, JW TI Chemical contaminants and their effects in fish and wildlife from the industrial zone of Sumgayit, Republic of Azerbaijan SO ECOTOXICOLOGY LA English DT Article DE chemical contaminants; biomarkers; wildlife; Sumgayit; Azerbaijan ID GENE-TOX PROGRAM; SALMONELLA MUTAGENICITY; ECOTOXICOLOGY; ASSAYS; GENOTOXICITY; POPULATION; DAMAGE; CARCINOGENICITY; PESTICIDES; TOXICOLOGY AB Sediment from a wetland adjacent to an industrial wastewater treatment plant in Sumgayit contained concentrations of total PAHs, total PCBs, aldrin, biphenyl, chlordane, DDT, mercury, beta-endosulfan, heptachlor, alpha-hexacyclohexane (alpha-HCH), gamma-HCH, and several individual PAH congeners that were elevated relative to published sediment quality guidelines. Chemical analyses of tissues from European pond turtles (Emys orbicularis) had increased levels of many of the same chemicals including aldrin, chlordane, heptachlor, alpha-HCH, total PCBs, total PAHs, and mercury, compared to reference turtles. In addition, turtle tissues contained elevated levels of DDD, hexachlorobenzene (HCB), and pentachlorobenzene that were not elevated in the sediment sample. Some differences were observed in contaminant levels between European pond turtles and Caspian turtles (Mauremys caspica) taken from the ponds in Sumgayit. Salmonella/microsome mutagenicity assays on pond sediments were negative or weakly positive. Micronuclei in European pond turtles were statistically correlated with tissue levels of mercury, heptachlor, DDD, HCB, and trans-nonachlor. Microcosm experiments using Russian sturgeon (Acipenser gueldenstaedtii) showed a positive dose-response relationship between exposure to suspended contaminated pond sediment and acute toxicity. Chemical and biological assays used in this study show the industrial area of Sumgayit is heavily contaminated with a complex mixture of toxic pollutants. Exposure to contaminated sediments produced acute effects in Russian sturgeon, but genotoxic effects appear to be slight. C1 Texas A&M Univ, Dept Wildlife & Fisheries Sci, College Stn, TX 77843 USA. Texas A&M Univ, Dept Vet Anat & Publ Hlth, College Stn, TX 77843 USA. Texas A&M Univ, Dept Oceanog, College Stn, TX 77843 USA. Texas A&M Univ, Dept Civil Engn, College Stn, TX 77843 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Sumgayit Ctr Environm Rehabil, Sumgayit 373200, Azerbaijan. W Texas A&M Univ, Dept Life Earth & Environm Sci, Abilene, TX 79601 USA. Acad Sci Azerbaijan Republ, Karaev Inst Physiol, Baku 307100, Azerbaijan. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77555 USA. Texas A&M Univ, Dept Marine Biol, Galveston, TX 77553 USA. RP Bickham, JW (reprint author), Texas A&M Univ, Dept Wildlife & Fisheries Sci, College Stn, TX 77843 USA. FU NIEHS NIH HHS [ES04917] NR 49 TC 25 Z9 26 U1 1 U2 25 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0963-9292 EI 1573-3017 J9 ECOTOXICOLOGY JI Ecotoxicology PD DEC PY 2003 VL 12 IS 6 BP 509 EP 521 DI 10.1023/B:ECTX.0000003038.02643.08 PG 13 WC Ecology; Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 742MG UT WOS:000186521000011 PM 14680332 ER PT J AU Farilla, L Bulotta, A Hirshberg, B Calzi, SL Khoury, N Noushmehr, H Bertolotto, C Di Mario, U Harlan, DM Perfetti, R AF Farilla, L Bulotta, A Hirshberg, B Calzi, SL Khoury, N Noushmehr, H Bertolotto, C Di Mario, U Harlan, DM Perfetti, R TI Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets SO ENDOCRINOLOGY LA English DT Article ID INSULIN-PRODUCING CELLS; HEPATOCYTE GROWTH-FACTOR; PANCREATIC BETA-CELLS; PROTEIN-KINASE; DIABETIC-RATS; MASS; DIFFERENTIATION; PROLIFERATION; EXENDIN-4; TRANSPLANTATION AB The peptide hormone, glucagon-like peptide 1 (GLP-1), has been shown to increase glucose-dependent insulin secretion, enhance insulin gene transcription, expand islet cell mass, and inhibit beta-cell apoptosis in animal models of diabetes. The aim of the present study was to evaluate whether GLP-1 could improve function and inhibit apoptosis in freshly isolated human islets. Human islets were cultured for 5 d in the presence, or absence, of GLP-1 ( 10 nM, added every 12 h) and studied for viability and expression of proapoptotic (caspase-3) and antiapoptotic factors (bcl-2) as well as glucose-dependent insulin production. We observed better-preserved three-dimensional islet morphology in the GLP-1-treated islets, compared with controls. Nuclear condensation, a feature of cell apoptosis, was inhibited by GLP-1. The reduction in the number of apoptotic cells in GLP-1-treated islets was particularly evident at d 3 (6.1% apoptotic nuclei in treated cultures vs. 15.5% in controls; P < 0.01) and at d 5 (8.9 vs. 18.9%; P < 0.01). The antiapoptotic effect of GLP-1 was associated with the downregulation of active caspase-3 ( P < 0.001) and the up-regulation of bcl-2 ( P < 0.01). The effect of GLP-1 on the intracellular levels of bcl-2 and caspase-3 was observed at the mRNA and protein levels. Intracellular insulin content was markedly enhanced in islets cultured with GLP-1 vs. control ( P < 0.001, at d 5), and there was a parallel GLP-1-dependent potentiation of glucose-dependent insulin secretion ( P < 0.01 at d 3; P < 0.05 at d 5). Our findings provide evidence that GLP-1 added to freshly isolated human islets preserves morphology and function and inhibits cell apoptosis. C1 Univ Roma La Sapienza, Dept Clin Sci, I-00161 Rome, Italy. Cedars Sinai Med Ctr, Div Neonatol, Los Angeles, CA 90048 USA. NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA 90095 USA. Cedars Sinai Med Ctr, Div Endocrinol, Los Angeles, CA 90048 USA. RP Perfetti, R (reprint author), Cedars Sinai Med Ctr, Div Endocrinol & Diabet & Metab, 8723 Alden Dr,SSB 290, Los Angeles, CA 90048 USA. RI Noushmehr, Houtan/C-9692-2013 OI Noushmehr, Houtan/0000-0003-4051-8114 NR 34 TC 374 Z9 420 U1 2 U2 35 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 DEC 1 PY 2003 VL 144 IS 12 BP 5149 EP 5158 DI 10.1210/en.2003-0323 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746WZ UT WOS:000186771800004 PM 12960095 ER PT J AU Akesson, L Ahren, B Manganiello, VC Holst, LS Edgren, G Degerman, E AF Akesson, L Ahren, B Manganiello, VC Holst, LS Edgren, G Degerman, E TI Dual effects of pituitary adenylate cyclase-activating polypeptide and isoproterenol on lipid metabolism and signaling in primary rat adipocytes SO ENDOCRINOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; NUCLEOTIDE PHOSPHODIESTERASE 3B; INSULIN-INDUCED PHOSPHORYLATION; CAMP-PHOSPHODIESTERASE; ADIPOSE-TISSUE; INHIBITOR WORTMANNIN; GLUCAGON-SECRETION; PACAP RECEPTORS; FATTY-ACIDS; IN-VIVO AB Pituitary adenylate cyclase-activating peptide ( PACAP) is a neuropeptide that exerts its effects throughout the body by elevating the intracellular amounts of cAMP. In adipocytes, an increased amount of cAMP is associated with increased lipolysis. In this work we evaluated the effects of PACAP38 on triglyceride metabolism in primary rat adipocytes. Stimulation of adipocytes with PACAP (0.1 - 100 nM) resulted in stimulation of lipolysis to the same extent as isoproterenol. Lipolysis was blocked by 25 muM of the protein kinase A inhibitor H-89 and potentiated in the presence of 10 muM OPC3911, a phosphodiesterase 3 inhibitor. In addition, PACAP38 induced activation of protein kinase A. Insulin efficiently inhibited PACAP38-induced lipolysis in a phosphatidyl inositol 3-kinase and phosphodiesterase 3-dependent manner. Interestingly, we also found that PACAP38, as well as isoproterenol, induced potentiation of lipogenesis in the presence of insulin. These results show that PACAP38 and isoproterenol mediate catabolic as well as anabolic effects in adipocytes, depending on the concentration of insulin present. We speculate that in the early postprandial state and during fasting, when insulin levels are low, PACAP and beta-adrenergic catecholamines induce lipolysis, whereas when higher levels of insulin are present, these agents potentiate the anabolic effect of insulin, i.e. storage of triglycerides. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Lund Univ, Dept Med, SE-22184 Lund, Sweden. Lund Univ, Dept Cell & Mol Biol, Sect Mol Signaling, SE-22184 Lund, Sweden. RP Akesson, L (reprint author), Biomed Ctr C11, SE-22184 Lund, Sweden. NR 45 TC 18 Z9 19 U1 0 U2 3 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 DEC 1 PY 2003 VL 144 IS 12 BP 5293 EP 5299 DI 10.1210/en.2003-0364 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746WZ UT WOS:000186771800022 PM 12960103 ER PT J AU Dixit, VD Mielenz, M Taub, DD Parvizi, N AF Dixit, VD Mielenz, M Taub, DD Parvizi, N TI Leptin induces growth hormone secretion from peripheral blood mononuclear cells via a protein kinase C- and nitric oxide-dependent mechanism SO ENDOCRINOLOGY LA English DT Article ID GH SECRETION; HUMAN-LYMPHOCYTES; IMMUNE-RESPONSE; IN-VITRO; STIMULATED GROWTH; PITUITARY-GLAND; GENE-PRODUCT; L-ARGININE; RECEPTOR; EXPRESSION AB Leptin is a key mediator of signals regulating food intake and energy expenditure and exerts potent immunomodulatory effects. We investigated the mechanisms mediating the action of leptin on GH secretion from peripheral blood mononuclear cells (PBMCs). Using immunofluorescence microscopy, we demonstrated a polarized expression pattern of leptin receptor protein on the surface of mononuclear cells and constitutive expression of GH in PBMCs. Leptin exhibited a dose-dependent stimulatory effect on GH secretion by PBMCs and also up-regulated the GH receptor gene expression. We did not observe any additive effects of leptin on GH secretion upon activation of cells with the plant mitogen phytohemagglutinin, unlike leptin, phytohemagglutinin exerted no effect on GH receptor mRNA expression. Leptin led to a nitric oxide (NO) synthase (NOS)-specific, dose-dependent increase in NO production from PBMCs because leptin-induced NO release was blocked by the addition of the NOS inhibitor N-omega-Nitro-L-arginine methyl ester and protein kinase C (PKC) inhibitor calphostin C. This leptin-induced GH secretion was dependent on both PKC and NO activation because the addition of PKC and NOS inhibitors inhibited leptin-induced GH production. Although the addition of sodium nitroprusside, a spontaneous liberator of NO, stimulated GH release from PBMCs, leptin had no additive or synergistic effect on sodium nitroprusside-induced GH production. Together, these findings demonstrate a unique action of leptin on immune cells via its ability to stimulate the GH production by blood mononuclear cells via PKC- and NO-dependent pathways. These data also support a probable role for local immune-derived GH in mediating some of the pleiotropic actions of leptin. C1 Inst Anim Sci Mariensee, D-31535 Neustadt, Germany. NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Parvizi, N (reprint author), Inst Anim Sci Mariensee, Hoelty Str 10, D-31535 Neustadt, Germany. NR 55 TC 47 Z9 53 U1 0 U2 0 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 DEC 1 PY 2003 VL 144 IS 12 BP 5595 EP 5603 DI 10.1210/en.2003-0600 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746WZ UT WOS:000186771800055 PM 12970164 ER PT J AU Tsai, WC Bhattacharyya, N Han, LY Hanover, JA Rechler, MM AF Tsai, WC Bhattacharyya, N Han, LY Hanover, JA Rechler, MM TI Insulin inhibition of transcription stimulated by the forkhead protein Foxo1 is not solely due to nuclear exclusion SO ENDOCRINOLOGY LA English DT Article ID FACTOR-BINDING PROTEIN-1; FKHR PHOSPHORYLATION SITES; C-TERMINAL FRAGMENT; RAT HEPATOMA-CELLS; GENE-EXPRESSION; KINASE-B; PROMOTER ACTIVITY; PHOSPHOENOLPYRUVATE CARBOXYKINASE; ALVEOLAR RHABDOMYOSARCOMA; CAENORHABDITIS-ELEGANS AB The FOXO family of forkhead transcription factors stimulates the transcription of target genes involved in many fundamental cell processes, including cell survival, cell cycle progression, DNA repair, and insulin sensitivity. The activity of FOXO proteins is principally regulated by activation of protein kinase B (PKB)/Akt by insulin and other cytokines. PKB/Akt phosphorylates three consensus sites in FOXO proteins, leading to their export from the nucleus and the inhibition of FOXO-stimulated transcription. It has been widely accepted that the decreased transcription results from reduced abundance of FOXO proteins in the nucleus. In the present study we mutated Leu(375) to alanine in the nuclear export signal of Foxo1 (mouse FOXO1), so that it would remain in the nucleus of H4IIE rat hepatoma cells after insulin treatment, and determined whether insulin could still inhibit transcription stimulated by the Foxo1 mutant. Despite the retention of the Foxo1 mutant in the nucleus, insulin inhibited L375A-Foxo1-stimulated transcription to the same extent as transcription stimulated by wild-type Foxo1. Similar results were obtained using reporter plasmids containing the rat IGF-binding protein-1 promoter or a minimal promoter with three copies of the insulin response element to which FOXO proteins bind. We conclude that insulin can inhibit Foxo1-stimulated transcription even when nuclear export of Foxo1 is prevented, indicating that insulin inhibition can occur by direct mechanisms that do not depend on altering the subcellular distribution of the transcription factor. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Rechler, MM (reprint author), Bldg 10,Room 8D12,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 77 TC 45 Z9 45 U1 0 U2 1 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 DEC 1 PY 2003 VL 144 IS 12 BP 5615 EP 5622 DI 10.1210/en.2003-0481 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 746WZ UT WOS:000186771800057 PM 14500580 ER PT J AU de Serres, FJ AF de Serres, FJ TI Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE alpha-1 antitrypsin deficiency; alpha-1 protease; allpha-1 protease inhibitor; genetic epidemiology; Pi phenotypes; Pi subtypes; population genetics ID SEVERE ALPHA(1)-ANTITRYPSIN DEFICIENCY; SERPIN GENE-CLUSTER; NATURAL-HISTORY; LIVER-TRANSPLANTATION; CLINICAL-FEATURES; LUNG-FUNCTION; PI Z; EMPHYSEMA; RISK; PHENOTYPES AB Articles in the literature on alpha-1 antitrypsin (AAT) deficiency have been interpreted as indicating that ANT deficiency is a rare disease that affects mainly Caucasians (whites) from northern Europe. In a recent publication on the worldwide racial and ethnic distribution of AAT deficiency, new data were presented demonstrating that it is also found in various populations of African blacks; Arabs and Jews in the Middle East; and Central, Far East, and Southeast Asians, as well as whites in Australia, Europe, New Zealand, and North America. The new data on the prevalence of AAT deficiency in other major racial groups worldwide will affect the standards for the diagnosis of AAT deficiency by the medical community, with the realization that is not a rare disease of whites in northern Europe and immigrants from these countries in the New World. In a total population of 4.4 billion in the 58 countries surveyed, there are at least 116 million carriers (those with Pi phenotypes PiMS and PiMZ) and 3.4 million with deficiency allele combinations (phenotypes PiSS, PiSZ, and PiZZ) for the two most prevalent deficiency alleles PiS and PiZ; therefore, the new data suggest that AAT deficiency may be on of the most common serious single-locus genetic diseases in the world. Particularly important is the unique susceptibility of AAT-deficient individuals to exposure to chemical and particulate environmental agents. Such exposures are known to result in both lung and liver disease as well as other adverse health effects. C1 NIEHS, LMT, Res Triangle Pk, NC 27709 USA. RP de Serres, FJ (reprint author), NIEHS, LMT, MD F1 06,POB 12233, Res Triangle Pk, NC 27709 USA. NR 58 TC 47 Z9 50 U1 0 U2 4 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 DEC PY 2003 VL 111 IS 16 BP 1851 EP 1854 DI 10.1289/ehp.6511 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 751BY UT WOS:000187034000028 PM 14654440 ER PT J AU O'Fallon, LR Wolfle, GM Brown, D Dearry, A Olden, K AF O'Fallon, LR Wolfle, GM Brown, D Dearry, A Olden, K TI Strategies for setting a national research agenda that is responsive to community needs SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE community partnerships; environmental health; health disparities; outreach strategies; prevention research; public health; research agenda; Town Meetings; translational research ID ENVIRONMENTAL-HEALTH SCIENCES; PARTICIPATORY RESEARCH; PUBLIC-HEALTH; HARLEM AB Setting a national environmental health research agenda requires broad public input, including that from leading scientists, health care professionals, and communities. Contributions from these diverse constituencies are essential to formulating a research and education strategy that both advances our understanding of the causes and mechanisms of environmentally related diseases and translates such findings into effective prevention and clinical applications to protect those most affected by adverse environmental exposures. Given the increasing number of individual researchers working with communities to address environmental health needs during the past decade, it is also essential for research institutions to foster relationships with communities to understand and respond to their unique public health needs, as well as to communicate research advances in a manner that is both understandable and culturally appropriate. To achieve broad public input and to foster community-university partnerships, the National Institute of Environmental Health Sciences (NIEHS) supports various workshops, roundtables, and advisory groups. In particular, the NIEHS finds Town Meetings to be a successful model for bringing academic researchers together with community residents, state and local departments of health, and community-based organizations to foster greater awareness of community needs, public health needs, and environmental health science research. Since 1998, the NIEHS has supported 16 Town Meetings across the country. In this article we highlight the major outcomes of,these meetings to demonstrate the effectiveness of this mechanism for enhancing cooperation among researchers, community residents, and public health officials with the goal of improving public health and setting a national research agenda. C1 NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. Univ Texas, Ctr Hlth Sci, San Antonio, TX USA. RP O'Fallon, LR (reprint author), NIEHS, Div Extramural Res & Training, POB 12233 MD EC-21, Res Triangle Pk, NC 27709 USA. NR 16 TC 19 Z9 20 U1 1 U2 5 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 DEC PY 2003 VL 111 IS 16 BP 1855 EP 1860 DI 10.1289/ehp.6267 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 751BY UT WOS:000187034000029 PM 14644657 ER PT J AU Zhang, ZJ Xing, GQ Russell, S Obeng, K Post, RM AF Zhang, ZJ Xing, GQ Russell, S Obeng, K Post, RM TI Unidirectional cross-tolerance from levetiracetam to carbamazepine in amygdala-kindled seizures SO EPILEPSIA LA English DT Article DE cross-tolerance; levetiracetam; carbamazepine; kindling; rat ID ANTIEPILEPTIC DRUG LEVETIRACETAM; TEMPORAL-LOBE EPILEPSY; CONTINGENT TOLERANCE; ANTICONVULSANT LEVETIRACETAM; MAINTENANCE TREATMENT; BIPOLAR DISORDER; RAT-BRAIN; UCB L059; LAMOTRIGINE; MODEL AB Purpose: Tolerance is a potential problem in long-term anticonvulsant therapy of epilepsy, bipolar disorder, and neuropathic pain. The present study was designed to determine whether cross-tolerance occurs between levetiracetam (LEV) and carbamazepine (CBZ) in amygdala-kindled rats. Methods: Male Sprague-Dawley rats were implanted with an electrode into the left amygdala. While kindling stimulation was started, animals received repeated treatment (i.p.) with saline (n = 7) or LEV (150 mg/kg, n = 8). Saline-injected rats were subsequently challenged with a single dose of 150 mg/kg LEV when full kindling developed (stage greater than or equal to4). Both groups of rats were then administered long-term CBZ (5 mg/kg) until rats developed complete tolerance. All CBZ-tolerant rats were subsequently reexposed to LEV (150 mg/kg) for an additional 10 consecutive days. Results: Repeated LEV treatment significantly suppressed the increase in seizure stage, seizure duration, and afterdischarge duration induced by amygdala stimulation, markedly increasing the number of stimulations to achieve a kindling major motor seizure. The LEV challenge produced a more robust suppression of seizure stage in saline-injected rats compared with LEV-treated animals. CBZ treatment markedly suppressed fully kindled seizures in rats initially injected with saline, and then anticonvulsant tolerance rapidly developed after 3-4 days of repeated treatment. In contrast, rats that had initially received repeated LEV treatment did not show a response to treatment with CBZ (5 mg/kg). When CBZ-tolerant rats were subsequently exposed to LEV (150 mg/kg), noticeable anticonvulsant effects were observed; but these were gradually lost with increasing numbers of LEV exposures. Conclusions: Whereas LEV shows potent antiepileptogenic and anticonvulsant effects in amygdala-kindled rats, its repeated treatment induces anticonvulsant tolerance and unidirectional cross-tolerance to CBZ. In contrast, anticonvulsant tolerance to CBZ does not transfer to LEV. The mechanistic implications of the present results for clinical therapeutics remain to be evaluated. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Zhang, ZJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. OI Xing, Guoqiang/0000-0002-4706-3063 NR 46 TC 13 Z9 13 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD DEC PY 2003 VL 44 IS 12 BP 1487 EP 1493 DI 10.1111/j.0013-9580.2003.34803.x PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 755RF UT WOS:000187424700002 PM 14636317 ER PT J AU Biesecker, LG AF Biesecker, LG TI Heritable syndromes hypothalamic hamartoma and seizures: using rare syndromes to understand more with common disorders SO EPILEPTIC DISORDERS LA English DT Article; Proceedings Paper CT 7th Eilat Conference on New Antiepileptic Drugs (EILAT 7) CY MAY 09-13, 2004 CL VILLASIMIUS, ITALY DE hypothalamic hamartoma; gelastic epilepsy; multiple abnormalities; developmental biology; heritable diseases; Pallister-Hall ID PALLISTER-HALL SYNDROME; FACIAL-DIGITAL SYNDROME; BARDET-BIEDL-SYNDROME; GENE AB Manifestations of non-syndromic hypothalamic hamartomas are different from those of the syndromic hamartomas, and the syndromic ones are rare. In spite of the rarity of the syndromic hamartomas, they can be a powerful biological tool to help us understand the pathophysiology of these heritable disorders. Several disorders that include hypothalamic hamartomas are reviewed here and the current understanding of the biology of the lesions is summarized. C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), Natl Human Genome Res Inst, NIH, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 15 TC 6 Z9 6 U1 0 U2 0 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 1294-9361 J9 EPILEPTIC DISORD JI Epileptic Disord. PD DEC PY 2003 VL 5 IS 4 BP 235 EP 238 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 774RD UT WOS:000188996800008 PM 14975792 ER PT J AU Lenfant, C AF Lenfant, C TI Obesity and diabetes: Is the worst yet to come for cardiovascular disease? SO ETHNICITY & DISEASE LA English DT Editorial Material ID ADOLESCENTS; PREVALENCE; CHILDREN; TRENDS C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 1 Z9 1 U1 0 U2 0 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD WIN PY 2003 VL 13 IS 1 BP 3 EP 5 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 802ML UT WOS:000220167500001 PM 12723005 ER PT J AU Shukla, S Saini, P Smriti Jha, S Ambudkar, SV Prasad, R AF Shukla, S Saini, P Smriti Jha, S Ambudkar, SV Prasad, R TI Functional characterization of Candida albicans ABC transporter Cdr1p SO EUKARYOTIC CELL LA English DT Article ID HUMAN P-GLYCOPROTEIN; AZOLE ANTIFUNGAL AGENTS; MULTIDRUG TRANSPORTER; CYSTIC-FIBROSIS; ATP HYDROLYSIS; CATALYTIC CYCLE; RESISTANCE; BINDING; PROTEIN; YEAST AB In view of the importance of Candida drug resistance protein (Cdr1p) in azole resistance, we have characterized it by overexpressing it as a green fluorescent protein (GFP)-tagged fusion protein (Cdr1p-GFP). The overexpressed Cdr1p-GFP in Saccharomyces cerevisiae is shown to be specifically labeled with the photoaffinity analogs iodoarylazidoprazosin (LAAP) and azidopine, which have been used to characterize the drug-binding sites on mammalian drug-transporting P-glycoproteins. While nystatin could compete for the binding of IAAP, miconazole specifically competed for azidopine binding, suggesting that IAAP and azidopine bind to separate sites on Cdr1p. Cdr1p was subjected to site-directed mutational analysis. Among many mutant variants of Cdr1p, the phenotypes of F774A and DeltaF774 were particularly interesting. The analysis of GFP-tagged mutant variants of Cdr1p revealed that a conserved F774, in predicted transmembrane segment 6, when changed to alanine showed increased binding of both photoaffinity analogues, while its deletion (DeltaF774), as revealed by confocal microscopic analyses, led to mislocalization of the protein. The mislocalized DeltaF774 mutant Cdr1p could be rescued to the plasma membrane as a functional transporter by growth in the presence of a Cdr1p substrate, cycloheximide. Our data for the first time show that the drug substrate-binding sites of Cdr1p exhibit striking similarities with those of mammalian drug-transporting P-glycoproteins and despite differences in topological organization, the transmembrane segment 6 in Cdr1p is also a major contributor to drug substrate-binding site(s). C1 Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Prasad, R (reprint author), Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. RI Ambudkar, Suresh/B-5964-2008; Jha, Sudhakar /B-2308-2009 NR 48 TC 82 Z9 87 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD DEC PY 2003 VL 2 IS 6 BP 1361 EP 1375 DI 10.1128/EC.2.6.1361-1375.2003 PG 15 WC Microbiology; Mycology SC Microbiology; Mycology GA 754ZN UT WOS:000187363500021 PM 14665469 ER PT J AU Harter, MC Conway, KP Merikangas, KR AF Harter, MC Conway, KP Merikangas, KR TI Associations between anxiety disorders and physical illness SO EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE LA English DT Article DE anxiety disorders; comorbidity; physical illness; psychiatric epidemiology; psychosomatic medicine ID NATIONAL-COMORBIDITY-SURVEY; PANIC DISORDER; PSYCHIATRIC-DISORDERS; DIAGNOSTIC-CRITERIA; MEDICAL ILLNESS; PREVALENCE; DEPRESSION; RECOGNITION; POPULATION; BIOLOGY AB Objective In contrast to the literature on the association of depression with medical illness, less is known about the comorbidity among anxiety and somatic disorders. Although associations between anxiety disorders and medical illnesses have been reported, prior studies have not adjusted for the effects of gender, substance abuse/dependence, and depression. This study examined the patterns of comorbidity of anxiety disorders and physical illnesses. Method A total of 262 probands were selected from treatment settings or were randomly recruited from the community. DSM-III-R diagnoses were obtained based on direct interview (SADS) or family history information, and lifetime history of numerous medical illnesses were obtained. Results Patients with a lifetime anxiety disorder reported higher rates of several medical illnesses than did persons without anxiety. After controlling for the effects of gender, comorbid substance abuse/dependence and/or depression, significant associations were found between anxiety disorder and cardiac disorders (OR = 4.6), hypertension (OR = 2.4), gastrointestinal problems (OR = 2.4), genitourinary disorders (OR = 3.5), and migraine (OR = 5.0). A similar pattern was observed for probands with panic or generalized anxiety disorder (GAD). Conclusions Anxiety disorders were associated with a specific pattern of cardiac disorders, hypertension, gastrointestinal problems, genitourinary difficulties, and migraine; individuals presenting with anxiety disorders or medical illness need therefore to be evaluated carefully for comorbidity. C1 Univ Freiburg, Med Ctr, Dept Psychiat & Psychotherapy, D-79104 Freiburg, Germany. NIDA, NIH, Bethesda, MD 20892 USA. NIMH, Bethesda, MD 20892 USA. RP Harter, MC (reprint author), Univ Freiburg, Med Ctr, Dept Psychiat & Psychotherapy, Hauptstr 5, D-79104 Freiburg, Germany. OI Conway, Kevin/0000-0002-7638-339X FU NIAAA NIH HHS [AAO7080, AA09978]; NIDA NIH HHS [DA05348]; NIMH NIH HHS [MH36197] NR 36 TC 113 Z9 118 U1 1 U2 9 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0940-1334 J9 EUR ARCH PSY CLIN N JI Eur. Arch. Psych. Clin. Neurosci. PD DEC PY 2003 VL 253 IS 6 BP 313 EP 320 DI 10.1007/s00406-003-0449-y PG 8 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 758MM UT WOS:000187637900007 PM 14714121 ER PT J AU Andreolotti, AG Bragado, MJ Tapia, JA Jensen, RT Garcia-Marin, LJ AF Andreolotti, AG Bragado, MJ Tapia, JA Jensen, RT Garcia-Marin, LJ TI Cholecystokinin rapidly stimulates CrkII function in vivo in rat pancreatic acini - Formation of CrkII-protein complexes SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE Crk; protein complex; CCK; transduction pathways; pancreatic acini ID GROWTH-FACTOR RECEPTOR; SMOOTH-MUSCLE-CELLS; TYROSINE PHOSPHORYLATION; ACTIN CYTOSKELETON; PHOSPHOLIPASE-C; SIGNALING PATHWAYS; ADAPTER PROTEINS; ASSOCIATION; P130(CAS); SRC AB Crk belongs to a family of adapter proteins whose structure allows interaction with tyrosine-phosphorylated proteins and is therefore an important modulator of downstream signals, representing a convergence of the actions of numerous stimuli. Recently, it was demonstrated that cholecystokinin (CCK) induced tyrosine phosphorylation of proteins related to fiber stress formation in rat pancreatic acini. Here, we investigated whether CCK receptor activation signals through CrkII and forms complexes with tyrosine-phosphorylated proteins in rat pancreatic acini. We demonstrated that CCK promoted the transient formation of CrkII-paxillin and CrkII-p130(Cas) complexes with maximal effect at 1 min. Additionally, CCK decreased the electrophoretic mobility of CrkII. This decrease was time- and concentration-dependent and inversely related with its function. Carbachol and bombesin also decreased CrkII electrophoretic mobility, whereas epidermal growth factor, vasoactive intestinal peptide, secretin or pituitary adenylate cyclase-activating polypeptide had no effect. CCK-induced CrkII electrophoretic shift was dependent on the Src family of tyrosine kinases and occurred in the intact animal, suggesting a physiological role of CrkII mediating CCK actions in the exocrine pancreas in vivo. C1 Univ Extremadura, Fac Vet, Dept Fisiol, Caceres 10071, Spain. Univ Extremadura, Dept Bioquim Biol Mol & Genet, Caceres, Spain. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Garcia-Marin, LJ (reprint author), Univ Extremadura, Fac Vet, Dept Fisiol, Avda Univ S-N, Caceres 10071, Spain. RI Bragado, Maria/L-6988-2014; Garcia-Marin, Luis /L-4680-2014; Tapia, Jose/C-5181-2008 OI Bragado, Maria/0000-0001-7770-0775; Garcia-Marin, Luis /0000-0002-1795-7381; Tapia, Jose/0000-0002-3614-6867 NR 35 TC 8 Z9 8 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD DEC PY 2003 VL 270 IS 23 BP 4706 EP 4713 DI 10.1046/j.1432-1033.2003.03869.x PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 742RP UT WOS:000186532100013 PM 14622258 ER PT J AU Lipska, BK Lerman, DN Khaing, ZZ Weinberger, DR AF Lipska, BK Lerman, DN Khaing, ZZ Weinberger, DR TI The neonatal ventral hippocampal lesion model of schizophrenia: effects on dopamine and GABA mRNA markers in the rat midbrain SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE animal model; dopamine transporter; dopamine; GAD-67; schizophrenia; tyrosine hydroxylase ID PHASEOLUS-VULGARIS-LEUKOAGGLUTININ; NUCLEUS-ACCUMBENS DOPAMINE; PREFRONTAL CORTEX; TYROSINE-HYDROXYLASE; TRANSPORTER BINDING; ANIMAL-MODEL; MICE LACKING; IN-VIVO; ANTEROGRADE TRANSPORT; PLACE PREFERENCE AB The neonatal ventral hippocampal lesion in the rat has been used as a model of schizophrenia, a human disorder associated with changes in markers of dopamine and gamma-aminobutyric acid (GABA) circuits in various regions of the brain. We investigated whether alterations in mRNA markers related to the activity of midbrain dopaminergic and GABAergic neurons are associated with this model. We used in situ hybridization histochemistry to assess expression of mRNAs for dopamine transporter (DAT), tyrosine hydroxylase (TH) and glutamate decarboxylase-67 (GAD67) in the midbrain of adult rats with neonatal and adult ibotenic acid lesions of the ventral hippocampus. Neonatally lesioned rats showed in adulthood significantly reduced expression of DAT mRNA in the substantia nigra and the ventral tegmental area but no changes in the expression of TH and GAD67 mRNAs in these midbrain regions. Adult lesioned rats showed no changes in the expression of any of these genes. As the neonatal ventral hippocampal lesion reproduces many aspects of schizophrenia and is used as an animal model of this disorder, these results suggest that the reduction in DAT mRNA could result from developmental neuropathology in the ventral hippocampus and may thus represent a molecular substrate of the disease process. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Programme, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Programme, Bldg 10,Rm 4N306, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 57 TC 55 Z9 56 U1 1 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2003 VL 18 IS 11 BP 3097 EP 3104 DI 10.1046/j.1460-9568.2003.03047.x PG 8 WC Neurosciences SC Neurosciences & Neurology GA 750PZ UT WOS:000187006400019 PM 14656305 ER PT J AU Petralia, RS Wang, YX Wenthold, RJ AF Petralia, RS Wang, YX Wenthold, RJ TI Internalization at glutamatergic synapses during development SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE AMPA; caveolin; clathrin; NMDA; rat ID AMPA RECEPTOR TRAFFICKING; CLATHRIN-MEDIATED ENDOCYTOSIS; SYNAPTIC VESICLE ENDOCYTOSIS; NMDA RECEPTORS; DENDRITIC SPINES; HIPPOCAMPAL-NEURONS; SURFACE EXPRESSION; LATERAL MOVEMENTS; NERVOUS-SYSTEM; LIPID RAFTS AB Glutamate receptors are internalized from the cell membrane via clathrin-coated pits. However, little is known about where this occurs - whether at or near the synapse or at some distance from it. In this study we used immunogold localization in the rat brain (mainly hippocampus) to show that clathrin-coated pits are found both at the edge of the synaptic active zone and at further postsynaptic distances, including on the sides of the spine; we also localize these pits specifically to glutamatergic synapses. In addition, we show that clathrin-coated pits can internalize both N-methyl-D-aspartate (in vivo) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (in vitro data only) receptors at extrasynaptic sites not associated directly with synapses. Also, caveolin might be prevalent at excitatory synapses, although it is not known whether it is involved in receptor internalization, receptor stabilization, or some other function. C1 NIDCD, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Petralia, RS (reprint author), NIDCD, Neurosci Lab, NIH, 50-4142,50 South Dr,MSC 8027, Bethesda, MD 20892 USA. NR 62 TC 59 Z9 65 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 2003 VL 18 IS 12 BP 3207 EP 3217 DI 10.1046/j.1460-9568.2003.03074.x PG 11 WC Neurosciences SC Neurosciences & Neurology GA 755MM UT WOS:000187406700006 PM 14686895 ER PT J AU Fujita, M Ichise, M van Dyck, CH Zoghbi, SS Tamagnan, G Mukhin, AG Bozkurt, A Seneca, N Tipre, D DeNucci, CC Iida, H Vaupel, DB Horti, AG Koren, AO Kimes, AS London, ED Seibyl, JP Baldwin, RM Innis, RB AF Fujita, M Ichise, M van Dyck, CH Zoghbi, SS Tamagnan, G Mukhin, AG Bozkurt, A Seneca, N Tipre, D DeNucci, CC Iida, H Vaupel, DB Horti, AG Koren, AO Kimes, AS London, ED Seibyl, JP Baldwin, RM Innis, RB TI Quantification of nicotinic acetylcholine receptors in human brain using [I-123]5-I-A-85380 SPET SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE high-affinity type nicotinic receptors; compartmental modeling; equilibrium; distribution volume ID POSITRON-EMISSION-TOMOGRAPHY; BENZODIAZEPINE RECEPTORS; ATTENUATION CORRECTION; NONHUMAN-PRIMATES; I-123 IOMAZENIL; BINDING; SUBTYPES; 5-IODO-A-85380; ALPHA-4-BETA-2; AFFINITY AB The purpose of this study was to assess the utility of a new single-photon emission tomography ligand, [I-123]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380), to measure regional nAChR binding in human brain. Six healthy nonsmoker subjects (two men and four women, age 33 15 years) participated in both a bolus (dose: 317+/-42 MBq) and a bolus plus constant infusion (dose of bolus: 98+/-32 MBq, B/I=6.7+/-2.6 h, total dose: 331+/-55 MBq) study. The study duration was 5-8 h and 14 h in the former and the latter, respectively. Nonlinear least-squares compartmental analysis was applied to bolus studies to calculate total (V) and specific (V-S') distribution volumes. A two-tissue compartment model was applied to identify V-S'. V-T' was also calculated in B/I studies. In bolus studies, V-T' was well identified by both one- and two-tissue compartment models, with a coefficient of variation of less than 5% in most regions. The two-compartment model gave V values of 51, 22, 27, 32, 20, 19, 20, and 17 ml cm(-3) in thalamus, cerebellum, putamen, pons, and frontal, parietal, temporal, and occipital cortices, respectively. The two-compartment model did not identify V-S' well. B/I studies provided poor accuracy of V measurement, possibly due to deviations from equilibrium conditions. These results demonstrate the feasibility of quantifying high-affinity type nAChRs using [I-123]5-I-A-85380 in humans and support the use of V measured by bolus studies. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare Syst, West Haven, CT USA. Yale Univ, Sch Med, Dept Radiol, West Haven, CT 06516 USA. NIDA, Brain Imaging Ctr, Intramural Res Program, Baltimore, MD USA. Natl Cardiovasc Ctr, Res Inst, Dept Invest Radiol, Osaka, Japan. Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA USA. Inst Neurodegenerat Disorders, New Haven, CT USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Room B3-10,1 Ctr Dr,MSC-0135, Bethesda, MD 20892 USA. EM FujitaM@intra.nimh.nih.gov RI Iida, Hidehiro/D-4582-2011 FU NIDA NIH HHS [P50 DA84733] NR 37 TC 34 Z9 36 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD DEC PY 2003 VL 30 IS 12 BP 1620 EP 1629 DI 10.1007/S00259-003-1320-0 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 762QG UT WOS:000187993200004 PM 14523584 ER PT J AU Gahl, WA AF Gahl, WA TI Early oral cysteamine therapy for nephropathic cystinosis SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Article; Proceedings Paper CT International Symposium on Early Diagnosis of Inherited Metabolic Diseases CY NOV 21-23, 2001 CL FULDA, GERMANY DE cysteamine; cystinosis; Fanconi syndrome; newborn screening; renal failure ID LEUKOCYTE GRANULAR FRACTIONS; CORNEAL CRYSTALS; GENE CTNS; TRANSPORT; LYSOSOMES; DEPLETION; DELETION; CHILDREN; PROTEIN; REMOVAL AB Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder in which intracellular cystine accumulates due to impaired transport out of lysosomes. The clinical manifestations include renal tubular Fanconi syndrome in the 1st year of life, with hypophosphatemic rickets, hypokalemia, polyuria, dehydration and acidosis, growth retardation, hypothyroidism, photophobia, renal glomerular deterioration by 10 years of age, and late complications such as myopathy, pancreatic insufficiency, and retinal blindnesss. The cystinosis gene, CTNS, codes for cystinosin, a 367 amino acid protein with seven transmembrane domains. More than 50 CTNS mutations have been identified, but approximately 50% of Northern European patients have a 57257-bp deletion which removes the first nine exons of CTNS. The mainstay of cystinosis therapy is oral cysteamine (Cystagon). This aminothiol can lower intracellular cystine content by 95%, and has proven efficacy in delaying renal glomerular deterioration, enhancing growth, preventing hypothyroidism, and lowering muscle cystine content. Its early and diligent use is critical; in one study, for every month of treatment prior to 3 years of age, 14 months' worth of later renal function were preserved. Several examples of individual patients treated early and having preserved renal function and normal growth are available. Newborn screening using a chip containing cDNA to detect common CTNS mutations may allow diagnosis and treatment in the first weeks of life. Conclusion: Early diagnosis and treatment of nephropathic cystinosis can change the course of this disease. C1 NICHHD, Sect Human Biochem Genet, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NICHHD, Sect Human Biochem Genet, NIH, MSC 1851 Bldg 10,Room 10C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov NR 23 TC 39 Z9 42 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6199 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD DEC PY 2003 VL 162 SU 1 BP S38 EP S41 DI 10.1007/s00431-003-1349-x PG 4 WC Pediatrics SC Pediatrics GA 765ZH UT WOS:000188320600011 PM 14610675 ER PT J AU Abi-Dargham, A Kegeles, LS Martinez, D Innis, RB Laruelle, M AF Abi-Dargham, A Kegeles, LS Martinez, D Innis, RB Laruelle, M TI Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: results from a large cohort SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; amphetamine; addiction; SPECT ID POSITRON-EMISSION-TOMOGRAPHY; INBRED RAT STRAINS; RHESUS-MONKEYS; HUMAN-BRAIN; NUCLEUS-ACCUMBENS; SQUIRREL-MONKEYS; ANTAGONIST SCH-23390; NONHUMAN-PRIMATES; RECEPTOR AGONISTS; COMPUTERIZED-TOMOGRAPHY AB A positive experience during a first encounter with a drug of abuse is predictive of subsequent use and might represent a vulnerability factor to develop addiction. This paper presents a meta-analysis of data acquired in 60 healthy volunteers who underwent a low-dose amphetamine challenge (0.3 mg/kg, i.v.) during imaging of dopamine D-2 receptor availability with SPECT and the D-2/D-3 radiotracer [I-123]IBZM. Amphetamine-stimulated DA release induced a small, significant and highly variable decrease in striatal D-2 receptor availability (-8.3 +/- 6.7%). The magnitude of the decrease in D-2 receptor availability was significantly associated with the positive reinforcing effects of the drug reported by the subject (r(2) = 0.14, p = 0.003). Age was associated with decreased potency of dopamine to elicit positive reinforcing effects. This study indicates that both a large dopaminergic response and young age during a first encounter with a drug of abuse potential contribute to higher positive reinforcing effects. (C) 2003 Elsevier B.V./ECNP. All rights reserved. C1 Columbia Univ, Dept Psychiat, New York, NY 10027 USA. Columbia Univ, Dept Radiol, New York, NY 10027 USA. NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Laruelle, M (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, Div Funct Brain Mapping, Unit 31, 1051 Riverside Dr, New York, NY 10032 USA. EM m1393@columbia.edu FU NIDA NIH HHS [R01 DA10219-01]; NIMH NIH HHS [K02 MH01603-01, R01MH54192-0] NR 82 TC 47 Z9 47 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD DEC PY 2003 VL 13 IS 6 BP 459 EP 468 DI 10.1016/j.euroneuro.2003.08.007 PG 10 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 765QT UT WOS:000188295500007 PM 14636962 ER PT J AU Xiao, XD Athanasiou, M Sidorov, IA Horikawa, I Cremona, G Blair, D Barret, JC Dimitrova, DS AF Xiao, XD Athanasiou, M Sidorov, IA Horikawa, I Cremona, G Blair, D Barret, JC Dimitrova, DS TI Role of Ets/Id proteins for telomerase regulation in human cancer cells SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE telomerase regulation; Ets; Id2; c-Myc; Sp1 ID REVERSE-TRANSCRIPTASE GENE; CATALYTIC SUBUNIT HTERT; C-MYC; ID PROTEINS; INCREASED EXPRESSION; CELLULAR SENESCENCE; DIRECT ACTIVATION; PROMOTER; IDENTIFICATION; PHENOTYPE AB Most human cancers express telomerase but its activity is highly variable and regulated by complex mechanisms. Recently, we have proposed that Ets proteins may be important for regulation of telomerase activity in leukemic cells. Here we provide further evidence for the role of Ets family members and related Id proteins in telomerase regulation and characterize the underlying molecular mechanisms. By using PCR-based and gel shift assays we demonstrated specific binding to a core hTERT promoter of Ets2, Fli1, Id2, c-Myc, Mad1, and Sp1 in lysates from subclones of U937 cells. Further analysis of binding of purified proteins and various mutants of the hTERT promoter suggested the existence of a trimolecular Ets-Id2-DNA complex, and Ets inhibitory activity mediated by c-Myc and the Ets binding site on the core hTERT promoter at -293 bp from the transcription initiation site as well as a positive Ets regulatory effect mediate through another Ets binding site at -36 bp. This analysis provided evidence for the existence of negative and positive Ets regulatory site and suggested a complex interplay between Ets/Id family members and c-Myc that may be an important determinant of the diversity of telomerase activity in leukemia and other cancers. (C) 2003 Elsevier Inc. All rights reserved. C1 NCI, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. NCI, Lab Biosyst & Canc, CCR, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Basic Res Lab, CCR, NIH, Frederick, MD 21702 USA. RP Xiao, XD (reprint author), NCI, Lab Expt & Computat Biol, NIH, Bldg 469,Rm 246,Rm 139,POB B,Miller Dr, Frederick, MD 21702 USA. OI Sidorov, Igor/0000-0001-6519-4983 FU NCI NIH HHS [N01-CO-12400] NR 36 TC 27 Z9 29 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 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD DEC PY 2003 VL 75 IS 3 BP 238 EP 247 DI 10.1016/S0014-4800(03)00092-3 PG 10 WC Pathology SC Pathology GA 744RJ UT WOS:000186645700007 PM 14611815 ER PT J AU Schrader, WT AF Schrader, WT TI Career choices in the biosciences: What companies are looking for when they are filling a position SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article AB Holding a Ph.D. or other doctoral degree in the biological sciences used to allow for only one main career path. Faculty positions at either research-intensive universities or at predominantly teaching institutions defined the career path very well. The situation is considerably more complex now. Many individuals decide to pursue careers in for-profit organizations, either by personal preference, geographic needs, or simply as an expedient way to continue in biology in a meaningful way. This article arises from the need to define a better understanding of the nature of corporate job seeking for potential job applicants. The author draws upon his experience over a thirty-year scientific career in industry and academics. The distinctions he makes are helpful for job-seekers in this new environment. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Schrader, WT (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD DEC PY 2003 VL 228 IS 11 BP 1261 EP 1265 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 833FG UT WOS:000222321300003 PM 14681540 ER PT J AU Lee, JH Ahn, KS Lee, CH Youn, SJ Kim, JW Lee, DY Lee, ES Steinert, PM Yang, JM AF Lee, JH Ahn, KS Lee, CH Youn, SJ Kim, JW Lee, DY Lee, ES Steinert, PM Yang, JM TI Keratin 9 gene mutations in five Korean families with epidermolytic palmoplantar keratoderma SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE epidermolytic palmoplantar keratoderma; keratin 9 gene; mutations ID ROD DOMAIN SEGMENT; INTERMEDIATE FILAMENTS; 1A; HYPERKERATOSIS; H1 AB Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant disease characterized clinically by localized palmoplantar thickening and histopathologically by granular degeneration of the epidermis. Recent molecular biological studies have revealed that EPPK is caused by mutations of the keratin 9 gene in sequences mainly encoding the highly conserved 1 A rod domain. Here we demonstrate a novel mutation of N160H (position 8 of the 1 A domain) and two other previously reported mutations, R162W and N160S, in five unrelated Korean families with EPPK. The three-dimensional structure of the 1 A domain of the related vimentin intermediate filament protein chain is now known. Based on its likely similarity to the keratin 9 chain, we predict that inappropriate amino acid substitutions in position 10 of 1 A will likely interfere with coiled-coil dimer stability, and those in position 8 will interfere with tetramer stability. Accordingly, these mutations compromise the structural integrity of the keratin intermediate filaments leading to the pathology of EPPK. C1 Sungkyunkwan Univ, Sch Med, Dept Dermatol, Samsung Med Ctr, Seoul 135710, South Korea. Samsung Biomed Res Inst, Clin Res Ctr, Seoul, South Korea. Inha Univ, Sch Med, Dept Biochem, Inchon, South Korea. NIAMSD, Skin Biol Lab, NIH, Bethesda, MD USA. RP Yang, JM (reprint author), Sungkyunkwan Univ, Sch Med, Dept Dermatol, Samsung Med Ctr, 50 Ilwon Dong, Seoul 135710, South Korea. NR 24 TC 6 Z9 9 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD DEC PY 2003 VL 12 IS 6 BP 876 EP 881 DI 10.1111/j.0906-6705.2003.00012.x PG 6 WC Dermatology SC Dermatology GA 753XY UT WOS:000187274700019 PM 14675368 ER PT J AU Rhee, DJ Tamm, ER Russell, P AF Rhee, DJ Tamm, ER Russell, P TI Donor corneoscleral buttons: a new source of trabecular meshwork for research SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE trabecular meshwork; cell culture; glaucoma; corneoscleral buttons; molecular biology ID PRESSURES; MONKEYS; TISSUE AB The human trabecular meshwork (TM) is the major site of resistance for aqueous humor outflow. The purpose of this investigation was to determine the suitability of TMs harvested from donor corneoscleral buttons (buttons) for laboratory studies. Histologic examination using light and electron microscopy was performed. Additionally, the effect of incubation in serum free media on histologic appearance was studied. Total RNA extraction was performed on 45 buttons and four whole eyes. Some TMs were used as a source for establishing primary cell cultures of TM endothelial cells. Compared with donor whole eyes, light microscopy showed comparable TM cellularity in the juxtacanalicular and corneoscleral TM; there was some loss of cells in the inner portion of uveal TM that was adjacent to the anterior chamber. The TM cells appeared healthy and structurally normal on transmissive electron microscopy. Usable quantities of total RNA could be extracted from buttons that had been stored up to 5 weeks. The amount of total RNA extracted correlated well with the histologic appearance. Incubation in serum free media did not have an effect on the histologic appearance. All attempts at establishing primary cell cultures were successful. Unused. donor corneoscleral buttons are an excellent source of TM. (C) 2003 Elsevier Ltd. All rights reserved. C1 NEI, Lab Mech Ocular Dis, NIH, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Dept Anat Mol Anat & Embryol, D-8520 Erlangen, Germany. RP Rhee, DJ (reprint author), Wills Eye Hosp & Res Inst, Glaucoma Serv, 900 Walnut St, Philadelphia, PA 19107 USA. OI Tamm, Ernst/0000-0002-6679-8743 FU NEI NIH HHS [EY 013997] NR 5 TC 24 Z9 24 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD DEC PY 2003 VL 77 IS 6 BP 749 EP 756 DI 10.1016/j.exer.2003.07.008 PG 8 WC Ophthalmology SC Ophthalmology GA 747LY UT WOS:000186807000012 PM 14609563 ER PT J AU Lipovsky, K Bennett, LA Chen, JC AF Lipovsky, K Bennett, LA Chen, JC TI B-cell deficiency and reduced B-cell reconstitution in hemoglobin-deficit mice SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; HEREDITARY MICROCYTIC ANEMIA; MARROW-TRANSPLANTATION; MOUSE; PHENOTYPE; NUMBERS; IRON; EXPANSION AB Objective. To study the effect of persistent hemoglobin-deficit mutation (hbd/hbd) on hematopoiesis and the function of hematopoietic stem cells (HSCs). Methods. Young and old mice homozygous for the spontaneous hbd/hbd mutation were compared to young and old wild-type control mice, all on the C57BL/6 background, over cellular composition in blood and bone marrow (BM) using cell counting, complete blood counts, and flow cytometry. BM cells from hbd/hbd mutants and normal controls were also tested for HSC engraftment in vivo using the competitive repopulation assay. Results. Both young and old hbdllzbd mutants exhibited a microcytic anemia with significantly (p < 0.01) lower levels of hemoglobin and mean corpuscular volume. There were significant declines in CD45R(+) B cells in both blood (p < 0.01) and BM (p < 0.05) in old hbdlhbd mice, suggesting that B-cell homeostasis was compromised. Total BM cells per mouse was significantly increased (p < 0.05) in old hbdlhbd mice. In the competitive repopulation assay in vivo, BM cells from old hbdlhbd donors showed slightly decreased contribution to T cells and myeloid cells but a significantly (p < 0.01) decreased engraftment in B lymphocytes, indicating that B-cell hematopoiesis was compromised in old hbdlhbd mice. These data differ from results previously obtained from normal C57BL/6 mice in which BM cell engraftment ability does not decrease with donor age. Conclusion. Persistent hbdlhbd mutation causes hematopoiesis defects in the B cell lineage. (C) 2003 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7C118,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov NR 23 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD DEC PY 2003 VL 31 IS 12 BP 1230 EP 1236 DI 10.1016/j.exphem.2003.08.007 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 814HE UT WOS:000220965000012 PM 14662329 ER PT J AU Anderson, WF Umar, A Hawk, ET AF Anderson, WF Umar, A Hawk, ET TI Cyclooxygenase inhibition in cancer prevention and treatment SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE cancer prevention; cancer treatment; cyclooxygenase inhibition; cyclooxygenase overexpression; nonsteroidal anti-inflammatory drugs ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MULTIPLE INTESTINAL NEOPLASIA; GROWTH-FACTOR RECEPTOR; HUMAN BREAST-CANCER; UPPER GASTROINTESTINAL TOXICITY; APC(DELTA-716) KNOCKOUT MICE; PROSTAGLANDIN-H SYNTHASE; CELL LUNG-CANCER; COLORECTAL-CANCER; COLON CARCINOGENESIS AB Several lines of evidence suggest that the cyclooxygenase enzymes (specifically COX-2) might be an important molecular target for the intervention of cancer at both early and late stages of some cancers, providing an opportunity for both cancer prevention and therapy. COX-2 is overexpressed during carcinogenesis, and appears to have a role in both tumour initiation and promotion and is amenable to intervention. This review discusses the importance of COX modulation via non-specific, as well as COX-2 specific COX inhibitors (NSAIDs and COX-2 selective inhibitors [COX1B]). A brief discussion on the pharmacoeconomic considerations of NSAID and COX1B use and safety issues that have recently been the focus of debate, will be presented. C1 NCI, Gastrointestinal & Others Canc Res Grp, Div Canc Prevent, EPN, Bethesda, MD 20892 USA. RP Hawk, ET (reprint author), NCI, Gastrointestinal & Others Canc Res Grp, Div Canc Prevent, EPN, Room 2141,6130 Execut Blvd, Bethesda, MD 20892 USA. EM eh51p@nih.gov NR 124 TC 18 Z9 19 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 EI 1744-7666 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD DEC PY 2003 VL 4 IS 12 BP 2193 EP 2204 DI 10.1517/14656566.4.12.2193 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 754GA UT WOS:000187293300006 PM 14640918 ER PT J AU Philp, D Nguyen, M Scheremeta, B St-Surin, S Villa, AM Orgel, A Kleinman, HK Elkin, M AF Philp, D Nguyen, M Scheremeta, B St-Surin, S Villa, AM Orgel, A Kleinman, HK Elkin, M TI Thymosin beta(4) increases hair growth by activation of hair follicle stem cells SO FASEB JOURNAL LA English DT Article DE matrix metalloproteinase-2; clonogenic keratinocytes ID VEIN ENDOTHELIAL-CELLS; FACTOR HGF ACTIVATOR; RAT VIBRISSA; IN-VIVO; BETA-4; BULGE; SKIN; COLLAGEN; ANAGEN; MATRIX AB Thymosin beta(4), a 43-amino acid polypeptide that is an important mediator of cell migration and differentiation, also promotes angiogenesis and wound healing. Here, we report that thymosin beta(4) stimulates hair growth in normal rats and mice. A specific subset of hair follicular keratinocytes in mouse skin expresses thymosin beta(4) in a highly coordinated manner during the hair growth cycle. These keratinocytes originate in the hair follicle bulge region, a niche for skin stem cells. Rat vibrissa follicle clonogenic keratinocytes, closely related, if not identical, to the bulge-residing stem cells, were isolated and their migration and differentiation increased in the presence of nanomolar concentrations of thymosin beta(4). Expression and secretion of the extracellular matrix-degrading enzyme matrix metalloproteinase-2 were increased by thymosin beta(4). Thus, thymosin beta(4) accelerates hair growth, in part, due to its effect on critical events in the active phase of the hair follicle cycle, including promoting the migration of stem cells and their immediate progeny to the base of the follicle, differentiation, and extracellular matrix remodeling. C1 NICHHD, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Kleinman, HK (reprint author), NIDCR, Cell Biol Sect, NIH, Bldg 30,Room 433,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM hkleinman@dir.nidcr.nih.gov NR 46 TC 4 Z9 4 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD DEC PY 2003 VL 17 IS 15 BP 385 EP + DI 10.1096/fj.03-0244fje PG 16 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 763GX UT WOS:000188067500024 PM 14657002 ER PT J AU Mozzicato, S Joshi, BV Jacobson, KA Liang, BT AF Mozzicato, S Joshi, BV Jacobson, KA Liang, BT TI Role of direct RhoA-phospholipase D interaction in mediating adenosine-induced protection from cardiac ischemia SO FASEB JOURNAL LA English DT Article DE receptor; monomeric G protein; heart cell; myocyte; A(3) agonist ID A(3) RECEPTORS; SIMULATED ISCHEMIA; A(1); ACTIVATION; MYOCYTES; GENE; CARDIOMYOCYTES; INJURY; KINASE; HEART AB Activation of adenosine A(1) or A(3) receptors protects heart cells from ischemia-induced injury. The A(3) receptor signals via RhoA and phospholipase D (PLD) to induce cardioprotection. The objective of the study was to investigate how RhoA activates PLD to achieve the anti-ischemic effect of adenosine A(3) receptors. In an established cardiac myocyte model of preconditioning using the cultured chick embryo heart cells, overexpression of the RhoA-noninteracting PLD1 mutant I870R selectively blocked the A(3) agonist (Cl-IBMECA, 10 nM)-induced cardioprotection. 1870R caused a significantly higher percentage of cardiac cells killed in A(3) agonist-treated than in A(1) agonist (CCPA, 10 nM)-treated myocytes (ANOVA and posttest comparison, P<0.01). Consistent with its inhibitory effect on the PLD activity, I870R attenuated the Cl-IBMECA-mediated PLD activation. Cl-IBMECA caused a 41 +/- 15% increase in PLD activity in mock-transfected myocytes (P<0.01, paired t test) while having only a slight stimulatory effect on the PLD activity in I870R-transfected cells. To further test the anti-ischemic role of a direct RhoA-PLD1 interaction, atrial cardiac myocytes were rendered null for native adenosine receptors by treatment with irreversible A(1) antagonist m-DITC-XAC and were selectively transfected with the human adenosine A(1) or A(3) receptor cDNA individually or they were cotransfected with cDNAs encoding either receptor plus I870R. 1870R preferentially inhibited the human A(3) receptor-mediated protection from ischemia. The RhoA-noninteracting PLD1 mutant caused a significantly higher percentage of cardiac cells killed in myocytes cotransfected with the human A(3) receptor than in those cells expressing the human A(1) receptor (ANOVA and posttest comparison, P<0.01). The present data provided the first demonstration of a novel physiological role for the direct RhoA-PLD1 interaction, that of potent protection from cardiac ischemia. The study further supported the concept that a divergent signaling mechanism mediates the anti-ischemic effect of adenosine A(1) and A(3) receptors. C1 Univ Connecticut, Ctr Hlth, Dept Cardiol, Farmington, CT 06030 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Connecticut, Ctr Hlth, Dept Cardiol, 263 Farmington Ave, Farmington, CT 06030 USA. EM bliang@uchc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 29 TC 2 Z9 2 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD DEC PY 2003 VL 17 IS 15 BP 406 EP + DI 10.1096/fj.03-0592fje PG 13 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 763GX UT WOS:000188067500010 PM 14688204 ER PT J AU Kouprina, N Larionov, V AF Kouprina, N Larionov, V TI Exploiting the yeast Saccharomyces cerevisiae for the study of the organization and evolution of complex genomes SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE yeast artificial chromosome; transformation-associated recombination cloning; gene isolation; complex genome ID TRANSFORMATION-ASSOCIATED RECOMBINATION; ARTIFICIAL CHROMOSOME LIBRARIES; RAT PROSTATE-CANCER; TRANSGENIC MICE; HOMOLOGOUS RECOMBINATION; MAMMALIAN-CELLS; IN-VIVO; YAC LIBRARY; HUMAN DNA; ENZYMATIC AMPLIFICATION AB Yeast artificial chromosome (YAC) cloning systems have advanced the analysis of complex genomes considerably. They permit the cloning of larger fragments than do bacterial artificial chromosome systems, and the cloned material is more easily modified. We recently developed a novel YAC cloning system called transformation-associated recombination (TAR) cloning. Using in vivo recombination in yeast, TAR cloning selectively isolates, as circular YACs, desired chromosome segments or entire genes from complex genomes. The ability to do that without constructing a representative genomic library of random clones greatly facilitates analysis of gene function and its role in disease. In this review, we summarize how recombinational cloning techniques have advanced the study of complex genome organization, gene expression, and comparative genomics. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, NIH, Bldg 37,Room 5032,90000 Rockville Pike, Bethesda, MD 20892 USA. NR 123 TC 11 Z9 13 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-6445 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD DEC PY 2003 VL 27 IS 5 BP 629 EP 649 DI 10.1016/S0168-6445(03)00070-6 PG 21 WC Microbiology SC Microbiology GA 751CJ UT WOS:000187035000004 PM 14638416 ER PT J AU Schisterman, EF Buck, GM Lynch, CD AF Schisterman, EF Buck, GM Lynch, CD TI Trying to avoid bias in case-control and case-cohort studies SO FERTILITY AND STERILITY LA English DT Letter ID INFERTILITY C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. OI Schisterman, Enrique/0000-0003-3757-641X NR 5 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD DEC PY 2003 VL 80 IS 6 BP 1537 EP 1538 DI 10.1016/j.fertnstert.2003.09.001 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 754CB UT WOS:000187284200053 PM 14667911 ER PT J AU Saslow, WM AF Saslow, WM TI Multicarrier transport: Batteries, semiconductors, mixed ionic-electronic conductors, and biology SO FOUNDATIONS OF PHYSICS LA English DT Article DE multicarrier transport; batteries; semiconductors; biology ID LEAD-ACID CELL; DISCHARGE; CHARGE; HE-3; SLOW AB Multicarrier systems, such as car batteries and semiconductors, have surprisingly complex transport properties. Even for steady-state transport, one can find counterexamples to standard assumptions about local electroneutrality, constancy in space of the electric field, linearity in space of the voltage, and the relationship between dissipation, voltage, and current. Moreover, unless recombination processes occur, boundaries impose conditions that can disturb the response far into the bulk to remove memory of the boundaries. Because the demands of the chemical reactions at the electrodes cannot be satisfied by diffusion alone, car batteries are electrically active even when they are neither charging nor discharging. We offer practical advice on battery care for bike-riders, say, who only occasionally use their cars. For semiconductors, recombination does occur, which in transport enables partial currents to adjust from their surface to their bulk values. For mixed ionic electronic conductors, bulk recombination may be essential to an understanding of "blocking electrodes.'' The voltage associated with both current-producing and non-current-producing surface reactions provides a natural explanation for the bioelectric fields observed during root and other growth processes. C1 Texas A&M Univ, Dept Phys, College Stn, TX 77843 USA. NIH, Struct Biol Lab, Bethesda, MD 20892 USA. RP Saslow, WM (reprint author), Texas A&M Univ, Dept Phys, College Stn, TX 77843 USA. NR 29 TC 0 Z9 0 U1 0 U2 2 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0015-9018 J9 FOUND PHYS JI Found. Phys. PD DEC PY 2003 VL 33 IS 12 BP 1713 EP 1734 DI 10.1023/A:1026225504102 PG 22 WC Physics, Multidisciplinary SC Physics GA 734QB UT WOS:000186067100002 ER PT J AU Sidorkina, O Espey, MG Miranda, KM Wink, DA Laval, J AF Sidorkina, O Espey, MG Miranda, KM Wink, DA Laval, J TI Inhibition of poly(ADP-ribose) polymerase (PARP) by nitric oxide and reactive nitrogen oxide species SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE PARP; nitric oxide; nitroxyl; Angeli's salt; zinc finger motif; free radicals ID DNA-DAMAGE; NITROSATIVE STRESS; MOLECULAR TARGETS; CHEMICAL BIOLOGY; HUMAN-CELLS; NO DONORS; IN-VIVO; MECHANISMS; APOPTOSIS; TRANSCRIPTION AB The poly(ADP-ribose) polymerase (PARP) family of nuclear enzymes is involved in the detection and signaling of single strand breaks induced either directly by ionizing radiation or indirectly by the sequential action of various DNA repair proteins. Therefore, PARP plays an important role in maintaining genome stability. Because PARP proteins contain two zinc finger motifs, these enzymes can be targets for reactive nitrogen oxide intermediates (RNOS) generated as a result of nitric oxide (NO) biosynthesis in an aerobic environment. The effects of RNOS on the activity of purified PARP were examined using donor compounds. Both NO and nitroxyl (HNO) donors were found to be inhibitory in a similar time and concentration manner, indicating that PARP activity can be modified under both nitrosative and oxidative conditions. Moreover, these RNOS donors elicited comparable PARP inhibition in Sf21 insect cell extract and intact human MCF-7 cancer cells. The concentrations of donor required for 90% inhibition of PARP activity produce RNOS at a similar magnitude to those generated in the cellular microenvironment of activated leukocytes, suggesting that cellular scavenging of RNOS may not be protective against PARP modification and that inhibition of PARP may be significant under inflammatory conditions. (C) 2003 Elsevier Inc. C1 NCI, Radiat Biol Branch, NIH, Tumor Biol Sect, Bethesda, MD 20892 USA. Inst Gustave Roussy, LBPA, ENS, UMR 8113,Grp Reparat ADN, Villejuif, France. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Tumor Biol Sect, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 56 TC 53 Z9 54 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC 1 PY 2003 VL 35 IS 11 BP 1431 EP 1438 DI 10.1016/j.freeradbiomed.2003.08.015 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 744XE UT WOS:000186657500009 PM 14642390 ER PT J AU McKim, SE Gabele, E Isayama, F Lambert, JC Tucker, LM Wheeler, MD Connor, HD Mason, RP Doll, MA Hein, DW Arteel, GE AF McKim, SE Gabele, E Isayama, F Lambert, JC Tucker, LM Wheeler, MD Connor, HD Mason, RP Doll, MA Hein, DW Arteel, GE TI Inducible nitric oxide synthase is required in alcohol-induced liver injury: Studies with knockout mice SO GASTROENTEROLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA; RAT-LIVER; SENSITIZES HEPATOCYTES; KUPFFER CELLS; FREE-RADICALS; TNF-ALPHA; ETHANOL; PEROXYNITRITE; MECHANISM AB Background & Aims: Oxidative stress contributes to early alcohol-induced liver injury, and superoxide (O-2(.)-) production from NADPH oxidase plays a key role. However, the production of the free radical nitric oxide (NO.) by inducible nitric oxide synthase (iNOS) could also be involved. Methods: To test this hypothesis, iNOS knockout (B6.129P2-Nos2(tm1 Lau)) and wild-type mice were fed high-fat control or ethanol-containing diets for 4 weeks. Results: Mean body weight gains were not significantly different between treatment groups, and average urine ethanol concentrations were similar in wild-type and iNOS knockout mice. After 4 weeks, serum alanine aminotransferase (ALT) levels were increased significantly about 4-fold over control values (29 +/- IU/L) by enteral ethanol (113 +/- 20) in wild-type mice; this effect of ethanol was significantly blunted in iNOS knockout mice (50 +/- 9). Similar protective effects against liver damage were observed if wild-type mice were treated with the iNOS inhibitor N-(3-aminomethyl)benzyl-acetamindine (1400W). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver in wild-type mice but had no effect in iNOS knockout mice. The accumulation of 4-hydroxynonenal (lipid peroxidation) and 3-nitrotyrosine (reactive nitrogen species formation) protein adducts caused by alcohol was completely blocked in iNOS knockout mice. Conclusions: These data strongly support the hypothesis that iNOS is required for the pathogenesis of early alcohol-induced hepatitis by production of nitric oxide-derived pro-oxidants (e.g., peroxynitrite). C1 Univ Louisville, Hlth Sci Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ N Carolina, Dept Pharmacol, Lab Hepatobiol & Toxicol, Chapel Hill, NC 27515 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Arteel, GE (reprint author), Univ Louisville, Hlth Sci Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. RI Hein, David/A-9707-2008 NR 54 TC 138 Z9 143 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD DEC PY 2003 VL 125 IS 6 BP 1834 EP 1844 DI 10.1053/S0016-5085(03)01511-7 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 752QA UT WOS:000187177600034 PM 14724835 ER PT J AU Baxter, LL Pavan, WJ AF Baxter, LL Pavan, WJ TI Pmell17 expression is Mitf-dependent and reveals cranial melanoblast migration during murine development SO GENE EXPRESSION PATTERNS LA English DT Article DE Pmel17; melanocyte; neural crest; melanoblast; melanoma; Mitf; Matp; retinal pigmented epithelium; Silver; pigment cell; tyrosinase; dopachrome tautomerase; melanogenic enzyme; Hypopigmentation ID MELANOCYTE LINEAGE; ANTIGEN GP100; IN-VIVO; GENE; MICROPHTHALMIA; TRANSCRIPTION; PROTEIN; SILVER; LOCUS; KIT AB In situ hybridization (ISH) analysis of the murine melanosomal gene, Pmel17, demonstrated robust expression in the presumptive retinal pigmented epithelium (RPE) starting at E9.5, and in neural crest-derived melanoblasts starting at E10.5. Pmel17 expression is not detectable in;embryos mutated for Microphthalmia-associated transcription factor (Mitf), demonstrating transcriptional dependence of Pmel17 on Mitf in the RPE. Pmel17 expression in dorsal regions precedes dopachrome tautomerase (Dct) ISH expression, suggesting Pmel17 identifies melanoblasts at an earlier developmental stage. Dorsally localized Pmel17-positive cells at the forebrain/midbrain and midbrain/hindbrain boundaries at E10.5 reveal migratory pathways for cranial melanoblasts that have not been previously described in mouse using Dct expression. (C) 2003 Elsevier B.V. All rights reserved. C1 NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Mouse Embryol Sect, Genet Dis Res Branch, NIH, Bldg 49,Room 4A82,49 Convent Dr, Bethesda, MD 20892 USA. NR 25 TC 47 Z9 49 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD DEC PY 2003 VL 3 IS 6 BP 703 EP 707 DI 10.1016/j.modgep.2003.07.002 PG 5 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 755JA UT WOS:000187398700002 PM 14643677 ER PT J AU Holmes, A Hariri, AR AF Holmes, A Hariri, AR TI The serotonin transporter gene-linked polymorphism and negative emotionality: placing single gene effects in the context of genetic background and environment SO GENES BRAIN AND BEHAVIOR LA English DT Editorial Material ID ASSOCIATION; EXPRESSION; RECEPTORS C1 NIAAA, Sect Behav Sci & Genet, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Dev Imaging Genom Program,Western Psychiat Inst &, Pittsburgh, PA 15213 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. RI Hariri, Ahmad/D-5761-2011 NR 15 TC 38 Z9 38 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD DEC PY 2003 VL 2 IS 6 BP 332 EP 335 DI 10.1046/j.1601-183X.2003.00052.x PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 748NK UT WOS:000186867800004 PM 14653304 ER PT J AU Barr, CS Newman, TK Becker, ML Parker, CC Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD AF Barr, CS Newman, TK Becker, ML Parker, CC Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD TI The utility of the non-human primate model for studying gene by environment interactions in behavioral research SO GENES BRAIN AND BEHAVIOR LA English DT Editorial Material DE aggression; gene x environment interaction; nonhuman primate; play; serotonin transporter; stress ID SEROTONIN TRANSPORTER PROMOTER; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; DIMINISHED SOCIAL COMPETENCE; ANXIETY-RELATED TRAITS; DOPAMINE-D4 RECEPTOR; ALCOHOL-CONSUMPTION; EARLY EXPERIENCE; LIFE STRESS; PERSONALITY; POLYMORPHISM AB Variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has been associated with anxiety and harm avoidance and is weakly associated with a number of neuropsychiatric disorders, including Type II alcoholism, which has a high rate of comorbidity with antisocial personality disorder. Studies have also demonstrated interactions between 5-HTTLPR variation and environmental stress on the incidence of depression. As in humans, there is a serotonin transporter gene promoter length polymorphism in rhesus macaques that produces similar decreases in transcriptional efficiency. Macaques with histories of early-life stress have been shown to exhibit impulsive aggression, incompetent social behavior and increased behavioral and endocrine responsivity to stress. In this paper, we review studies performed previously in our lab and present preliminary data examininng interactions between early rearing and serotonin transporter gene promoter variation on the incidences of play behavior and aggression in infant rhesus macaques. The data presented here highlight the importance of considering gene-environment interactions when studying childhood risk factors for aggression, anxiety and related neuropsychiatric disorders and support the use of the nonhuman primate for studing gene by environment interactions in behavioral research. C1 NIAAA, DICBR, Clin Studies Primate Unit, NIH, Poolesville, MD USA. NICHD, Lab Comparat Ethol, NIH, Poolesville, MD USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. NIAAA, Neurogenet Lab, NIH, Rockville, MD USA. RP Barr, CS (reprint author), NIAAA, NIHAC, NIH, POB 529,Bldg 112, Poolesville, MD 20837 USA. EM cbarr@mail.nih.gov RI Goldman, David/F-9772-2010; Lesch, Klaus-Peter/J-4906-2013 OI Goldman, David/0000-0002-1724-5405; Lesch, Klaus-Peter/0000-0001-8348-153X NR 43 TC 169 Z9 172 U1 5 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1601-1848 EI 1601-183X J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD DEC PY 2003 VL 2 IS 6 BP 336 EP 340 DI 10.1046/j.1601-1848.2003.00051.x PG 5 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 748NK UT WOS:000186867800005 PM 14653305 ER PT J AU Hariri, AR Weinberger, DR AF Hariri, AR Weinberger, DR TI Functional neuroimaging of genetic variation in serotonergic neurotransmission SO GENES BRAIN AND BEHAVIOR LA English DT Editorial Material DE amygdala; emotion; FMRI; PET; prefrontal cortex; serotonin ID POSITRON-EMISSION-TOMOGRAPHY; TRYPTOPHAN-HYDROXYLASE GENE; ANXIETY-RELATED TRAITS; KNOCK-OUT MICE; TRANSPORTER GENE; HUMAN AMYGDALA; PROMOTER POLYMORPHISM; PERSONALITY-TRAITS; AFFECTIVE-DISORDER; MONOAMINE-OXIDASE AB Serotonin (5-hydroxytryptamine; 5-HT) is a potent modulator of the physiology and behavior involved in generating appropriate responses to environmental cues such as danger or threat. Furthermore, genetic variation in 5-HT subsystem genes can impact upon several dimensions of emotional behavior including neuroticism and psychopathology, but especially anxiety traits. Recently, functional neuroimaging has provided a dramatic illustration of how a promoter polymorphism in the human 5-HT transporter (5-HTT) gene, which has been weakly related to these behaviors, is strongly related to the engagement of neural systems, namely the amygdala, subserving emotional processes. In this commentary, we discuss how functional neuroimaging can be used to characterize the effects of polymorphisms in 5-HT subsystem genes on the response of neural circuits underlying the generation and regulation of mood and temperament as well as susceptibility to affective illness. We argue that in time, such knowledge will allow us to not only transcend phenomenological diagnosis and represent mechanisms of disease, but also identify at-risk individuals and biological pathways for the development of new treatments. C1 US Dept HHS, NIMH, Intramural Res Program, Clin Brain Disorders Branch,NIH, Bethesda, MD USA. RP Hariri, AR (reprint author), Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Dev Imaging Genom Program,Dept Psychiat, 3811 O Hara St,E-729, Pittsburgh, PA 15213 USA. RI Hariri, Ahmad/D-5761-2011 NR 79 TC 78 Z9 83 U1 1 U2 7 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD DEC PY 2003 VL 2 IS 6 BP 341 EP 349 DI 10.1046/j.1601-183X.2003.00048.x PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 748NK UT WOS:000186867800006 PM 14653306 ER PT J AU Murphy, DL Uhl, GR Holmes, A Ren-Patterson, R Hall, FS Sora, I Detera-Wadleigh, S Lesch, KP AF Murphy, DL Uhl, GR Holmes, A Ren-Patterson, R Hall, FS Sora, I Detera-Wadleigh, S Lesch, KP TI Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders SO GENES BRAIN AND BEHAVIOR LA English DT Review DE BDNF; complex genetics; DAT; endophenotypes; knockout mice; MAO; NET; serotonin transporter ID TRANSPORTER KNOCKOUT MICE; OBSESSIVE-COMPULSIVE DISORDER; MONOAMINE-OXIDASE-A; NIGROSTRIATAL DOPAMINERGIC FUNCTION; MOUSE SOMATOSENSORY CORTEX; FAMILY-BASED ASSOCIATION; ANXIETY-RELATED TRAITS; SEROTONIN-TRANSPORTER; NEUROTROPHIC FACTOR; OUT MICE AB Current evidence indicates that virtually all neuropsychiatric disorders, like many other common medical disorders, are genetically complex, with combined influences from multiple interacting genes, as well as from the environment. However, additive or epistatic gene interactions have proved quite difficult to detect and evaluate in human studies. Mouse phenotypes, including behaviors and drug responses, can provide relevant models for human disorders. Studies of gene-gene interactions in mice could thus help efforts to understand the molecular genetic bases of complex human disorders. The serotonin transporter (SERT, 5-HTT, SLC6A4) provides a relevant model for studying such interactions for several reasons: human variants in SERT have been associated with several neuropsychiatric and other medical disorders and quantitative traits; SERT blockers are effective treatments for a number of neuropsychiatric disorders; there is a good initial understanding of the phenotypic features of heterozygous and homozygous SERT knockout mice; and there is an expanding understanding of the interactions between variations in SERT expression and variations in the expression of a number of other genes of interest for neuropsychiatry and neuropharmacology. This paper provides examples of experimentally-obtained interactions between quantitative variations in SERT gene expression and variations in the expression of five other mouse genes: DAT, NET, MAOA, 5-HT18 and BDNF. In humans, all six of these genes possess polymorphisms that have been independently investigated as candidates for neuropsychiatric and other disorders in a total of > 500 reports. In the experimental studies in mice reviewed here, gene-gene interactions resulted in either synergistic, antagonistic (including 'rescue' or 'complementation') or more complex, quantitative alterations. These were identified in comparisons of the behavioral, physiological and neurochemical phenotypes of wildtype mice vs. mice with single allele or single gene targeted disruptions and mice with partial or complete disruptions of multiple genes. Several of the descriptive phenotypes could be best understood on the basis of intermediate, quantitative alterations such as brain serotonin differences. We discuss the ways in which these interactions could provide models for studies of gene-gene interactions in complex human neuropsychiatric and other disorders to which SERT may contribute, including developmental disorders, obesity, polysubstance abuse and others. C1 NIMH, Clin Sci Lab, DHHS, NIH, Bethesda, MD 20892 USA. NIDA, DHHS, Mol Neurobiol Res Branch, NIH, Baltimore, MD USA. NIAAA, NIMH, Sect Behav Sci & Genet, DHHS,NIH, Bethesda, MD USA. Tohoku Univ, Sch Med, Dept Neurosci, Sendai, Miyagi 980, Japan. NIMH, DHHS, Mood & Anxiety Disorders Program, NIH, Bethesda, MD USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. RP Murphy, DL (reprint author), NIMH, Clin Sci Lab, DHHS, NIH, Bldg 10,Room 3D41,10 Ctr Dr, Bethesda, MD 20892 USA. RI Hall, Frank/C-3036-2013; Lesch, Klaus-Peter/J-4906-2013 OI Hall, Frank/0000-0002-0822-4063; Lesch, Klaus-Peter/0000-0001-8348-153X NR 136 TC 89 Z9 92 U1 3 U2 12 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD DEC PY 2003 VL 2 IS 6 BP 350 EP 364 DI 10.1046/j.1601-183X.2003.00049.x PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 748NK UT WOS:000186867800007 PM 14653307 ER PT J AU Holmes, A Li, Q Murphy, DL Gold, E Crawley, JN AF Holmes, A Li, Q Murphy, DL Gold, E Crawley, JN TI Abnormal anxiety-related behaviour in serotonin transporter null mutant mice: the influence of genetic background SO GENES BRAIN AND BEHAVIOR LA English DT Review DE 5-HT1A receptor; anxiety; gene; genetic background; inbred strains; mouse; serotonin; serotonin transporter ID ELEVATED PLUS-MAZE; INBRED MOUSE STRAINS; QUANTITATIVE TRAIT LOCI; KNOCK-OUT MICE; 5-HT TRANSPORTER; PROMOTER POLYMORPHISM; DEFICIENT MICE; BINDING-SITES; TARGETED DISRUPTION; LOCOMOTOR-ACTIVITY AB Serotonin transporter (5-HTT) null mutant mice provide a model system to study the role genetic variation in the 5-HTT plays in the regulation of emotion. Anxiety-like behaviors were assessed in 5-HTT null mutants with the mutation placed on either a B6 congenic or a 12956 congenic background. Replicating previous findings, B6 congenic 5-HTT null mutants exhibited increased anxiety-like behavior and reduced exploratory locomotion on the light H dark exploration and elevated plus-maze tests. In contrast, 12956 congenic 5-HTT null mutant mice showed no phenotypic abnormalities on either test. 5-HTT null mutants on the 12956 background showed reduced 5-HT1A receptor binding (as measured by quantitative autoradiography) and reduced 5-HT1A receptor function (as measured by 8-OH-DPAT-indcued hypothermia). These data confirm that the 5-HTT null mutation produced alterations in brain 5-HT function in mice on the 12956 background, thereby discounting the possibility that the absence of an abnormal anxiety-like phenotype in these mice was due to a suppression of the mutation by 129 modifier genes. Anxiety-like behaviors in the light H dark exploration and elevated plus-maze tests were significantly higher in 12956 congenic +/+ mice as compared to B6 congenic +/+ mice. This suggests that high baseline anxiety-like behavior in the 12956 strain might have precluded detection of the anxiety-like effects of the 5-HTT null mutation on this background. Present findings provide further evidence linking genetic variation in the 5-HTT to abnormalities in mood and anxiety. Furthermore, these data highlight the utility of conducting behavioral phenotyping of mutant mice on multiple genetic backgrounds. C1 NIMH, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77550 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Holmes, A (reprint author), NIMH, Lab Behav Neurosci, NIH, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 104 TC 202 Z9 204 U1 1 U2 19 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD DEC PY 2003 VL 2 IS 6 BP 365 EP 380 DI 10.1046/j.1601-183X.2003.00050.x PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 748NK UT WOS:000186867800008 PM 14653308 ER PT J AU Chatterjee, N Hartge, P Wacholder, S AF Chatterjee, N Hartge, P Wacholder, S TI Adjustment for competing risk in kin-cohort estimation SO GENETIC EPIDEMIOLOGY LA English DT Article DE BRCA1/2 mutations; cause-specific hazard; cohort study; multiple outcomes; penetrance ID ESTIMATING PENETRANCE; BREAST-CANCER; MUTATION; DESIGNS; BRCA1 AB Kin-cohort design can be used to study the effect of a genetic mutation on the risk of multiple events, using the same study. In this design, the outcome data consist of the event history of the relatives of a sample of genotyped subjects. Existing methods for kin-cohort estimation allow estimation of the risk of one event at a time with the assumption that the censoring events are unrelated to the genetic mutation under study. These methods, however, may produce biased estimates of risk when multiple events are related to the genetic mutation, and follow-up of some of the events may be censored by the onset of other events. Using a competing risk framework to address this problem, we show that cause-specific hazard functions for carriers and noncarriers are identifiable from kin-cohort data. For estimation, we propose an extension of a composite-likelihood approach we described previously. We illustrate the use of the proposed method for estimation of the risk of ovarian cancer from BRCA1/2 mutations in the absence of breast cancer, based on data from the Washington Ashkenazi Kin-Cohort Study. We also evaluate the performance of the proposed estimation method, based on simulated data that were generated following the setup of the Washington Ashkenazi Study. Published 2003 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Chatterjee, N (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 8038, Rockville, MD 20852 USA. NR 14 TC 12 Z9 12 U1 1 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2003 VL 25 IS 4 BP 303 EP 313 DI 10.1002/gepi.10269 PG 11 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 748KQ UT WOS:000186861400003 PM 14639700 ER PT J AU Mathias, RA Wilson, AF Beaty, TH Liang, KY AF Mathias, RA Wilson, AF Beaty, TH Liang, KY TI Model comparison and the likelihood ratio test in segregation analysis SO GENETIC EPIDEMIOLOGY LA English DT Letter C1 NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Mathias, RA (reprint author), NHGRI, Inherited Dis Res Branch, NIH, 333 Cassell Dr,Suite 1200, Baltimore, MD 21224 USA. RI Liang, Kung-Yee/F-8299-2011; Wilson, Alexander/C-2320-2009 NR 4 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2003 VL 25 IS 4 BP 382 EP 383 DI 10.1002/gepi.10273 PG 2 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 748KQ UT WOS:000186861400011 PM 14639708 ER PT J AU Rong, YS Golic, KG AF Rong, YS Golic, KG TI The homologous chromosome is an effective template for the repair of mitotic DNA double-strand breaks in drosophila SO GENETICS LA English DT Article ID SITE-SPECIFIC ENDONUCLEASE; I-SCEI ENDONUCLEASE; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; INTRAGENIC RECOMBINATION; MULTIPLE PATHWAYS; GENE CONVERSION; YEAST; MELANOGASTER; HETEROZYGOSITY AB In recombinational DNA double-strand break repair a homologous template for gene conversion may be located at several different genomic positions: on the homologous chromosome in diploid organisms, on the sister chromatid after DNA replication, or at an ectopic position. The use of the homologous chromosome in mitotic gene conversion is thought to be limited in the yeast Saccharomyces cerevisiae and mammalian cells. In contrast, by studying the repair of double-strand breaks generated by the I-Scel rare-cutting endonuclease, we find that the homologous chromosome is frequently used in Drosophila melanogaster, which we Suggest is attributable to somatic pairing of homologous chromosomes in mitotic cells of Drosophila. We also find that Drosophila mitotic cells Of the germ line, like yeast, employ the homologous recombinational repair pathway more often than imperfect nonhomologous end joining. C1 Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. RP Rong, YS (reprint author), NCI, LMCB, NIH, Bldg 37,Room 6056,37 Convent Dr, Bethesda, MD 20892 USA. RI rong, yikang/G-6179-2011 FU NIGMS NIH HHS [R01 GM065604, GM-5604] NR 51 TC 62 Z9 65 U1 2 U2 6 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD DEC PY 2003 VL 165 IS 4 BP 1831 EP 1842 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 760HJ UT WOS:000187805300016 PM 14704169 ER PT J AU Margulies, EH Blanchette, M Haussler, D Green, ED AF Margulies, EH Blanchette, M Haussler, D Green, ED CA NISC Comparative Sequencing Progra TI Identification and characterization of multi-species conserved sequences SO GENOME RESEARCH LA English DT Article ID GENOMIC DNA-SEQUENCES; FACTOR-BINDING SITES; REGULATORY ELEMENTS; NONCODING SEQUENCES; MOUSE GENOME; MULTIPLE ALIGNMENT; MESSENGER-RNA; REGIONS; PREDICTION; DISCOVERY AB Comparative sequence analysis has become an essential component of studies aiming to elucidate genome function. The increasing availability of genomic sequences from multiple vertebrates is creating the need for computational methods that can detect highly conserved regions in a robust fashion. Towards that end, we are developing approaches for identifying sequences that are conserved across multiple species; we call these "Multi-species Conserved Sequences" (or MCSs). Here we report two strategies for MCS identification, demonstrating their ability to detect virtually all known actively conserved sequences (specifically, coding sequences) but very little neutrally evolving sequence (specifically, ancestral repeats). Importantly, we find that a substantial fraction of the bases within MCSs (similar to70%) resides within non-coding regions; thus, the majority of sequences conserved across multiple vertebrate species has no known function. Initial characterization of these MCSs has revealed sequences that correspond to clusters of transcription factor-binding sites, non-coding RNA transcripts, and other candidate functional elements. Finally, the ability to detect MCSs represents a valuable metric for assessing the relative contribution of a species' sequence to identifying genomic regions of interest, and our results indicate that the currently available genome sequences are insufficient for the comprehensive identification of MCSs in the human genome. C1 Natl Ctr Human Genome Res, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Natl Ctr Human Genome Res, NIH Intramural Sequencing Ctr, NISC, NIH, Bethesda, MD 20892 USA. Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95964 USA. Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95964 USA. RP Haussler, D (reprint author), Natl Ctr Human Genome Res, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM haussler@cse.ucsc.edu; egreen@nhgri.nih.gov NR 67 TC 228 Z9 237 U1 2 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 2003 VL 13 IS 12 BP 2507 EP 2518 DI 10.1101/gr.1602203 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 749KZ UT WOS:000186920200001 PM 14656959 ER PT J AU Cartwright, WS Solano, PL AF Cartwright, WS Solano, PL TI The economics of public health: financing drug abuse treatment services SO HEALTH POLICY LA English DT Article DE drug abuse treatment; cost-benefit analysis; financing; rationing ID METHADONE; OUTCOMES AB Drug abuse treatment financing exhibits a heterogeneous set of sources from federal, state, and local governments, as well as private sources from insurance, patient out-of-pocket, and charity. A public health model of drug abuse treatment is presented for a market that can be characterized by excess demand in many communities and an implied policy of rationing. According to best estimates, as many as 6.7 million individuals may need treatment, but only an estimated 1.5 million individuals actually participated in treatment episodes. Since, as demonstrated empirically, drug abuse treatment has a robust and positive social net benefit to society, it is perplexing that treatment financing stops with a rationing outcome that inhibits social welfare. The justification for public financing is centered on the external costs of drug addiction, but subsidization is grounded in the reality that a large number of addicted individuals do not have sufficient resources to pay for treatment out-of-pocket, nor do they have private insurance coverage. Social welfare losses are generated by financial arrangements that are inconsistent with rational budgeting theory and as such would lead to non-optimal organization and management of the drug abuse treatment system. Published by Elsevier Ireland Ltd. C1 NIDA, NIH, Bethesda, MD 20892 USA. Univ Delaware, Sch Urban Affairs & Publ Policy, Newark, DE 19716 USA. RP Cartwright, WS (reprint author), NIDA, NIH, 6001 Execut Blvd,Room 4222,MSC 9565, Bethesda, MD 20892 USA. NR 25 TC 22 Z9 22 U1 1 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-8510 J9 HEALTH POLICY JI Health Policy PD DEC PY 2003 VL 66 IS 3 BP 247 EP 260 DI 10.1016/S0168-8510(03)00066-6 PG 14 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 753VL UT WOS:000187251200004 PM 14637010 ER PT J AU Ellison, GL Warren, JL Knopf, KB Brown, ML AF Ellison, GL Warren, JL Knopf, KB Brown, ML TI Racial differences in the receipt of bowel surveillance following potentially curative colorectal cancer surgery SO HEALTH SERVICES RESEARCH LA English DT Article DE colorectal neoplasms; SEER-Medicare; colonoscopy; blacks; surveillance ID COLON-CANCER; MEDICARE BENEFICIARIES; ADJUVANT CHEMOTHERAPY; RECTAL-CANCER; BREAST-CANCER; CARE; POPULATION; RACE; RESECTION; PHYSICIAN AB Objective. To investigate racial differences in posttreatment bowel surveillance after colorectal cancer surgery in a large population of Medicare patients. Data Sources. We used a large population-based dataset: Surveillance, Epidemiology, and End Results (SEER) linked to Medicare data. Study Design. This is a retrospective cohort study. We analyzed data from 44,768 non-Hispanic white, 2,921 black, and 4,416 patients from other racial/ethnic groups, aged 65 and older at diagnosis, who had a diagnosis of local or regional colorectal cancer between 1986 and 1996, and were followed through December 31, 1998. Cox Proportional Hazards models were used to investigate the relation of race and receipt of posttreatment bowel surveillance. Data Collection. Sociodemographic, hospital, and clinical characteristics were collected at the time of diagnosis for all members of the cohort. Surgery and bowel surveillance with colonoscopy, sigmoidoscopy, and barium enema were obtained from Medicare claims using ICD-9-CM and CPT-4 codes. Principal Findings. The chance of surveillance within 18 months of surgery was 57 percent, 48 percent, and 45 percent for non-Hispanic whites, blacks, and others, respectively. After adjusting for sociodemographic, hospital, and clinical characteristics, blacks were 25 percent less likely than whites to receive surveillance if diagnosed between 1991 and 1996 (RR = 0.75, 95 percent Cl = 0.70-0.81). Conclusions. Elderly blacks were less likely than non-Hispanic whites to receive posttreatment bowel surveillance and this result was not explained by measured racial differences in sociodemographic, hospital, and clinical characteristics. More research is needed to explore the influences of patient- and provider-level factors on racial differences in posttreatment bowel surveillance. C1 Macro Int, QRC Div, Bethesda, MD 20814 USA. NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Annapolis Oncol Hematol Ctr, Annapolis, MD USA. RP Ellison, GL (reprint author), Macro Int, QRC Div, 7315 Wisconsin Ave,Suite 200W, Bethesda, MD 20814 USA. NR 43 TC 32 Z9 34 U1 0 U2 0 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD DEC PY 2003 VL 38 IS 6 BP 1885 EP 1903 DI 10.1111/j.1475-6773.2003.00207.x PN 2 PG 19 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 761BM UT WOS:000187879400011 PM 14727802 ER PT J AU Foss, FM Waldmann, TA AF Foss, FM Waldmann, TA TI Interleukin-2 receptor-directed therapies for cutaneous lymphomas SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID T-CELL LEUKEMIA; ANTI-TAC; HEMATOLOGIC MALIGNANCIES; DENILEUKIN DIFTITOX; HUMANIZED ANTIBODY; MYCOSIS-FUNGOIDES; FUSION PROTEIN; IL-2 RECEPTOR; UP-REGULATION; MURINE MODEL AB The interleukin-2 receptor alpha subunit (IL-2Ralpha, CD25) has proven to be an effective target for immune intervention. Most resting normal cells, including the normal T-cells of patients who have leukemia, do not express IL-2Ralpha. Select malignant T cells, including those of patients who have human T-lymphotrophic virus (HTLV)-l - associated adult T-cell leukemia (ATL) and those who have cutaneous T-cell lymphoma (CTCL) express this receptor subunit. To exploit the differences in IL-2Ralpha expression between normal and leukemic cells, several IL-2R-directed approaches have been introduced including: (1) unmodified murine antibodies directed toward IL-2Ralpha, (2) humanized versions of such IL-2R-directed antibodies, (3) the anti-IL-Ralpha monoclonal antibodies armed with toxins or radionuclides, and (4) the IL2-diphtheria toxin fusion protein. C1 Tufts Univ New England Med Ctr, Boston, MA 02111 USA. NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. RP Foss, FM (reprint author), Tufts Univ New England Med Ctr, 750 Washington St, Boston, MA 02111 USA. NR 30 TC 13 Z9 14 U1 3 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD DEC PY 2003 VL 17 IS 6 BP 1449 EP + DI 10.1016/S0889-8588(03)00110-2 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 753VY UT WOS:000187252600012 PM 14710895 ER PT J AU Promrat, K Liang, TJ AF Promrat, K Liang, TJ TI Chemokine systems and hepatitis C virus infection: Is truth in the genes of the beholders? SO HEPATOLOGY LA English DT Editorial Material ID POLYMORPHISMS; HIV-1; INFLAMMATION; RESISTANCE; FREQUENCY; GENOTYPE; LIVER; CCR5 C1 Brown Univ, Div Gastroenterol, Providence, RI 02908 USA. NIDDK, Liver Dis Sect, NIH, Bethesda, MD USA. RP Promrat, K (reprint author), Brown Univ, Div Gastroenterol, 830 Chalkstone Ave, Providence, RI 02908 USA. NR 19 TC 7 Z9 8 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2003 VL 38 IS 6 BP 1359 EP 1362 DI 10.1016/j.hep.2003.10.008 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 751BC UT WOS:000187032100005 PM 14647045 ER PT J AU Sugimoto, K Ikeda, F Stadanlick, J Nunes, FA Alter, H Chang, KM AF Sugimoto, K Ikeda, F Stadanlick, J Nunes, FA Alter, H Chang, KM TI Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection SO HEPATOLOGY LA English DT Article ID HEPATITIS-C VIRUS; IMMUNE-RESPONSES; PERIPHERAL-BLOOD; DENDRITIC CELLS; CORE PROTEIN; QUANTITATIVE-ANALYSIS; LYMPHOCYTE RESPONSE; ENVELOPE PROTEIN; PLUS RIBAVIRIN; VIRAL LOAD AB Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCV-specific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P = .001) and scope (14/36 vs. 4/36 pools, P = .002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R = -0.51, P = .049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4(+)CD25(+) regulatory T cells (7.3% chronic vs. 2.5% recovered, P = .002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4(+)CD25(+) regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence. C1 Univ Penn, Dept Med, Div Gastroenterol, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Penn Hosp, Philadelphia, PA 19107 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Chang, KM (reprint author), Univ Penn, Dept Med, GI Div, Univ & Woodland Ave, Philadelphia, PA 19104 USA. RI Yang, Chen/G-1379-2010 FU NCRR NIH HHS [M01-RR00040]; NIAAA NIH HHS [AA12849]; NIAID NIH HHS [AI47519] NR 50 TC 265 Z9 291 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2003 VL 38 IS 6 BP 1437 EP 1448 DI 10.1016/j.hep.2003.09.026 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 751BC UT WOS:000187032100015 PM 14647055 ER PT J AU Wiest, R Cadelina, G Milstien, S McCuskey, RS Garcia-Tsao, G Groszmann, RJ AF Wiest, R Cadelina, G Milstien, S McCuskey, RS Garcia-Tsao, G Groszmann, RJ TI Bacterial translocation up-regulates GTP-cyclohydrolase I in mesenteric vasculature of cirrhotic rats SO HEPATOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; CYTOKINE-GENERATING ORGAN; AORTIC ENDOTHELIAL-CELLS; HYPERDYNAMIC CIRCULATION; TETRAHYDROBIOPTERIN SYNTHESIS; PORTAL-HYPERTENSION; MESSENGER-RNA; SYSTEMIC INFLAMMATION; LYMPH-NODES; LIPOPOLYSACCHARIDE AB In cirrhosis, arterial vasodilation and the associated hemodynamic disturbances are most prominent in the mesenteric circulation, and its severity has been linked to bacterial translocation (BT) and endotoxemia. Synthesis of nitric oxide (NO), the main vasodilator implicated, is dependent on the essential cofactor tetrahydrobiopterin (BH4). The key enzyme involved in BH4 synthesis is GTP-cyclohydrolase I (GTPCH-I), which is stimulated by endotoxin. Therefore, we investigated GTPCH-I activity and BH4 biosynthesis in the mesenteric vasculature of cirrhotic rats with ascites, as well as their relationship with BT and endotoxemia, serum NO, and mean arterial pressure (MAP). GTPCH-I activity and BH4 content in mesenteric vasculature was determined by high-performance liquid chromatography. BT was assessed by standard bacteriologic culture of mesenteric lymph nodes (MLNs). Serum endotoxin was measured by a kinetic turbidimetric limulus amebocyte lysate assay, and serum NO metabolite (NOx) concentrations were assessed by chemiluminescence. BT was associated with local lymphatic and systemic appearance of endotoxin and was accompanied by increases in serum NOx levels. GTPCH-I activity and BH4 content in mesenteric vasculatare were both increased in animals with BT and correlated significantly (r = 0.69, P < .01). Both GTPCH-1 activity and BH4 levels significantly correlated with serum endotoxin and NOx levels (r = 0.69 and 0.54, 0.81 and 0.53, P < .05). MAP (a marker of systemic vasodilatation) correlated with endotoxemia (r = 0.58, P < .03) and with GTPCH-1 activity (r = 0.69, P < .01). In conclusion, in cirrhotic animals BT appears to lead to endotoxemia, stimulation of GTPCH-1, increased BH4 synthesis, and further enhancement of vascular NO production that leads to aggravation of vasodilatation. C1 Vet Adm Med Ctr, Hepat Hemodynam Lab, West Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. NIMH, Bethesda, MD 20892 USA. Univ Arizona, Coll Med, Dept Cell Biol & Anat, Tucson, AZ USA. RP Groszmann, RJ (reprint author), Vet Adm Med Ctr, Hepat Hemodynam Lab 111J, 950 Campbell Ave, West Haven, CT 06516 USA. NR 50 TC 63 Z9 65 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2003 VL 38 IS 6 BP 1508 EP 1515 DI 10.1016/j.hep.2003.09.039 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 751BC UT WOS:000187032100022 PM 14647062 ER PT J AU Cavin, LG Romieu-Mourez, R Panta, GR Sun, JY Factor, VM Thorgeirsson, SS Sonenshein, GE Arsura, M AF Cavin, LG Romieu-Mourez, R Panta, GR Sun, JY Factor, VM Thorgeirsson, SS Sonenshein, GE Arsura, M TI Inhibition of CK2 activity by TGF-beta 1 promotes I kappa B-alpha protein stabilization and apoptosis of immortalized hepatocytes SO HEPATOLOGY LA English DT Article ID CASEIN KINASE-II; CALPAIN-MEDIATED DEGRADATION; TRANSGENIC MICE; CONSTITUTIVE PHOSPHORYLATION; HEPATOCELLULAR CARCINOMAS; TRANSCRIPTION FACTORS; GENE-TRANSCRIPTION; ACTIVATION; GROWTH; LIVER AB Nuclear factor kappaB (NF-kappaB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor kappaB (IkappaB)-alpha protein following treatment of hepatocytes with transforming growth factor (TGF)-beta1 promoted NF-kappaB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IkappaB-alpha protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-kappaB levels following treatment with TGF-beta1. We show that both messenger RNA (mRNA) and protein levels of the CK2alpha catalytic subunit are down-regulated following TGF-beta1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IkappaB protein, which is followed by the shutoff of constitutive NF-kappaB activity and induction of apoptosis. Ectopic expression of CK2alpha inhibits TGF-beta1-induced apoptosis through sustained activation of NF-kappaB. Conversely, expression of a kinase-dead mutant of CK2alpha potentiates TGF-beta1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-beta1 transgenic mice and human HCC cell lines display enhanced CK2 licB kinase activity that contributes in part to an elevated NF-kappaB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-beta1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-beta1-induced liver carcinogenesis. C1 Univ Tennessee, Coll Med, Dept Pharmacol, Canc Inst,Ctr Anticanc Drug Res, Memphis, TN 38163 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. NCI, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Arsura, M (reprint author), Univ Tennessee, Coll Med, Dept Pharmacol, Canc Inst,Ctr Anticanc Drug Res, 874 Union Ave, Memphis, TN 38163 USA. RI sun, jiyuan/B-3828-2010 FU NCI NIH HHS [CA82742, CA78616-S1, CA78616] NR 37 TC 50 Z9 52 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2003 VL 38 IS 6 BP 1540 EP 1551 DI 10.1016/j.hep.2003.09.019 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 751BC UT WOS:000187032100025 PM 14647065 ER PT J AU Oliver, B AF Oliver, B TI Gene expression - Fast males SO HEREDITY LA English DT Editorial Material ID DROSOPHILA-MELANOGASTER; EVOLUTION; SEX; TRANSCRIPTION C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 11 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 0018-067X J9 HEREDITY JI Heredity PD DEC PY 2003 VL 91 IS 6 BP 535 EP 536 DI 10.1038/sj.hdy.6800371 PG 2 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 747DQ UT WOS:000186790300002 PM 14571260 ER PT J AU Temple, JL Scordalakes, EM Bodo, C Gustafsson, JA Rissman, EF AF Temple, JL Scordalakes, EM Bodo, C Gustafsson, JA Rissman, EF TI Lack of functional estrogen receptor beta gene disrupts pubertal male sexual behavior SO HORMONES AND BEHAVIOR LA English DT Article DE GnRH; LHRH; ER beta; male sexual behavior; puberty; gonadotropins; negative feedback; knockout mouse ID CENTRAL-NERVOUS-SYSTEM; ALPHA-KNOCKOUT MOUSE; MESSENGER-RNA; MICE LACKING; FEMALE MICE; PARAVENTRICULAR NUCLEUS; OXYTOCIN NEURONS; HORMONE NEURONS; ERKO MALE; RAT AB The estrogen receptor-beta (ERbeta) mediates estrogen action in the female gonads, reproductive tract, and central nervous system. In addition, in rats and mice, gonadotropin-releasing hormone (GnRH-I) neurons coexpress ERbeta. Here we asked if ERbeta plays a role in the onset of puberty and in hypothalamic-pituitary-gonadal (HPG) axis function in male mice. We examined mating behavior, testosterone concentrations, steroid negative feedback on gonadotropins, and GnRH-I function in male ERbeta knockout (ERbetaKO) and wild-type (WT) mice. Peripubertal ERbetaKO males displayed their first ejaculation at a significantly older age than WT littermates. Castrated, adult ERbetaKO mice had significantly higher plasma luteinizing hormone (LH) than WT counterparts. Estradiol (E2) treatment reduced LH and follicle stimulating hormone (FSH) concentrations to an equivalent degree in castrates of both genotypes. In three different measures of the adult GnRH-I system, no genotypic differences were observed. These data show that ERbeta plays an important role in the timing of male sexual behavior at puberty, but does not appear to be involved in adult HPG axis functioning. Furthermore, our data suggest that a primary role of ERbeta may be to regulate ejaculatory behavior. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. Univ Virginia, Sch Med, Program Neurosci, Charlottesville, VA 22908 USA. NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Novum, Ctr Biotechnol, S-14186 Huddinge, Sweden. Karolinska Inst, Novum, Dept Med Nutr, S-14186 Huddinge, Sweden. RP Rissman, EF (reprint author), Univ Virginia, Sch Med, Dept Biochem & Mol Genet, Jordan Hall,POB 800733, Charlottesville, VA 22908 USA. FU NIMH NIH HHS [K02 MH01349, R01 MH57759] NR 42 TC 40 Z9 43 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 0018-506X J9 HORM BEHAV JI Horm. Behav. PD DEC PY 2003 VL 44 IS 5 BP 427 EP 434 DI 10.1016/j.yhbeh.2003.09.002 PG 8 WC Behavioral Sciences; Endocrinology & Metabolism SC Behavioral Sciences; Endocrinology & Metabolism GA 752KV UT WOS:000187160400007 PM 14644637 ER PT J AU Xu, L Tsuji, K Mostowski, H Candotti, F Rosenberg, A AF Xu, L Tsuji, K Mostowski, H Candotti, F Rosenberg, A TI Evidence that the mouse 3 ' kappa light chain enhancer confers position-independent transgene expression in T- and B-lineage cells SO HUMAN GENE THERAPY LA English DT Article ID LOCUS-CONTROL REGION; BETA-GLOBIN GENE; MURINE LEUKEMIA-VIRUS; HUMAN CD2 GENE; LONG TERMINAL REPEAT; KAPPA 3 ENHANCER; ERYTHROLEUKEMIA-CELLS; TRANSCRIPTION FACTOR; RETROVIRAL VECTORS; HIGH-LEVEL AB One of the major obstacles for successful application of murine leukemia virus (MLV) vectors to genetic therapy of lymphocyte disorders is low levels of transgene expression or the eventual loss of expression. To overcome this problem, an improved retroviral vector was constructed utilizing the myeloproliferative sarcoma virus (MPSV) long terminal repeat (LTR), which provided a significantly higher level of transgene expression in human lymphoid cells than did MLV vectors. Nevertheless, transgene expression remained low in a large percentage of transduced cells. To address whether lymphocyte enhancer elements might improve transgene expression mediated by retroviral vectors in lymphocytes, we cloned the mouse immunoglobulin 3' kappa light chain enhancer gene (mE3') into the MPSV vector. We found that the mE3' conferred a higher, more uniform and sustained level of expression in transduced T- and B-cell lines, and in primary T cells, than did the control vector lacking this element. Integration sites were diverse and a single copy of the proviral genome was present in all examined transduced cells. The mE3' failed to enhance transgene expression in most nonlymphoid cells, indicating it is relatively lineage-specific. Taken together, these results provide strong evidence that the mE3' functions as a locus control region (LCR) in conferring enhanced integration-site-independent expression of a retroviral transgene. C1 NHGRI, Div Therapeut Prot, NIH, Bethesda, MD 20892 USA. NHGRI, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, US FDA,NIH, Bethesda, MD 20892 USA. NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, A (reprint author), NHGRI, Div Therapeut Prot, NIH, Bethesda, MD 20892 USA. NR 49 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD DEC PY 2003 VL 14 IS 18 BP 1753 EP 1764 DI 10.1089/104303403322611764 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 753RX UT WOS:000187245300006 PM 14670126 ER PT J AU Yan, D Park, HJ Ouyang, XM Pandya, A Doi, K Erdenetungalag, R Du, LL Matsushiro, N Nance, WE Griffith, AJ Liu, XZ AF Yan, D Park, HJ Ouyang, XM Pandya, A Doi, K Erdenetungalag, R Du, LL Matsushiro, N Nance, WE Griffith, AJ Liu, XZ TI Evidence of a founder effect for the 235delC mutation of GJB2 (connexin 26) in east Asians SO HUMAN GENETICS LA English DT Article ID NONSYNDROMIC HEARING-LOSS; SENSORINEURAL DEAFNESS; RECESSIVE DEAFNESS; GENE; POPULATIONS; PREVALENCE; IMPAIRMENT; EXPRESSION; FREQUENCY; CHINA AB Mutations in the GJB2 gene encoding connexin 26 (Cx26) are a major cause of autosomal recessive and sporadic cases of congenital deafness in most populations. The 235delC mutation of GJB2 is the most frequent known mutation in some east Asian populations, with a carrier frequency of approximately 1%. In order to study the origin of 235delC among east Asians, we analyzed single-nucleotide polymorphisms (SNPs) within the coding region of GJB2 and flanking the 235delC mutation. We observed significant linkage disequilibrium between 235delC and five linked polymorphic markers, suggesting that 235delC arose from a common founder. The detection of 235delC only in east Asians, but not in Caucasians, and the small chromosomal interval of the shared haplotype suggest that 235delC is an ancient mutation that arose after the divergence of Mongoloids and Caucasians. Similarly, the finding that this mutation appears on a single haplotype provides no support for the possibility that recurrent mutation is the explanation for the high frequency of the allele. C1 Univ Miami, Dept Otolaryngol, Miami, FL 33136 USA. Natl Inst Deafness & Other Commun Disorders, Sect Gene Struct, NIH, Rockville, MD USA. Natl Inst Deafness & Other Commun Disorders, Funct & Hearing Sect, NIH, Rockville, MD USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USA. Osaka Univ, Grad Sch Med, Dept Otolaryngol & Sensory Organ Surg, Osaka, Japan. Maternal & Child Hlth Res Ctr, Dept Human Genet, Ulaanbaatar, Mongol Peo Rep. RP Liu, XZ (reprint author), Univ Miami, Dept Otolaryngol, 1666 NW 12th Ave, Miami, FL 33136 USA. FU NIDCD NIH HHS [Z01-DC000060-02, Z01-DC000064-02, DC05575] NR 34 TC 66 Z9 73 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD DEC PY 2003 VL 114 IS 1 BP 44 EP 50 DI 10.1007/s00439-003-1018-1 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 743UX UT WOS:000186592900006 PM 14505035 ER PT J AU Lingaas, F Comstock, KE Kirkness, EF Sorensen, A Aarskaug, T Hitte, C Nickerson, ML Moe, L Schmidt, LS Thomas, R Breen, M Galibert, F Zbar, B Ostrander, EA AF Lingaas, F Comstock, KE Kirkness, EF Sorensen, A Aarskaug, T Hitte, C Nickerson, ML Moe, L Schmidt, LS Thomas, R Breen, M Galibert, F Zbar, B Ostrander, EA TI A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog SO HUMAN MOLECULAR GENETICS LA English DT Article ID HOGG-DUBE-SYNDROME; RADIATION HYBRID MAP; SPONTANEOUS PNEUMOTHORAX; ATAXIA-TELANGIECTASIA; CANCER SYNDROME; HUMAN GENOME; CELL CANCER; EKER RAT; LINKAGE; TUMORS AB Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German Shepherd dogs. The disease is characterized by bilateral, multifocal tumors in the kidneys, uterine leiomyomas and nodules in the skin consisting of dense collagen fibers. We previously mapped RCND to canine chromosome 5 (CFA5) with a highly significant LOD score of 16.7 (theta=0.016). We have since narrowed the RCND interval following selection and RH mapping of canine genes from the 1.3x canine genome sequence. These sequences also allowed for the isolation of gene-associated BACs and the characterization of new microsatellite markers. Ordering of newly defined markers and genes with regard to recombinants localizes RCND to a small chromosomal region that overlaps the human Birt-Hogg-Dube locus, suggesting the same gene may be responsible for both the dog and the phenotypically similar human disease. We herein describe a disease-associated mutation in exon 7 of canine BHD that leads to the mutation of a highly conserved amino acid of the encoded protein. The absence of recombinants between the disease locus and the mutation in US and Norwegian dogs separated by several generations is consistent with this mutation being the disease-causing mutation. Strong evidence is provided that the RCND mutation may have a homozygous lethal effect (P<0.01). C1 Fred Hutchinson Canc Res Ctr, Clin Biol Div, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA. Norwegian Sch Vet Sci, N-0033 Oslo, Norway. Inst Genom Res, Rockville, MD 20850 USA. Fac Med, CNRS, UMR 6061, F-35043 Rennes, France. Natl Canc Inst, Ctr Canc Res, Immunobiol Lab, Frederick, MD 21702 USA. Natl Canc Inst, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Anim Hlth Trust, Newmarket CB8 7UU, Suffolk, England. N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27606 USA. RP Ostrander, EA (reprint author), Fred Hutchinson Canc Res Ctr, Clin Biol Div, 1100 Fairview Ave N,D4-100,POB 19024, Seattle, WA 98109 USA. OI Ostrander, Elaine/0000-0001-6075-9738 FU NCI NIH HHS [K05 CA 90574]; PHS HHS [N01-C0-12400] NR 48 TC 113 Z9 116 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 1 PY 2003 VL 12 IS 23 BP 3043 EP 3053 DI 10.1093/hmg/ddg336 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 743RJ UT WOS:000186587100001 PM 14532326 ER PT J AU Sundstrom, J Sullivan, L D'Agostino, RB Jacques, PF Selhub, J Rosenberg, IH Wilson, PWF Levy, D Vasan, RS AF Sundstrom, J Sullivan, L D'Agostino, RB Jacques, PF Selhub, J Rosenberg, IH Wilson, PWF Levy, D Vasan, RS TI Plasma homocysteine, hypertension incidence, and blood pressure tracking - The Framingham Heart Study SO HYPERTENSION LA English DT Article DE hypertension, detection and control; blood pressure; homocysteine; metabolism; epidemiology; longitudinal studies ID CARDIOVASCULAR-DISEASE; ENDOTHELIAL FUNCTION; CONTROLLED TRIAL; RISK FACTOR; HYPERHOMOCYSTEINEMIA; ACID; HEALTH; STROKE; ATHEROSCLEROSIS; RATIONALE AB Plasma homocysteine is cross- sectionally associated with blood pressure in large, community- based studies. It is unknown whether elevated plasma homocysteine predicts hypertension incidence. We investigated the relations of baseline plasma total homocysteine levels to hypertension incidence and blood pressure tracking in 2104 Framingham Heart Study participants ( mean age, 57 years; 58% women), who were free of hypertension, myocardial infarction, heart failure, atrial fibrillation, or renal failure at baseline. Baseline mean +/- SD plasma homocysteine was 10.1 +/- 3.7 mu mol/ L. On follow- up 4 years from baseline, 360 persons ( 17.1%) had developed hypertension, and 878 persons ( 41.7%) had progressed to a higher blood pressure stage. In unadjusted analyses, a 1- SD higher log homocysteine value was associated with increased odds of developing hypertension ( odds ratio [ OR], 1.18; 95% confidence interval [ CI], 1.05 to 1.32) and increased odds of blood pressure progression ( OR, 1.17; 95% CI, 1.07 to 1.27). The relations of plasma homocysteine to the incidence of hypertension or blood pressure progression were statistically nonsignificant in age- and sex- adjusted logistic regression models ( OR, 0.98; 95% CI, 0.87 to 1.11 and OR, 1.05; 95% CI, 0.96 to 1.16, respectively) and in multivariable models adjusted for age, sex, body mass index, diabetes, interim weight change, smoking, serum creatinine, baseline blood pressure, and blood pressure category ( OR, 0.92; 95% CI, 0.81 to 1.06 and OR, 1.07; 95% CI, 0.97 to 1.18, respectively). In conclusion, we found no major relation of baseline plasma homocysteine levels to hypertension incidence or longitudinal blood pressure progression in a large, community- based cohort of nonhypertensive individuals after adjustment for age, sex, and other important covariates. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Div Endocrinol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Math, Boston, MA 02118 USA. Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. RI Sundstrom, Johan/A-6286-2009; OI Sundstrom, Johan/0000-0003-2247-8454; Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [1R01HL67288-01, K24HL04334, N01-HC-25195, N01-HV-28178, R01HL71039] NR 36 TC 62 Z9 65 U1 2 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD DEC PY 2003 VL 42 IS 6 BP 1100 EP 1105 DI 10.1161/01.HYP.0000101690.58391.13 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 752TR UT WOS:000187183700006 PM 14597642 ER PT J AU Chobanian, AV Bakris, GL Black, HR Cushman, WC Green, LA Izzo, JL Jones, DW Materson, BJ Oparil, S Wright, JT Roccella, EJ AF Chobanian, AV Bakris, GL Black, HR Cushman, WC Green, LA Izzo, JL Jones, DW Materson, BJ Oparil, S Wright, JT Roccella, EJ CA Natl High Blood Pressure Educ Prog TI Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure SO HYPERTENSION LA English DT Review ID OBSTRUCTIVE SLEEP-APNEA; ISOLATED SYSTOLIC HYPERTENSION; NUTRITION EXAMINATION SURVEY; TYPE-2 DIABETES-MELLITUS; CORONARY-HEART-DISEASE; CONVERTING-ENZYME-INHIBITOR; LEFT-VENTRICULAR MASS; RANDOMIZED CONTROLLED-TRIALS; POSITIVE AIRWAY PRESSURE; PLACEBO-CONTROLLED TRIAL AB The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence- based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure ( BP) of greater than 140 mm Hg is a more important cardiovascular disease ( CVD) risk factor than diastolic BP; beginning at 115/ 75 mm Hg, CVD risk doubles for each increment of 20/ 10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals ( systolic BP 120 - 139 mm Hg or diastolic BP 80 - 89 mm Hg) require health- promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high- risk conditions that are compelling indications for the use of other antihypertensive drug classes ( angiotensin- converting enzyme inhibitors, angiotensin- receptor blockers, beta- blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP ( < 140/ 90 mm Hg, or < 130/ 80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount. C1 NHLBI, Natl High Blood Pressure Educ Program, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Vet Affairs Med Ctr, Memphis, TN USA. Univ Michigan, Ann Arbor, MI 48109 USA. SUNY Buffalo, Sch Med, Buffalo, NY 14260 USA. Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. Univ Miami, Miami, FL 33152 USA. Univ Alabama, Birmingham, AL USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Roccella, EJ (reprint author), NHLBI, Natl High Blood Pressure Educ Program, NIH, Bldg 31,Room 4A10,31 Ctr Dr MSC 2480, Bethesda, MD 20892 USA. RI Lakic, Dragana/F-8688-2011 NR 386 TC 6507 Z9 6929 U1 112 U2 801 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD DEC PY 2003 VL 42 IS 6 BP 1206 EP 1252 DI 10.1161/01.HYP.0000107251.49515.c2 PG 47 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 752TR UT WOS:000187183700022 PM 14656957 ER PT J AU Sausville, E AF Sausville, E TI Signal Transduction Modulators in Cancer Therapy - Second International Symposium - 23-25 October 2003, Amsterdam, the Netherlands SO IDRUGS LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Sausville, E (reprint author), NCI, Executive Plaza N Suite 843,6130 Executive Blvd,M, Bethesda, MD 20892 USA. EM sausville@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU CURRENT DRUGS LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1P 6LB, ENGLAND SN 1369-7056 J9 IDRUGS JI IDrugs PD DEC PY 2003 VL 6 IS 12 BP 1130 EP 1134 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 761HM UT WOS:000187895500008 ER PT J AU Margulies, DH AF Margulies, DH TI Molecular interactions: Stiff or floppy (or somewhere in between?) SO IMMUNITY LA English DT Editorial Material ID ACTIVATING IMMUNORECEPTOR NKG2D; PEPTIDE-MHC; RECOGNITION; RECEPTOR; LIGANDS; BINDING; MECHANISM; COMPLEX; MICA C1 NIAID, Mol Biol Sect, Immunol Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH,Dept Hlth & Human Serv, Bldg 10,Room 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 16 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC PY 2003 VL 19 IS 6 BP 772 EP 774 DI 10.1016/S1074-7613(03)00331-5 PG 3 WC Immunology SC Immunology GA 753KN UT WOS:000187230700002 PM 14670294 ER PT J AU Lazarevic, V Myers, AJ Scanga, CA Flynn, JL AF Lazarevic, V Myers, AJ Scanga, CA Flynn, JL TI CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M-tuberculosis infection SO IMMUNITY LA English DT Article ID NITRIC-OXIDE SYNTHASE; DENDRITIC CELLS; MEDIATED-IMMUNITY; LEISHMANIA-MAJOR; CD40-CD40 LIGAND; CD8(+) CTL; MICE; ACTIVATION; STIMULATION; HEAT-SHOCK-PROTEIN-70 AB CD40(-/-) mice succumbed to low-dose aerosol infection with M. tuberculosis due to deficient IL-12 production leading to impaired priming of lFN-gamma T cell responses. In contrast, CD40L(-/-) mice were resistant to M. tuberculosis. This asymmetry in outcome of infection between the two knockout strains is likely due to the existence of an alternative ligand for CD40. Both in vitro M. tuberculosis infection and recombinant M. tuberculosis Hsp70 elicited IL-12 production from WT dendritic cells. This response was absent in both CD40(-/-) dendritic cells and CD40(-/-) mice, suggesting that M. tuberculosis Hsp70 serves as an alternative ligand for CD40 in vivo. C1 Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Flynn, JL (reprint author), Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RI Lazarevic, Vanja/B-1160-2009 FU NIAID NIH HHS [N01 AI-75320, R01 AI37859]; PHS HHS [A50732] NR 32 TC 84 Z9 88 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC PY 2003 VL 19 IS 6 BP 823 EP 835 DI 10.1016/S1074-7613(03)00324-8 PG 13 WC Immunology SC Immunology GA 753KN UT WOS:000187230700008 PM 14670300 ER PT J AU Kirk, AD AF Kirk, AD TI Crossing the bridge: large animal models in translational transplantation research SO IMMUNOLOGICAL REVIEWS LA English DT Review ID TOTAL-LYMPHOID IRRADIATION; RENAL-ALLOGRAFT SURVIVAL; DONOR BONE-MARROW; NONHUMAN PRIMATE MODEL; MAJOR HISTOCOMPATIBILITY COMPLEX; T-CELL-ACTIVATION; CLINICAL INTESTINAL TRANSPLANTATION; MIXED LYMPHOHEMATOPOIETIC CHIMERISM; INTRAHEPATIC ISLET ALLOGRAFTS; KIDNEY GRAFT-REJECTION AB Many methods for reducing the immunosuppressive requirements of allotransplantation have been proposed based on a growing understanding of physiological and allospecific immunity. As these regimens are developed for clinical application, they require validation in models that are reasonably predictive of their performance in humans. This article provides an overview of the large animal models commonly used to test immunomodulatory organ transplant protocols. The rationale for the use of large animals and the effects of common immunosuppressants in the dog, pig, and non-human primate are reviewed. Promising methods for the induction of allospecific tolerance are surveyed with references to early human trials where appropriate. C1 NIDDKD, Transplantat Sect, Transplantat & Autoimmun Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kirk, AD (reprint author), NIDDK, Transplantat Surg Sect, Transplantat & Autimmun Branch, NIH, Bldg 10,Room 11S-219, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 212 TC 87 Z9 89 U1 1 U2 5 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD DEC PY 2003 VL 196 IS 1 BP 176 EP 196 DI 10.1046/j.1600-065X.2003.00081.x PG 21 WC Immunology SC Immunology GA 740ZU UT WOS:000186434000013 PM 14617205 ER PT J AU Gaur, D Storry, JR Reid, ME Barnwell, JW Miller, LH AF Gaur, D Storry, JR Reid, ME Barnwell, JW Miller, LH TI Plasmodium falciparum is able to invade erythrocytes through a trypsin-resistant pathway independent of glycophorin B SO INFECTION AND IMMUNITY LA English DT Article ID CONTINUOUS CULTURE; MALARIA PARASITES; ANTI-U; INVASION; RECEPTOR; SURFACE; CELL; HETEROGENEITY; INDIVIDUALS; LIGAND AB Plasmodium falciparum invades erythrocytes through multiple ligand-receptor interactions, with redundancies in each pathway. One such alternate pathway is the trypsin-resistant pathway that enables P. falciparum to invade trypsin-treated erythrocytes. Previous studies have shown that this trypsin-resistant pathway is dependent on glycophorin B, as P. falciparum strains invade trypsin-digested glycophorin B-deficient erythrocytes at a highly reduced efficiency. Furthermore, in a recent study, the P. falciparum 7G8 strain did not invade glycophorin B-deficient erythrocytes, a finding that was not confirmed in the present study. To analyze the degree of dependence on glycophorin B for invasion by P. falciparum through the trypsin-resistant pathway, we have studied the invasion phenotypes of five parasite strains, 3D7, HB3, Dd2, 7G8, and Indochina I, on trypsin-treated normal and glycophorin B-deficient erythrocytes. Invasion was variably reduced in glycophorin B-deficient erythrocytes. Four strains, 3D7, HB3, Dd2, and Indochina 1, invaded trypsin-treated erythrocytes, while invasion by the 7G8 strain was reduced by 90%. Among the four strains, invasion by 3D7, HB3, and Dd2 of trypsin-digested glycophorin B-deficient erythrocytes was further reduced. However, Indochina I invaded trypsin-digested glycophorin B-deficient erythrocytes at the same efficiency as its invasion of trypsin-digested normal erythrocytes. This strongly suggests that the Indochina I strain of P. falciparum is not dependent on glycophorin B to invade through a trypsin-resistant pathway as are the strains 3D7, HB3, and Dd2. Thus, P. falciparum is able to invade erythrocytes through a glycophorin B-independent, trypsin-resistant pathway. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. New York Blood Ctr, Immunohaematol Lab, New York, NY 10021 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Natl Ctr Infect Dis, Chamblee, GA 30341 USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 4 Ctr Dr,Bldg 4,Room B1-41, Bethesda, MD 20892 USA. NR 47 TC 26 Z9 28 U1 0 U2 0 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 DEC PY 2003 VL 71 IS 12 BP 6742 EP 6746 DI 10.1128/IAI.71.12.6742-6746.2003 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500009 PM 14638759 ER PT J AU Singh, S Kennedy, MC Long, CA Saul, AJ Miller, LH Stowers, AW AF Singh, S Kennedy, MC Long, CA Saul, AJ Miller, LH Stowers, AW TI Biochemical and immunological characterization of bacterially expressed and refolded Plasmodium falciparum 42-kilodalton C-terminal merozoite surface protein 1 SO INFECTION AND IMMUNITY LA English DT Article ID RECEPTOR-BINDING DOMAIN; PROTECTS AOTUS MONKEYS; MALARIA VACCINE; IMMUNE-RESPONSE; IN-VITRO; ANTIBODIES; FRAGMENT; INVASION; EFFICACY; INHIBIT AB Protection against Plasmodium falciparum can be induced by vaccination in animal models with merozoite surface protein 1 (MSP1), which makes this protein an attractive vaccine candidate for malaria. In an attempt to produce a product that is easily scaleable and inexpensive, we expressed the C-terminal 42 kDa of MSP1 (MSP1(42)) in Escherichia coli, refolded the protein to its native form from insoluble inclusion bodies, and tested its ability to elicit antibodies with in vitro and in vivo activities. Biochemical, biophysical, and immunological characterization confirmed that refolded E. coli MSP1(42) was homogeneous and highly immunogenic. In a formulation suitable for human use, rabbit antibodies were raised against refolded E. coli MSP1(42) and tested in vitro in a P. falciparum growth invasion assay. The antibodies inhibited the growth of parasites expressing either homologous or heterologous forms of P. falciparum MSP1(42). However, the inhibitory activity was primarily a consequence of antibodies directed against the C-terminal 19 kDa of MSP1 (MSP1(19)). Vaccination of nonhuman primates with E. coli MSP1(42) in Freund's adjuvant protected six of seven Aotus monkeys from virulent infection with P. falciparum. The protection correlated with antibody-dependent mechanisms. Thus, this new construct, E. coli MSP1(42), is a viable candidate for human vaccine trials. C1 NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. RP Singh, S (reprint author), NIAID, Malaria Vaccine Dev Unit, NIH, Bldg TW1,Rm 1210A,5640 Fisher Lane, Rockville, MD 20852 USA. RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 NR 32 TC 58 Z9 63 U1 0 U2 0 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 DEC PY 2003 VL 71 IS 12 BP 6766 EP 6774 DI 10.1128/IAI.71.12.6766-6774.2003 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500012 PM 14638762 ER PT J AU Dinglasan, RR Fields, I Shahabuddin, M Azad, AF Sacci, JB AF Dinglasan, RR Fields, I Shahabuddin, M Azad, AF Sacci, JB TI Monoclonal antibody MG96 completely blocks Plasmodium yoelii development in Anopheles stephensi SO INFECTION AND IMMUNITY LA English DT Article ID MALARIA PARASITE DEVELOPMENT; MOSQUITO-MIDGUT ANTIBODIES; MUCIN-TYPE GLYCOPROTEIN; AEDES-AEGYPTI; DIFFERENTIAL DISPLAY; FALCIPARUM; TRANSMISSION; IDENTIFICATION; FECUNDITY; SURFACE AB In spite of research efforts to develop vaccines against the causative agent of human malaria, Plasmodium falciparum, effective control remains elusive. The predominant vaccine strategy focuses on targeting parasite blood stages in the vertebrate host. An alternative approach has been the development of transmission-blocking vaccines (TBVs). TBVs target antigens on parasite sexual stages that persist within the insect vector, anopheline mosquitoes, or target mosquito midgut proteins that are presumed to mediate parasite development. By blocking parasite development within the insect vector, TBVs effectively disrupt transmission and the resultant cascade of secondary infections. Using a mosquito midgut-specific mouse monoclonal antibody (MG96), we have partially characterized membrane-bound midgut glycoproteins in Anopheles gambiae and Anopheles stephensi. These proteins are present on the microvilli of midgut epithelial cells in both blood-fed and unfed mosquitoes, suggesting that the expression of the protein is not induced as a result of blood feeding. MG96 exhibits a dose-dependent blocking effect against Plasmodium yoelii development in An. stephensi. We achieved 100% blocking of parasite development in the mosquito midgut. Preliminary deglycosylation assays indicate that the epitope recognized by MG96 is a complex oligosaccharide. Future investigation of the carbohydrate epitope as well as gene identification should provide valuable insight into the possible mechanisms of ookinete attachment and invasion of mosquito midgut epithelial cells. C1 Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Dinglasan, RR (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 655 W Baltimore St, Baltimore, MD 21201 USA. OI Dinglasan, Rhoel/0000-0001-5433-8179; Dinglasan, Rhoel/0000-0001-6563-1506 NR 36 TC 37 Z9 39 U1 2 U2 4 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 DEC PY 2003 VL 71 IS 12 BP 6995 EP 7001 DI 10.1128/IAI.71.12.6995-7001.2003 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500039 PM 14638789 ER PT J AU Lasco, TM Yamamoto, T Yoshimura, T Allen, SS Cassone, L McMurray, DN AF Lasco, TM Yamamoto, T Yoshimura, T Allen, SS Cassone, L McMurray, DN TI Effect of Mycobacterium bovis BCG vaccination on mycobacterium-specific cellular proliferation and tumor necrosis factor alpha production from distinct guinea pig leukocyte populations SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL PULMONARY TUBERCULOSIS; EXPERIMENTAL AIRBORNE TUBERCULOSIS; HOST-PARASITE RELATIONSHIPS; MESSENGER-RNA EXPRESSION; BETA-T-CELL; GAMMA-INTERFERON; ALVEOLAR MACROPHAGES; CYTOKINE PRODUCTION; HUMAN-MONOCYTES; LYMPHOCYTES-T AB In this study, we focused on three leukocyte-rich guinea pig cell populations, bronchoalveolar lavage (BAL) cells, resident peritoneal cells (PC), and splenocytes (SPC). BAL cells, SPC, and PC were stimulated either with live attenuated Mycobacterium tuberculosis H37Ra or with live or heat-killed virulent M. tuberculosis H37Rv (multiplicity of infection of 1:100). Each cell population was determined to proliferate in response to heat-killed virulent H37Rv, whereas no measurable proliferative response could be detected upon stimulation with live mycobacteria. Additionally, this proliferative capacity (in SPC and PC populations) was significantly enhanced upon prior vaccination with Mycobacterium bovis BCG. Accordingly, in a parallel set of experiments we found a strong positive correlation between production of antigen-specific bioactive tumor necrosis factor alpha (TNF-alpha) and prior vaccination with BCG. A nonspecific stimulus, lipopolysaccharide, failed to induce this effect on BAL cells, SPC, and PC. These results showed that production of bioactive TNF-alpha from mycobacterium-stimulated guinea pig cell cultures positively correlates with the vaccination status of the host and with the virulence of the mycobacterial strain. C1 Texas A&M Univ Syst, Hlth Sci Ctr, Dept Med Microbiol & Immunol, College Stn, TX 77843 USA. Texas A&M Univ, Coll Vet Med, College Stn, TX 77843 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Lasco, TM (reprint author), Colorado State Univ, Dept Microbiol Immunol & Pathol, 320B Microbiol Bldg,1682 Campus Delivery, Ft Collins, CO 80523 USA. FU NIAID NIH HHS [R01 AI015495, R01 AI 15495] NR 39 TC 23 Z9 27 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 DEC PY 2003 VL 71 IS 12 BP 7035 EP 7042 DI 10.1128/IAI.71.12.7035-7042.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500043 PM 14638793 ER PT J AU Reid, SD Montgomery, AG Voyich, JM DeLeo, FR Lei, BF Ireland, RM Green, NM Liu, MY Lukomski, S Musser, JM AF Reid, SD Montgomery, AG Voyich, JM DeLeo, FR Lei, BF Ireland, RM Green, NM Liu, MY Lukomski, S Musser, JM TI Characterization of an extracellular virulence factor made by group A Streptococcus with homology to the Listeria monocytogenes internalin family of proteins SO INFECTION AND IMMUNITY LA English DT Article ID LEUCINE-RICH REPEAT; HUMAN SEROLOGIC RESPONSE; EPITHELIAL-CELLS; MAMMALIAN-CELLS; SURFACE PROTEIN; PRECIPITIN ANALYSIS; CRYSTAL-STRUCTURE; YERSINIA-PESTIS; GENOME SEQUENCE; POPULATION-GENETICS AB Leucine-rich repeats (LRR) characterize a diverse array of proteins and function to provide a versatile framework for protein-protein interactions. Importantly, each of the bacterial LRR proteins that have been well described, including those of Listeria monocytogenes, Yersinia pestis, and Shigella flexneri, have been implicated in virulence. Here we describe an 87.4-kDa group A Streptococcus (GAS) protein (designated Slr, for streptococcal leucine-rich) containing 10 1/2 sequential units of a 22-amino-acid C-terminal LRR homologous to the LRR of the L. monocytogenes internalin family of proteins. In addition to the LRR domain, slr encodes a gram-positive signal secretion sequence characteristic of a lipoprotein and a putative N-terminal domain with a repeated histidine triad motif (HxxHxH). Real-time reverse transcriptase PCR assays indicated that slr is transcribed abundantly in vitro in the exponential phase of growth. Flow cytometry confirmed that Slr was attached to the GAS cell surface. Western immunoblot analysis of sera obtained from 80 patients with invasive infections, noninvasive soft tissue infections, pharyngitis, and rheumatic fever indicated that Slr is produced in vivo. An isogenic mutant strain lacking slr was significantly less virulent in an intraperitoneal mouse model of GAS infection and was significantly more susceptible to phagocytosis by human polymorphonuclear leukocytes. These studies characterize the first GAS LRR protein as an extracellular virulence factor that contributes to pathogenesis and may participate in evasion of the innate host defense. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. RP Reid, SD (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Dept Microbiol & Immunol, Med Ctr Blvd, Winston Salem, NC 27157 USA. OI DeLeo, Frank/0000-0003-3150-2516 NR 83 TC 35 Z9 35 U1 0 U2 0 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 DEC PY 2003 VL 71 IS 12 BP 7043 EP 7052 DI 10.1128/IAI.71.12.7043-7052.2003 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500044 PM 14638794 ER PT J AU Banks, DJ Lei, BF Musser, JM AF Banks, DJ Lei, BF Musser, JM TI Prophage induction and expression of prophage-encoded virulence factors in group A Streptococcus serotype M3 strain MGAS315 SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN PHARYNGEAL CELLS; CYSTEINE PROTEASE; GENOME SEQUENCE; MOLECULAR CHARACTERIZATION; GENE-EXPRESSION; PYOGENES; TOXIN; BACTERIOPHAGES; PROTEINASE; RESPONSES AB The genome of the highly virulent group A Streptococcus (GAS) serotype M3 strain MGAS315 has six prophages that encode six proven or putative virulence factors. We examined prophage induction and expression of prophage-encoded virulence factors by this strain under in vitro conditions inferred to approximate in vivo conditions. Coculture of strain MGAS315 with Detroit 562 (D562) human epithelial pharyngeal cells induced the prophage encoding streptococcal pyrogenic exotoxin K (SpeK) and extracellular phospholipase A(2) (Sla) and the prophage encoding streptodornase (Sdn). Increased gene copy numbers after induction correlated with increased speK, sla, and sdn transcript levels. Although speK and sla are located contiguously in prophage Phi315.4, these genes were transcribed independently. Whereas production of immunoreactive SpeK was either absent or minimal during coculture of GAS with D562 cells, production of immunoreactive Sla increased substantially. In contrast, despite a lack of induction of the prophage encoding speA during coculture of GAS with D562 cells, the speA transcript level and production of immunoreactive streptococcal pyrogenic exotoxin A (SpeA) increased. Exposure of strain MGAS315 to hydrogen peroxide, an oxidative stressor, induced the prophage encoding mitogenic factor 4 (MF4), and there was a concomitant increase in the mf4 transcript. All prophages of strain MGAS315 that encode virulence factors were induced during culture with mitomycin C, a DNA-damaging agent. However, the virulence factor gene transcript levels and production of the encoded proteins decreased after mitomycin C treatment. Taken together, the results indicate that a complex relationship exists among environmental culture conditions, prophage induction, and production of prophage-encoded virulence factors. C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Musser, JM (reprint author), Baylor Coll Med, Dept Pathol, 1 Baylor Plaza, Houston, TX 77030 USA. NR 35 TC 55 Z9 59 U1 1 U2 4 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 DEC PY 2003 VL 71 IS 12 BP 7079 EP 7086 DI 10.1128/IAI.71.12.7079-7086.2003 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500048 PM 14638798 ER PT J AU Kaplan, G Post, FA Moreira, AL Wainwright, H Kreiswirth, BN Tanverdi, M Mathema, B Ramaswamy, SV Walther, G Steyn, LM Barry, CE Bekker, LG AF Kaplan, G Post, FA Moreira, AL Wainwright, H Kreiswirth, BN Tanverdi, M Mathema, B Ramaswamy, SV Walther, G Steyn, LM Barry, CE Bekker, LG TI Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL SUBSETS; GRANULOMA-FORMATION; INFECTION; IDENTIFICATION; MACROPHAGES; PROTEIN; MICE; FAS; CYTOTOXICITY AB Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated. C1 Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. Lab Mycobacterial Immun & Pathogenesis, Newark, NJ USA. Univ Cape Town, Infect Dis Unit, ZA-7925 Cape Town, South Africa. Univ Cape Town, Dept Thorac Surg, ZA-7925 Cape Town, South Africa. Univ Cape Town, Dept Clin Lab Sci, ZA-7925 Cape Town, South Africa. Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA. Univ Istanbul, Cerrahpasa Tip Fak, Istanbul, Turkey. NYU, Sch Med, Dept Pathol, New York, NY USA. NIAID, TB Res Sect, NIH, Rockville, MD USA. RP Kaplan, G (reprint author), Publ Hlth Res Inst, TB Ctr, 225 Warren St, Newark, NJ 07103 USA. RI Post, Frank/C-3791-2009; Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000734-12]; NIAID NIH HHS [AI22616, R01 AI054338, AI 54338]; PHS HHS [W00231] NR 33 TC 179 Z9 183 U1 1 U2 15 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 DEC PY 2003 VL 71 IS 12 BP 7099 EP 7108 DI 10.1128/IAI.71.12.7099-7108.2003 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500050 PM 14638800 ER PT J AU Ramsey, KH Sigar, IM Rana, SV Gupta, J Holland, SM Byrne, GI Morrow, JD AF Ramsey, KH Sigar, IM Rana, SV Gupta, J Holland, SM Byrne, GI Morrow, JD TI Inducible nitric oxide synthase regulates production of isoprostanes in vivo during chlamydial genital infection in mice SO INFECTION AND IMMUNITY LA English DT Article ID TRACT INFECTION; PROSTAGLANDIN BIOSYNTHESIS; LIPID-PEROXIDATION; STRESS STATUS; SUPEROXIDE; DISEASE; ACTIVATION; DEFICIENT; INDUCTION; INDEX AB Urinary nitrite and F-2-isoprostanes, an index of oxidant stress, were elevated during chlamydial genital infection of mice. Enhancement of urinary nitrite and F-2-isoprostanes was observed in phagocyte oxidase-deficient mice. Inhibition of inducible nitric oxide synthase reduced isoprostane excretion. We conclude that nitrogen radicals induce F-2-isoprostane production and excretion during murine chlamydial genital infection. C1 Midwestern Univ, Chicago Coll Osteopath Med, Dept Microbiol, Downers Grove, IL 60515 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA. Vanderbilt Univ, Med Ctr, Div Clin Pharmacol, Nashville, TN 37232 USA. RP Ramsey, KH (reprint author), Midwestern Univ, Chicago Coll Osteopath Med, Dept Microbiol, 555 31st St, Downers Grove, IL 60515 USA. FU NCI NIH HHS [P01 CA077839, CA77839]; NIAID NIH HHS [AI49354, R01 AI049354-04, AI19782, R01 AI049354, R01 AI019782, R15 AI037807, R15 AI037807-01A1]; NIDDK NIH HHS [DK48831, R01 DK048831]; NIGMS NIH HHS [GM15431, P50 GM015431, P01 GM015431] NR 24 TC 5 Z9 6 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 DEC PY 2003 VL 71 IS 12 BP 7183 EP 7187 DI 10.1128/IAI.71.12.7183-7187.2003 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500062 PM 14638813 ER PT J AU Groathouse, NA Heinzen, RA Boitano, S AF Groathouse, NA Heinzen, RA Boitano, S TI Functional BvgAS virulence control system in Bordetella bronchiseptica is necessary for induction of Ca2+ transients in ciliated tracheal epithelial cells SO INFECTION AND IMMUNITY LA English DT Article ID SIGNAL-TRANSDUCTION; COLONIZATION; MECHANISMS; MUCOSA AB To study initial Bordetella bronchiseptica-tracheal epithelial cell interactions, we coincubated B. bronchiseptica with rabbit tracheal explant cultures and assayed bacterial adherence and host cell Ca2+ signaling. Wild-type B. bronchiseptica (RB50) preferentially adhered to cilia and induced ciliated host cell Ca2+ transients within 2 min of coincubation, whereas coincubation with an avirulent strain (RB57) resulted in limited binding and Ca2+ signaling. The described cell system allows for assessment of initial B. bronchiseptica-host cell interactions that can contribute to pathogenicity or to host cell defense. C1 Univ Arizona, Arizona Resp Ctr, Dept Physiol, Tucson, AZ 85724 USA. NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Colorado State Univ, Dept Microbiol, Mycobacteria Res Labs, Ft Collins, CO 80523 USA. Univ Wyoming, Dept Zool & Physiol, Laramie, WY 82701 USA. Univ Wyoming, Dept Mol Biol, Laramie, WY 82701 USA. RP Boitano, S (reprint author), Univ Arizona, Arizona Hlth Sci Ctr, AHSC,1501 N Campbell Ave,Room 2338, Tucson, AZ 85724 USA. FU NCRR NIH HHS [P20 RR015553, RR15553]; NHLBI NIH HHS [HL64636, HL64039] NR 16 TC 5 Z9 5 U1 0 U2 0 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 DEC PY 2003 VL 71 IS 12 BP 7208 EP 7210 DI 10.1128/IAI.71.12.7208-7210.2003 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 747ZA UT WOS:000186835500067 PM 14638818 ER PT J AU Henrich, VC Burns, E Yelverton, DP Christensen, E Weinberger, C AF Henrich, VC Burns, E Yelverton, DP Christensen, E Weinberger, C TI Juvenile hormone potentiates ecdysone receptor-dependent transcription in a mammalian cell culture system SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE nuclear receptor; FXR; RXR; ecdysteroid; juvenile hormone ID RETINOID-X-RECEPTOR; DROSOPHILA-MELANOGASTER; NUCLEAR RECEPTOR; MOLECULAR ACTIONS; GENE ACTIVATION; ULTRASPIRACLE; IDENTIFICATION; INSECT; EXPRESSION; ISOFORMS AB Insect development is guided by the combined actions of ecdysteroids and juvenile hormones (JHs). The transcriptional effects of ecdysteroids are mediated by a protein complex consisting of the ecdysone receptor (EcR) and its heterodimeric partner, Ultraspiracle (USP), but a corresponding JH receptor has not been defined conclusively. Given that the EcR ligand binding domain (LBD) is similar to that of the JH-responsive rat farnesoid-X-activated receptor (FXR), we sought to define experimental conditions under which EcR-dependent transcription could be promoted by JH. Chinese hamster ovary (CHO) cells were transfected with a plasmid carrying an ecdysteroid-inducible reporter gene, a second plasmid expressing one of the three amino-terminal variants of Drosophila EcR or an EcR chimera, and a third plasmid expressing either the mouse retinoid X receptor (RXR), or its insect orthologue, USP. Each of the EcR variants responded to the synthetic ecdysteroid, muristerone A (murA), but a maximal response to 20-hydroxyecdysone (20E) was achieved only for specific EcR combinations with its heterodimeric partner. Notably, the Drosophila EcR isoforms were responsive to 20E only when paired with USP, and only EcRB2 activity was further potentiated by JHIII in the presence of 20E. EcR chimeras that fuse the activator domains from VP16 or the glucocorticoid receptor to the Drosophila EcR DNA-binding and ligand-binding domains were responsive to eedysteroids. Again, the effects of JHIII and 20E were associated with specific partners of the chimeric EcRs. In all experiments, the LBD of EcR proved to be the prerequisite component for potentiation by JHIII, and in this conformation may resemble the FXR LBD. Our results indicate that EcR responsiveness is influenced by the heterodimeric partner and that both the N-terminal domain of EcR and the particular ecdysteroid affect JHIII potentiation. (C) 2003 Elsevier Ltd. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Henrich, VC (reprint author), Univ N Carolina, Inst Hlth Sci & Soc, Dept Biol, 209 Forney Bldg, Greensboro, NC 27402 USA. NR 53 TC 34 Z9 34 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD DEC PY 2003 VL 33 IS 12 BP 1239 EP 1247 DI 10.1016/j.ibmb.2003.08.002 PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 751DD UT WOS:000187036800009 PM 14599496 ER PT J AU Buchholz, DR Tomita, A Fu, L Shi, YB AF Buchholz, DR Tomita, A Fu, L Shi, YB TI A dominant positive thyroid hormone receptor induces gene regulation and metamorphic transformation in the absence of thyroid hormone in vivo in transgenic frogs SO INTEGRATIVE AND COMPARATIVE BIOLOGY LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Integrative-and-Comparative-Biology CY 2004 CL New Orleans, LA SP Soc Integrative Comparative Biol C1 NICHD, LGRD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC INTEGRATIVE COMPARATIVE BIOLOGY PI MCLEAN PA 1313 DOLLEY MADISON BLVD, NO 402, MCLEAN, VA 22101 USA SN 1540-7063 J9 INTEGR COMP BIOL JI Integr. Comp. Biol. PD DEC PY 2003 VL 43 IS 6 BP 851 EP 851 PG 1 WC Zoology SC Zoology GA 831ZI UT WOS:000222235200196 ER PT J AU McKarns, SC Letterio, JJ Kaminski, NE AF McKarns, SC Letterio, JJ Kaminski, NE TI Concentration-dependent bifunctional effect of TGF-beta(1) on immunoglobulin production: a role for Smad3 in IgA production in vitro SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE TGF beta(1); Smad3; immunoglobulin ID GROWTH-FACTOR-BETA; TETRACHLORIDE-MEDIATED IMMUNOSUPPRESSION; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; CARBON-TETRACHLORIDE; IMMUNE-RESPONSES; ALLERGIC ENCEPHALOMYELITIS; SIGNAL-TRANSDUCTION; CELL RESPONSIVENESS; TARGETED DISRUPTION AB Injury to the liver results in rapid induction of transforming growth factor-betal (TGF-beta(1)) consistent with a role for TGF-beta(1) in repairing damaged tissue. In addition to its ubiquitous role in injury repair, TGF-beta(1) is also well established as a critical regulator of immune homeostasis; however, its mechanisms of action remain enigmatic. We have previously demonstrated that the hepatotoxic chlorinated hydrocarbon, carbon tetrachloride, suppresses helper T-lymphocyte function in a TGF-beta(1)-dependent manner. Here, we report that, in opposition to its immunosuppressive effects at picomolar concentrations, femtomolar concentrations of TGF-beta(1) augment T cell-dependent anti-sRBC IgM antibody forming cell (AFC) and T cell-independent DNP-Ficoll-induced AFC responses. These data support a concentration-dependent bifunctional effect by TGF-beta(1) on humoral immune responses in vitro. We further investigated a putative mechanistic role for Smad3, an intracellular mediator of TGF-beta(1) signaling, in propagating the inhibitory effects of TGF-beta(1) on humoral immune responses. Relative to wild type littermates, splenocytes from mice homologous for a null mutation in the gene encoding the TGF-beta receptor-activated Smad3 (Smad3(Exon8-/-)) were less sensitive to inhibition by TGF-beta(1) following anti-sRBC- and LPS-sensitization in vitro. In agreement, inhibition of IgM protein production by TGF-beta(1) was also dampened in LPS-sensitized Smad3(Exon8-/-) splenic B cells. Moreover, stimulation of IgA by TGF-beta(1) was abrogated in LPS-sensitized Smad3(Exon8-/-) splenocytes suggesting an additional role for Smad3 in regulating IgA production in vitro. Our results suggest that the effects of TGF-beta(1) on humoral immune responses fundamentally differ in a concentration-dependent manner and are mediated, in part, through Smad3 signaling. (C) 2003 Elsevier B.V. All rights reserved. C1 Michigan State Univ, Dept Pharmacol & Toxicol, Natl Food Safety & Toxicol Ctr 315, E Lansing, MI 48824 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Kaminski, NE (reprint author), Michigan State Univ, Dept Pharmacol & Toxicol, Natl Food Safety & Toxicol Ctr 315, E Lansing, MI 48824 USA. FU PHS HHS [P01 P42E504911-08C] NR 50 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD DEC PY 2003 VL 3 IS 13-14 BP 1761 EP 1774 DI 10.1016/j.intimp.2003.08.001 PG 14 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 751DY UT WOS:000187038600006 PM 14636827 ER PT J AU Rutter, K Sell, DR Fraser, N Obrenovich, M Zito, M Starke-Reed, P Monnier, VM AF Rutter, K Sell, DR Fraser, N Obrenovich, M Zito, M Starke-Reed, P Monnier, VM TI Green tea extract suppresses the age-related increase in collagen crosslinking and fluorescent products in C57BL/6 mice SO INTERNATIONAL JOURNAL FOR VITAMIN AND NUTRITION RESEARCH LA English DT Article DE glucose; polyphenols; oxidant stress; vitamin C; vitamin E ID LOW-DENSITY-LIPOPROTEIN; DIETARY RESTRICTION; SKIN COLLAGEN; OXIDATIVE STRESS; IN-VITRO; CALORIC RESTRICTION; MAILLARD REACTION; GROWTH-HORMONE; LIFE-SPAN; GLYCOXIDATION AB Collagen crosslinking during aging in part results from Maillard reaction endproducts of glucose and oxoaldehydes. Because of the tight link between oxidative and carbonyl stress, we hypothesized that natural antioxidants and "nutriceuticals" could block collagen aging in C57BL/6 mice. Six groups of young and adult mice received vitamin C, vitamin E, vitamin C&E, blueberry, green tea extract (GTE), or no treatment for a period of 14 weeks. Body weights and collagen glycation were unaltered by the treatment. However, GTE or vitamin C&E combined blocked tendon crosslinking at 10 months of age (p < 0.05, adult group). GTE also blocked fluorescent products at 385 and 440 nm (p = 0.052 and < 0.05, respectively) and tended to decrease skin pentosidine levels. These results suggest that green tea is able to delay collagen aging by an antioxidant mechanism that is in part duplicated by the combination of vitamin C and E. C1 Case Western Reserve Univ, Inst Pathol, Dept Pathol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. Yorktown High Sch, Arlington, VA 22207 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Rutter, K (reprint author), Case Western Reserve Univ, Inst Pathol, Dept Pathol, Cleveland, OH 44106 USA. EM vmm3@po.cwru.edu RI Monnier, Vincent/B-1371-2009 FU NEI NIH HHS [R01 EY007099, R01 EY007099-14]; NIA NIH HHS [AG 18629, R01 AG018629] NR 38 TC 35 Z9 35 U1 0 U2 3 PU VERLAG HANS HUBER PI BERN 9 PA LANGGASS-STRASSE 76, CH-3000 BERN 9, SWITZERLAND SN 0300-9831 J9 INT J VITAM NUTR RES JI Int. J. Vitam. Nutr. Res. PD DEC PY 2003 VL 73 IS 6 BP 453 EP 460 DI 10.1024//0300-9831.73.6.453 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 760QR UT WOS:000187846100008 PM 14743550 ER PT J AU Cassarino, DS Keahey, TM Stern, JB AF Cassarino, DS Keahey, TM Stern, JB TI Puzzling penile papules SO INTERNATIONAL JOURNAL OF DERMATOLOGY LA English DT Article ID SYRINGOMAS C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Washington, DC USA. Quest Diagnost Inc, Baltimore, MD USA. RP Cassarino, DS (reprint author), NCI, Pathol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 2 N212, Bethesda, MD 20892 USA. NR 11 TC 7 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0011-9059 J9 INT J DERMATOL JI Int. J. Dermatol. PD DEC PY 2003 VL 42 IS 12 BP 954 EP 956 DI 10.1111/j.1365-4632.2003.01859.x PG 3 WC Dermatology SC Dermatology GA 747GZ UT WOS:000186798000011 PM 14636192 ER PT J AU Schatzkin, A Kipnis, V Carroll, RJ Midthune, D Subar, AF Bingham, S Schoeller, DA Troiano, RP Freedman, LS AF Schatzkin, A Kipnis, V Carroll, RJ Midthune, D Subar, AF Bingham, S Schoeller, DA Troiano, RP Freedman, LS TI A comparison of a food frequency questionnaire with a 24-hour recall for use in an epidemiological cohort study: results from the biomarker-based Observing Protein and Energy Nutrition (OPEN) study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE attenuation factor; cohort study; dietary measurement error; doubly labelled water; energy intake; food frequency questionnaire; nutritional epidemiology; protein intake; 24-hour recall; urinary nitrogen ID DOUBLY LABELED WATER; DIETARY MEASUREMENT ERROR; PARA-AMINOBENZOIC ACID; VALIDATION; NITROGEN; URINE; CALIBRATION; INSTRUMENTS; CANCER; HUMANS AB Background Most large cohort studies have used a food frequency questionnaire (FFQ) for assessing dietary intake. Several biomarker studies, however, have cast doubt on whether the FFQ has sufficient precision to allow detection of moderate but important diet-disease associations. We use data from the Observing Protein and Energy Nutrition (OPEN) study to compare the performance of a FFQ with that of a 24-hour recall (24HR). Methods The OPEN study included 484 healthy volunteer participants (261 men, 223 women) from Montgomery County, Maryland, aged 40-69. Each participant was asked to complete a FFQ and 24HR on two occasions 3 months apart, and a doubly labelled water (DLW) assessment and two 24-hour urine collections during the 2 weeks after the first FFQ and 24HR assessment. For both the FFQ and 24HR and for both men and women, we calculated attenuation factors for absolute energy, absolute protein, and protein density. Results For absolute energy and protein, a single FFQ's attenuation factor is 0.04-0.16. Repeat administrations lead to little improvement (0.08-0.19). Attenuation factors for a single 24HR are 0.10-0.20, but four repeats would yield attenuations of 0.20-0.37. For protein density a single FFQ has an attenuation of 0.3-0.4; for a single 24HR the attenuation factor is 0.15-0.25 but would increase to 0.35-0.50 with four repeats. Conclusions Because of severe attenuation, the FFQ cannot be recommended as an instrument for evaluating relations between absolute intake of energy or protein and disease. Although this attenuation is lessened in analyses of energy-adjusted protein, it remains substantial for both FFQ and multiple 24HR. The utility of either of these instruments for detecting important but moderate relative risks (between 1.5 and 2.0), even for energy-adjusted dietary factors, is questionable. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. MRC, Dunn Human Nutr Unit, Cambridge, England. Univ Wisconsin, Madison, WI USA. Bar Ilan Univ, Dept Math Stat & Comp Sci, Ramat Gan, Israel. Gertner Inst Epidemiol & Hlth Policy Res, Tel Hashomer, Israel. RP Schatzkin, A (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 3040, Bethesda, MD 20892 USA. OI Troiano, Richard/0000-0002-6807-989X FU NCI NIH HHS [CA-57030]; NIEHS NIH HHS [P30-ES09106] NR 28 TC 192 Z9 194 U1 4 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 2003 VL 32 IS 6 BP 1054 EP 1062 DI 10.1093/ije/dyg264 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 756KA UT WOS:000187463200035 PM 14681273 ER PT J AU Jeronimo, J Castle, PE Herrero, R Burk, RD Schiffman, M AF Jeronimo, J Castle, PE Herrero, R Burk, RD Schiffman, M TI HPV testing and visual inspection for cervical cancer screening in resource-poor regions SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Editorial Material DE HPV DNA testing; visual inspection; cervical intraepithelial neoplasia; cervical cancer C1 NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Rockville, MD USA. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Jeronimo, J (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA78527] NR 4 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD DEC PY 2003 VL 83 IS 3 BP 311 EP 313 DI 10.1016/S0020-7292(03)00299-6 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 751DX UT WOS:000187038500014 PM 14643047 ER PT J AU Tataranni, PA Harper, IT Snitker, S Del Parigi, A Vozarova, B Bunt, J Bogardus, C Ravussin, E AF Tataranni, PA Harper, IT Snitker, S Del Parigi, A Vozarova, B Bunt, J Bogardus, C Ravussin, E TI Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE risk factor; indirect calorimetry; doubly labelled water; energy expenditure; physical activity ID DOUBLY-LABELED WATER; X-RAY ABSORPTIOMETRY; PHYSICAL-ACTIVITY; RESPIRATORY CHAMBER; METABOLIC PREDICTORS; AFFLUENT SOCIETIES; OBESE WOMEN; FOOD; DETERMINANTS; BALANCE AB BACKGROUND: Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited. OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world. DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35 +/- 12 y, 35 +/- 9% body fat; mean +/- s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.8 +/- 6.5 kg) over a follow-up period of 473 y were available in 74 (49M/25F) of the 92 subjects. RESULTS: The baseline calculated total energy intake (r = 0.25, P = 0.028) and RMR (r = -0.28, P = 0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight. CONCLUSION: Using state-of-the- art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population. C1 NIDDK, Clin Diabet & Nutr Sect, NIH, DHHS, Phoenix, AZ 85016 USA. Univ Maryland, Baltimore, MD 21201 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Tataranni, PA (reprint author), NIDDK, Clin Diabet & Nutr Sect, NIH, DHHS, 4212 N 16th St,Rm 541, Phoenix, AZ 85016 USA. NR 44 TC 87 Z9 91 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD DEC PY 2003 VL 27 IS 12 BP 1578 EP 1583 DI 10.1038/sj.ijo.0802469 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 748CK UT WOS:000186844500022 PM 12975636 ER PT J AU Gonzalez, OY Adams, G Teeter, LD Bui, TT Musser, JM Graviss, EA AF Gonzalez, OY Adams, G Teeter, LD Bui, TT Musser, JM Graviss, EA TI Extra-pulmonary manifestations in a large metropolitan area with a low incidence of tuberculosis SO INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 24-27, 2002 CL CHICAGO, ILLINOIS SP Infectious Dis Soc Amer DE mycobacterium tuberculosis; tuberculosis; extra-pulmonary tuberculosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEW-YORK-CITY; EXTRAPULMONARY TUBERCULOSIS; UNITED-STATES; MYCOBACTERIUM-TUBERCULOSIS; EPIDEMIOLOGY; POLYMORPHISM; SUSCEPTIBILITY; TRANSMISSION; EXPERIENCE AB BACKGROUND: The increases in extra-pulmonary tuberculosis (EPTB) have been largely due to human immunodeficiency virus co-infection. The rates of EPTB have remained constant despite the decline in pulmonary tuberculosis (PTB) cases. OBJECTIVE: To evaluate covariates associated with EPTB. METHODS: A 4-year cohort of EPTB patients was compared with PTB cases. Enrollees were assessed for TB risk, medical records were reviewed, and Mycobacterium tuberculosis isolates were fingerprinted. RESULTS: We identified 538 EPTB cases (28.6%) in a total of 1878 enrollees. The most common sites of infection were lymph nodes (43%) and pleura (23%). EPTB cases included 320 (59%) mates, 382 (71%) patients were culture-positive, and 332 (86.9%) patient isolates were fingerprinted. Fewer EPTB than PTB patients belonged to clustered M. tuberculosis strains (58% vs. 65%; P = 0.02). A multivariate model identified an increased risk for EPTB among African Americans (OR = 1.9, P = 0.01), HIV-seropositive (OR = 3.1, P < 0.01), liver cirrhosis (OR = 2.3, P = 0.02), and age <18 years (OR = 2.0, P = 0.04). Patients with concomitant pulmonary and extra-pulmonary infections were more likely to die within 6 months of TB diagnosis (OR = 2.3, P < 0.01). CONCLUSIONS: African American ethnicity is an independent risk factor for EPTB. Mortality at 6 months is partly due to the dissemination of M. tuberculosis and the severity of the underlying co-morbidity. C1 Baylor Coll Med, Infect Dis Sect, Dept Pathol, Dept Internal Med,Div Infect Dis, Houston, TX 77030 USA. Baylor Coll Med, Infect Dis Sect, Dept Pathol, Dept Pathol, Houston, TX 77030 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Graviss, EA (reprint author), Baylor Coll Med, Infect Dis Sect, Dept Pathol, Dept Internal Med,Div Infect Dis, 209E, Houston, TX 77030 USA. FU NIAID NIH HHS [N01-AO-02738]; NIDA NIH HHS [DA09238] NR 45 TC 54 Z9 56 U1 0 U2 0 PU INT UNION AGAINST TUBERCULOSIS LUNG DISEASE (I U A T L D) PI PARIS PA 68 BOULEVARD SAINT-MICHEL,, 75006 PARIS, FRANCE SN 1027-3719 J9 INT J TUBERC LUNG D JI Int. J. Tuberc. Lung Dis. PD DEC PY 2003 VL 7 IS 12 BP 1178 EP 1185 PG 8 WC Infectious Diseases; Respiratory System SC Infectious Diseases; Respiratory System GA 751AC UT WOS:000187029800010 PM 14677893 ER PT J AU Gastwirth, JL Miao, WW Zheng, G AF Gastwirth, JL Miao, WW Zheng, G TI Statistical issues arising in disparate impact cases and the use of the expectancy curve in assessing the validity of pre-employment tests SO INTERNATIONAL STATISTICAL REVIEW LA English DT Article DE banding; correlation; disparate impact; expectancy curve; grouping; pseudo-likelihood; total gain ID MAXIMUM-LIKELIHOOD-ESTIMATION; INTERVAL ESTIMATION; DISCRIMINATION; EMPLOYMENT AB Disparate impact cases concern the potential adverse effect seemingly neutral employment practices, such as passing a pre-employment test or possessing a fixed level of education, have on minority applicants. Their purpose is to eliminate discrimination by subterfuge, i.e., imposing a requirement that eliminates many minority individuals who could do the job but who do not meet the requirement. When a significantly higher fraction of applicants from minority groups fail the requirement compared to majority applicants, the requirement needs to be shown to be job-related. Statistical techniques used at the various stages of a disparate impact claim are described. Properties of the expectancy curve, which describes the utility of a pre-employment test and helps in defining a band of scores defining "equivalently skilled" applicants are discussed. C1 George Washington Univ, Dept Stat, Washington, DC 20052 USA. Macalester Coll, Dept Math, St Paul, MN 55105 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Gastwirth, JL (reprint author), George Washington Univ, Dept Stat, Washington, DC 20052 USA. NR 31 TC 2 Z9 2 U1 0 U2 3 PU INT STATISTICAL INST PI VOORBURG PA 428 PRINSES BEATRIXLAAN, 2270 AZ VOORBURG, NETHERLANDS SN 0306-7734 J9 INT STAT REV JI Int. Stat. Rev. PD DEC PY 2003 VL 71 IS 3 BP 565 EP 580 PG 16 WC Statistics & Probability SC Mathematics GA 746NU UT WOS:000186753100007 ER PT J AU Lin, DB Zhou, LZ Zelenka, PS Takemoto, D AF Lin, DB Zhou, LZ Zelenka, PS Takemoto, D TI Protein kinase C gamma regulation of Gap junction activity through caveolin-1-containing lipid rafts SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LENS EPITHELIAL-CELLS; INTERCELLULAR COMMUNICATION; GROWTH-FACTOR; TYROSINE PHOSPHORYLATION; PLASMA-MEMBRANE; LIVING CELLS; CONNEXIN43; CAVEOLAE; TRAFFICKING; ACTIVATION AB PURPOSE. To demonstrate the interactions of PKCgamma with caveolin (Cav-)-1 and connexin(Cx)43 in lipid rafts and its regulation of gap junctions. METHODS. N/N1003A lens epithelial cells, bovine primary lens epithelial cells, and stably transfected N/N1003A lens epithelial cells were used. Coimmunoprecipitation and Western blot analysis were used to detect protein expression and their interactions. Cav-1- containing lipid rafts and redistribution of Cav-1, PKCgamma, and Cx43 were analyzed by sucrose gradients and by consequent Western blot analysis. Cell surface gap junction Cx43 plaques were detected by confocal microscopy. PKCgamma activity was measured with a PKC assay kit. RESULTs. Cav-1 and -2 were found in N/N1003A and bovine primary lens epithelial cells. Cx43 was associated with Cav-1 in lipid rafts. Phorbol ester (TPA) and insulin-like growth factor (IGF)-1 recruited PKCgamma into Cav-1- containing lipid rafts and stimulated the interactions of PKCgamma with Cav-1 and Cx43. TPA and IGF-1 induced redistribution of Cav-1 and Cx43 from light-density fractions to higher density fractions on sucrose gradients. PKCgamma redistributed with Cav-1- and Cx43-containing fractions on stimulation with TPA or IGF-1. Overexpression of PKCgamma-enhanced green fluorescent protein (EGFP) increased the interaction of PKCgamma-EGFP with Cav-1 and Cx43 and decreased gap junction Cx43 plaques without exogenous growth factors. Overexpression of a loss-of-function PKCgamma mutant did not decrease gap junction Cx43 plaques or cause redistribution in lipid rafts, even though the PKCgamma mutant still interacted with Cav-1 and Cx43. CONCLUSIONS. Activation of PKCgamma by TPA or IGF-1 stimulated the interaction of PKC-gamma with Cav-1 and Cx43 in lipid rafts, causing Cx43, Cav-1, and PKCgamma to redistribute within the lipid rafts, and this resulted in a decrease in gap junction plaques. C1 Kansas State Univ, Dept Biochem, Manhattan, KS 66506 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD USA. RP Takemoto, D (reprint author), Kansas State Univ, Dept Biochem, 103 Willard Hall, Manhattan, KS 66506 USA. FU NEI NIH HHS [EY 13421] NR 34 TC 62 Z9 68 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2003 VL 44 IS 12 BP 5259 EP 5268 DI 10.1167/iovs03-0296 PG 10 WC Ophthalmology SC Ophthalmology GA 747JJ UT WOS:000186801200029 PM 14638725 ER PT J AU Wolfe, MD AF Wolfe, MD TI Mechanistic insights revealed through characterization of a novel chromophore in selenophosphate synthetase from Escherichia coli SO IUBMB LIFE LA English DT Article DE selenium; selenophosphate; post-translational modification; chromophore ID SELENIUM DONOR; OXIDASE AB The incorporation of selenium into specific proteins and tRNAs requires selenophosphate (SePO3) whose formation is catalyzed by selenophosphate synthetase. In a Mg/ATP-dependent reaction, selenophosphate synthetase catalyzes the phosphorylation of selenide to yield AMP, inorganic phosphate, and SePO3. In this report, a previously unrecognized chromophore covalently attached to selenophosphate synthetase is characterized. The UV/Vis spectrum of selenophosphate synthetase has a feature centered at 315 nm that is irreversibly destroyed. by alkylation. Moreover, addition of Zn2+, which is known to inhibit selenophosphate synthetase, reversibly quenches the 315 run absorption. Since Zn2+ is known to bind to Cys17, these data strongly suggest that this residue participates in the 315 nm absorption. Upon incubation with both Mg2+ and ATP, the lambda(max) of the chromophore shifts to 340 run, and it is shown that the shift requires binding of nucleotide having a hydrolyzable gamma-phosphoryl group. These data indicate that either the chromophore is directly involved in phosphoryl transfer or indirectly reflects a phosphorylation-dependent conformational change in selenophosphate synthetase. This work provides the first spectroscopic handle on catalytic steps associated with SePO3 synthesis, which will be used to study the molecular structure of the chromophore and its role in the catalytic mechanism of selenophosphate synthetase. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Wolfe, MD (reprint author), NHLBI, Biochem Lab, NIH, 50 South Dr MSC 8012, Bethesda, MD 20892 USA. EM wolfem@nhlbi.nih.gov NR 21 TC 2 Z9 3 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1521-6543 J9 IUBMB LIFE JI IUBMB Life PD DEC PY 2003 VL 55 IS 12 BP 689 EP 693 DI 10.1080/15216540310001643431 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 767AK UT WOS:000188416100008 PM 14769005 ER PT J AU Gonzales, MJ Johnson, E Dupnik, KM Imamichi, T Shafer, RW AF Gonzales, MJ Johnson, E Dupnik, KM Imamichi, T Shafer, RW TI Colinearity of reverse transcriptase inhibitor resistance mutations detected by population-based sequencing SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV-1; reverse transcriptase; drug resistance; clone; genome ID IMMUNODEFICIENCY-VIRUS TYPE-1; COMBINATION THERAPY; DRUG-RESISTANCE; IN-VIVO; HIV-1; REPLICATION; PROTEASE; LAMIVUDINE; FITNESS AB High-level resistance to multiple drugs is often detected by directly sequencing uncloned polymerase chain reaction products (population-based sequencing). It is not known, however, if this method of identifying mutations gives an accurate picture of individual viral genomes. To determine how often multidrug-resistant isolates consist of clones containing every mutation present in the population-based sequence, a mean of 2.8 molecular clones was sequenced from the plasma of 25 heavily treated persons whose population-based sequence contained multiple reverse transcriptase (RT) inhibitor resistance mutations (71 clones). The 25 population-based sequences contained a mean of 5.7 nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations and 1.2 nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations. The 71 clones contained a mean of 5.3 NRTI resistance mutations and 1.0 NNRTI resistance mutations. Sequences of clones closely resembled the population-based sequence: 3 6 (51%) clones had each of the RT inhibitor mutations present in the population-based sequence, 25 (35%) had all but 1 RT inhibitor mutation, 4 (6%) had all but 2 RT inhibitor mutations, 3 (4%) bad all but 3 RT inhibitor mutations, and 3 (4%) had all but 4 RT inhibitor mutations. Phenotypic testing of 29 clones showed that most clones were resistant to nearly all NRTIs and that those with NNRTI resistance mutations were also resistant to multiple NNRTIs. These data show that in heavily treated persons, most RT inhibitor resistance mutations are present in the same viral genomes (colinear) and that multidrug resistance often occurs within individual clones as well as within virus populations. C1 Stanford Univ, Div Infect Dis, Stanford, CA 94305 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Shafer, RW (reprint author), Stanford Univ, Div Infect Dis, Room S-156, Stanford, CA 94305 USA. FU FIC NIH HHS [R25 TW009337]; NIAID NIH HHS [AI-46148-03, R01 AI046148, R01 AI046148-08] NR 23 TC 13 Z9 13 U1 0 U2 1 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 DEC 1 PY 2003 VL 34 IS 4 BP 398 EP 402 DI 10.1097/00126334-200312010-00006 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 745XM UT WOS:000186716500006 PM 14615657 ER PT J AU Ciner, E Cyert, L Dobson, V Kulp, MT Maguire, M Moore, B Orel-Bixler, D Peskin, E Quinn, G Redford, M Schmidt, P Schultz, J AF Ciner, E Cyert, L Dobson, V Kulp, MT Maguire, M Moore, B Orel-Bixler, D Peskin, E Quinn, G Redford, M Schmidt, P Schultz, J CA Vision Preschoolers Study Grp TI Threshold visual acuity testing of preschool children using the crowded HOTV and Lea Symbols acuity tests SO JOURNAL OF AAPOS LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Optometry CY DEC 07-11, 2000 CL ORLANDO, FL SP Amer Acad Optometry ID AMBLYOPIA TREATMENT; PROTOCOL/ AB Purpose: To compare the testability and threshold acuity levels for very young children on the crowded HOTV logMAR distance visual acuity test presented on the BVAT apparatus and the Lea Symbols logMAR distance visual acuity chart. Methods: Subjects were 87 Head Start children from age 3 to 3.5 years. Testing consisted of binocular pretraining at near using a lap card as needed, binocular pretraining at 3 m, and threshold testing for each eye. The testing procedure, adapted from the Amblyopia Treatment Study, presented optotypes until the child was unable to correctly name or match three of three or three of four optotypes of a given size. Threshold acuity was the smallest size for which at least three optotypes were correctly identified. Results. Both near and distance pretraining were completed by 71% of children for HOW and by 75% for Lea Symbols (P = .39). The distribution of threshold acuities differed between the two tests. For the 69 eyes of 53 children who were successfully tested with both optotypes, results from the crowded HOW acuity test were on average 0.25 logMar (2.5 lines) better than those from the Lea Symbols acuity test (P < .001). Conclusions. The proportion of children between 3 and 3.5 years of age whose monocular visual acuity could be assessed was high and was similar for the two charts tested. Crowded HOW acuity results were better on average than results using Lea symbols. The different formats of the two tests may explain the observed differences in threshold acuity level. C1 Ohio State Univ, Coll Optometry, Vis Preschoolers Study Ctr, Columbus, OH 43218 USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. NE State Univ, Coll Optometry, Tablequah, OK USA. Univ Arizona, Dept Ophthalmol, Tucson, AZ USA. Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. Univ Penn, Dept Ophthalmol, Philadelphia, PA 19104 USA. New England Coll Optometry, Boston, MA USA. Univ Calif Berkeley, Sch Optometry, Berkeley, CA USA. Childrens Hosp Philadelphia, Div Pediat Ophthalmol, Philadelphia, PA USA. NEI, Bethesda, MD USA. Ohio State Univ, Coll Optometry, Columbus, OH USA. Univ Maryland Coll, Adelphi, MD USA. RP Ciner, E (reprint author), Ohio State Univ, Coll Optometry, Vis Preschoolers Study Ctr, 320 W 10th Ave,POB 182342, Columbus, OH 43218 USA. FU NEI NIH HHS [EY12550, EY12547, EY12534, EY12644, EY05804] NR 6 TC 21 Z9 21 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD DEC PY 2003 VL 7 IS 6 BP 396 EP 399 DI 10.1016/S1091-8531(03)00211-8 PG 4 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 758GC UT WOS:000187624700006 PM 14730291 ER PT J AU Foster, B Metcalfe, DD Prussin, C AF Foster, B Metcalfe, DD Prussin, C TI Human dendritic cell 1 and dendritic cell 2 subsets express Fc epsilon F-RI: Correlation with serum IgE and allergic asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE dendritic cell; IgE; IgE receptor asthma; allergy; flow cytometry ID HIGH-AFFINITY RECEPTOR; HUMAN BASOPHILS; PERIPHERAL-BLOOD; LANGERHANS CELLS; IN-VITRO; ALPHA; EOSINOPHILS; MONOCYTES; DISEASES; ANTIBODY AB Background: Type 1 dendritic cells (DC1) express the high-affinity IgE receptor (FcepsilonFRI); however, the regulation of FcepsilonRI expression by DCs is not well understood. Type 2 DC (DC2) expression of FcepsilonRI has not been demonstrated. Objective: We hypothesized that DC2 cells also express FcepsilonRI and that expression of FcepsilonRI by the DC1 and DC2 subsets correlates with serum IgE and allergic asthma disease status. Methods: To test these hypotheses, we quantitated FcepsilonRI a chain expression by the peripheral blood precursor DC1 (pDC1) and pDC2 subsets by using flow cytometry. Results: FcepsilonRI was expressed by the pDC1 and pDC2 subsets, as well as tissue DCs from tonsils. Relative FcepsilonRI expression by basophil, pDC1, and pDC2 subsets was 12:6.5:1, respectively. In both pDC subsets, FcepsilonRI expression was significantly greater in allergic asthmatic subjects than in nonatopic control subjects. pDC1 and pDC2 expression of FcepsilonRI was highly correlated to serum IgE concentration. The pDC1, pDC2, and basophil subsets demonstrated a similar magnitude of increase in FcepsilonRI expression relative to changes in serum IgE. Conclusions: FcepsilonRI expression is characteristic of both the DC1 and DC2 subsets. Furthermore, FcepsilonRI expression by these cells is highly correlated to serum IgE and to basophil FcepsilonRI expression and is greater in subjects with allergic asthma. These data support the concept that novel therapeutic approaches directly targeted at FcepsilonRI expression would affect both the sensitization and the effector phases of the allergen-specific immune response. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Prussin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205, Bethesda, MD 20892 USA. OI Prussin, Calman/0000-0002-3917-3326 NR 26 TC 79 Z9 82 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2003 VL 112 IS 6 BP 1132 EP 1138 DI 10.1016/j.jaci.2003.09.011 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 752HC UT WOS:000187154200016 PM 14657872 ER PT J AU Prussin, C Griffith, DT Boesel, KM Lin, H Foster, B Casale, TB AF Prussin, C Griffith, DT Boesel, KM Lin, H Foster, B Casale, TB TI Omalizumab treatment downregulates dendritic cell Fc epsilon F-RI expression SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE dendritic cells; IgE; anti-IgE; Fc epsilon RI; omalizumab; antigen-presenting cells ID PERIPHERAL-BLOOD; MONOCLONAL-ANTIBODY; ATOPIC PATIENTS; IGE; RECEPTOR; ANTIGEN; BASOPHILS; SUBSETS; MARKERS; ASTHMA AB Background: Dendritic cells (DCs) are potent antigen-presenting cells that express FcepsilonRI, the high-affinity IgE receptor. Although the downregulation of basophil FcepsilonRI during anti-IgE therapy with omalizumab is well documented, its effect on FcepsilonRI expression by DCs has not been reported. Objective: We hypothesized that IgE regulates surface FcepsilonRI expression by DCs in vivo and that, consequently, anti-IgE therapy decreases FcepsilonRI expression by DCs. Methods: In a randomized, double-blind, placebo-controlled clinical trial 24 subjects (16 receiving omalizumab and 8 receiving placebo) with seasonal allergic rhinitis received the study drug on days 0 and 28. Serial blood samples drawn on days 0, 7, 14, 28, and 42 were analyzed for precursor DC1 (pDC1) and pDC2 surface expression of FeepsilonRIalpha by using flow cytometry. Results: Omalizumab caused a significant decrease in surface FcepsilonRI expression at all time points examined in both the pDC1 and pDC2 subsets. No significant change was seen with placebo. The maximum decrease in FcepsilonRI expression in the omalizumab group was 52% and 83%, respectively, for the pDC1 and pDC2 subsets. The decrease in FcepsilonRI expression by both pDC subsets correlated with the decrease in serum-free IgE and was of a similar magnitude to that found in basophils. A 10-fold decrease in IgE corresponded to a 42% and 54% decrease in surface FcepsilonRI expression by the pDC1 and pDC2 subsets, respectively. Conclusion: These results demonstrate that anti-IgE therapy causes a rapid decrease in DC surface FcepsilonRI expression and establish that IgE is an important regulator of FcepsilonRI expression by DCs. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Creighton Univ, Dept Med, Div Allergy Immunol, Omaha, NE 68178 USA. RP Prussin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Bldg 10,Room 11C205, Bethesda, MD 20892 USA. RI Casale, Thomas/K-4334-2013; OI Casale, Thomas/0000-0002-3149-7377; Prussin, Calman/0000-0002-3917-3326 NR 24 TC 182 Z9 192 U1 1 U2 6 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2003 VL 112 IS 6 BP 1147 EP 1154 DI 10.1016/j.jaci.2003.10.003 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 752HC UT WOS:000187154200018 PM 14657874 ER PT J AU D'ambrosio, C Akin, C Wu, YL Magnusson, MK Metcalfe, DD AF D'ambrosio, C Akin, C Wu, YL Magnusson, MK Metcalfe, DD TI Gene expression analysis in mastocytosis reveals a highly consistent profile with candidate molecular markers SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE mastocytosis; microarray; tryptase ID BLOOD MONONUCLEAR-CELLS; C-KIT; MYELODYSPLASTIC SYNDROME; SYSTEMIC MASTOCYTOSIS; ACTIVATING MUTATION; HEMATOPOIETIC-CELLS; CATALYTIC DOMAIN; MAST-CELLS; APOPTOSIS; PROTEINS AB Background: Mastocytosis is a rare clonal disorder that might be accompanied by non-mast-cell clonal hematologic disorders, such as myeloproliferative or myelodysplastic syndromes. Objective: Our aim was to further understand the pathologic basis of mastocytosis and to identify novel molecular markers of disease. Methods: Microarray analysis was performed on RNA preparations obtained from bone marrow mononuclear cells of patients with mastocytosis. Results were compared with gene expression profiles performed on bone marrow mononuclear cells of healthy subjects. Results: Analysis of gene expression in neoplastic bone marrow tissues revealed highly consistent profiles. One hundred four genes were significantly upregulated, and 64 genes were significantly downregulated in the bone marrow of patients with mastocytosis. The most prominent differentially expressed gene was alpha-tryptase (44.6-fold increase). Also upregulated were genes involved in cell proliferation, neoplastic transformation, and apoptosis. Both hierarchical and K-means clustering analyses identified an identical group of 10 genes highly coordinately overexpressed in patients with mastocytosis, including genes for the mast-cell-associated enzymes alpha- and beta-tryptase and carboxypeptidase A. The expression level of 3 of these 10 genes (alpha-tryptase, the activating transcription factor type 3, and the muscle aponeurotic fibrosarcoma type F oncogene) was significantly correlated with serum tryptase levels, a surrogate marker of disease. Conclusion: The data presented in this study reveal significant differences in gene expression in the bone marrow of patients with mastocytosis compared with healthy subjects, demonstrate highly coordinated genes that might contribute to pathology, and identify 3 genes as candidate molecular markers for systemic disease. C1 NIAID, NIH, LAD, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, NIH, LAD, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. OI Akin, Cem/0000-0001-6301-4520 NR 41 TC 17 Z9 18 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2003 VL 112 IS 6 BP 1162 EP 1170 DI 10.1016/j.jaci.2003.07.008 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 752HC UT WOS:000187154200020 PM 14657877 ER PT J AU Cohen, SG AF Cohen, SG TI Pioneers and milestones - Loveless on wasp venom allergy and immunity - Part 1 SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Biographical-Item DE loveless; hymenoptera; wasp venom; allergy; immunity ID IMMUNOTHERAPY C1 NIAID, Natl Lib Med, NIH, Bethesda, MD 20892 USA. RP Cohen, SG (reprint author), NIAID, Natl Lib Med, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 15 TC 2 Z9 2 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD DEC PY 2003 VL 112 IS 6 BP 1248 EP 1252 DI 10.1016/j.jaci.2003.09.043 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 752HC UT WOS:000187154200038 PM 14657895 ER PT J AU King, RA Weisberg, RA AF King, RA Weisberg, RA TI Suppression of factor-dependent transcription termination by antiterminator RNA SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HK022 NUN PROTEIN; ESCHERICHIA-COLI; PHAGE-LAMBDA; BACTERIOPHAGE-LAMBDA; DNA HYBRID; ANTI-TERMINATION; IN-VITRO; POLYMERASE; RHO; REGION AB Nascent transcripts of the phage HK022 put sites modify the transcription elongation complex so that it terminates less efficiently at intrinsic transcription terminators and accelerates through pause sites. We show here that the modification also suppresses termination in vivo at two factor-dependent terminators, one that depends on the bacterial Rho protein and a second that depends on the HK022-encoded Nun protein. Suppression was efficient when the termination factors were present at physiological levels, but an increase in the intracellular concentration of Nun increased termination both in the presence and absence of put. put-mediated antitermination thus shows no apparent terminator specificity, suggesting that put inhibits a step that is common to termination at the different types of terminator. C1 NICHHD, Sect Microbial Genet, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Weisberg, RA (reprint author), NICHHD, Sect Microbial Genet, Genet Mol Lab, NIH, Bldg 6B,Room 3B308, Bethesda, MD 20892 USA. NR 48 TC 3 Z9 3 U1 0 U2 0 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 DEC PY 2003 VL 185 IS 24 BP 7085 EP 7091 DI 10.1128/JB.185.24.7085-7091.2003 PG 7 WC Microbiology SC Microbiology GA 752TM UT WOS:000187183300007 PM 14645267 ER PT J AU Bodenreider, O McCray, AT AF Bodenreider, O McCray, AT TI Exploring semantic groups through visual approaches SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE unified medical language system; semantic network; semantic relationships; information visualization; information exploration; graph; correspondence analysis ID VISUALIZATION AB Objectives. We investigate several visual approaches for exploring semantic groups, a grouping of semantic types from the Unified Medical Language System (UMLS) semantic network. We are particularly interested in the semantic coherence of the groups, and we use the semantic relationships as important indicators of that coherence. Methods. First, we create a radial representation of the number of relationships among the groups, generating a profile for each semantic group. Second, we show that, in our partition, the relationships are organized around a limited number of pivot groups and that partitions created at random do not exhibit this property. Finally, we use correspondence analysis to visualize groupings resulting from the association between semantic types and the relationships. Results. The three approaches provide different views on the semantic groups and help detect potential inconsistencies. They make outliers immediately apparent, and, thus, serve as a tool for auditing and validating both the semantic network and the semantic groups. (C) 2003 Elsevier Inc. All rights reserved. C1 NIH, Dept Hlth & Human Serv, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP NIH, Dept Hlth & Human Serv, Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, MS 43,Bldg 38A Rm B1N28U,8600 Rockville Pike, Bethesda, MD 20894 USA. EM olivier@nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 18 TC 68 Z9 69 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 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD DEC PY 2003 VL 36 IS 6 BP 414 EP 432 DI 10.1016/j.jbi.2003.11.002 PG 19 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 776BW UT WOS:000189096000002 PM 14759816 ER PT J AU Rindflesch, TC Fiszman, M AF Rindflesch, TC Fiszman, M TI The interaction of domain knowledge and linguistic structure in natural language processing: interpreting hypernymic propositions in biomedical text SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE natural language processing; semantic processing; knowledge representation; information extraction ID UMLS SEMANTIC NETWORK; INFORMATION EXTRACTION; CLINICAL-DATA; SYSTEM; MEDSYNDIKATE; RADIOLOGY; MEDICINE AB Interpretation of semantic propositions in free-text documents such as MEDLINE citations would provide valuable support for biomedical applications, and several approaches to semantic interpretation are being pursued in the biomedical informatics community. In this paper, we describe a methodology for interpreting linguistic structures that encode hypernymic propositions, in which a more specific concept is in a taxonomic relationship with a more general concept. In order to effectively process these constructions, we exploit underspecified syntactic analysis and structured domain knowledge from the Unified Medical Language System (UMLS). After introducing the syntactic processing on which our system depends, we focus on the UMLS knowledge that supports interpretation of hypernymic propositions. We first use semantic groups from the Semantic Network to ensure that the two concepts involved are compatible; hierarchical information in the Metathesaurus then determines which concept is more general and which more specific. A preliminary evaluation of a sample based on the semantic group Chemicals and Drugs provides 83% precision. An error analysis was conducted and potential solutions to the problems encountered are presented. The research discussed here serves as a paradigm for investigating the interaction between domain knowledge and linguistic structure in natural language processing, and could also make a contribution to research on automatic processing of discourse structure. Additional implications of the system we present include its integration in advanced semantic interpretation processors for biomedical text and its use for information extraction in specific domains. The approach has the potential to support a range of applications, including information retrieval and ontology engineering. Published by Elsevier Inc. C1 NIH, Lister Hill Natl Ctr Biomed Commun, NIH, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. RP Rindflesch, TC (reprint author), NIH, Lister Hill Natl Ctr Biomed Commun, NIH, Dept Hlth & Human Serv, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM tcr@nlm.nih.gov NR 60 TC 134 Z9 136 U1 4 U2 15 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 J9 J BIOMED INFORM JI J. Biomed. Inform. PD DEC PY 2003 VL 36 IS 6 BP 462 EP 477 DI 10.1016/j.jbi.2003.11.003 PG 16 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 776BW UT WOS:000189096000005 PM 14759819 ER PT J AU Mohanty, S Zubkov, S Campos-Olivas, R AF Mohanty, S Zubkov, S Campos-Olivas, R TI Letter to the Editor: H-1, C-13 and N-15 backbone assignments of the pheromone binding protein from the silk moth Antheraea polyphemus (ApolPBP) SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Antheraea polyphemus; NMR assignment; PBP; pheromone binding protein ID BOMBYX-MORI; NMR STRUCTURE; PH C1 SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Ctr Nacl Invest Oncol, Struct & Computat Biol Program, Madrid 28029, Spain. RP Mohanty, S (reprint author), SUNY Stony Brook, Dept Biochem & Cell Biol, Stony Brook, NY 11794 USA. RI Campos-Olivas, Ramon/L-9173-2014 OI Campos-Olivas, Ramon/0000-0002-5743-2221 NR 10 TC 6 Z9 7 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD DEC PY 2003 VL 27 IS 4 BP 393 EP 394 DI 10.1023/A:1025880932197 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 724YA UT WOS:000185514800010 PM 14512737 ER PT J AU Lia, X Peterkofsky, A Wang, GS AF Lia, X Peterkofsky, A Wang, GS TI Letter to the Editor: H-1, N-15, and C-13 chemical shift assignments of the Escherichia coli nitrogen regulatory phosphocarrier IIA(Ntr) SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE Escherichia coli; IIA(Ntr); nitrogen metabolism; PTS; sigma factor ID PHOSPHOTRANSFERASE SYSTEM; PROTEIN; NMR C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, GS (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 986805 Nebraska Med Ctr, Omaha, NE 68198 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD DEC PY 2003 VL 27 IS 4 BP 401 EP 402 PG 2 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 724YA UT WOS:000185514800014 ER PT J AU Kim, MK Li, W Shapiro, BA Chirikjian, GS AF Kim, MK Li, W Shapiro, BA Chirikjian, GS TI A comparison between elastic network interpolation and MD simulation of 16S ribosomal RNA SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article DE 16S ribosomal RNA; elastic network interpolation; intermediate conformation; molecular dynamics; normal mode analysis ID MOLECULAR-DYNAMICS SIMULATIONS; CENTRAL DOMAIN; CONFORMATIONAL TRANSITIONS; PROTEIN S15; MACROMOLECULES; MODEL AB In this paper a coarse-grained method called elastic network interpolation (ENI) is used to generate feasible transition pathways between two given conformations of the core central domain of 16S Ribosomal RNA (16S rRNA). The two given conformations are the extremes generated by a molecular dynamics (MD) simulation, which differ from each other by 10Angstrom in root-mean-square deviation (RMSD). It takes only several hours to build an ENI pathway on a 1.5GHz Pentium with 512 MB memory, while the MD takes several weeks on high-performance multi-processor servers such as the SGI ORIGIN 2000/2100. It is shown that multiple ENI pathways capture the essential anharmonic motions of millions of timesteps in a particular MD simulation. A coarse-grained normal mode analysis (NMA) is performed on each intermediate ENI conformation, and the lowest 1% of the normal modes (representing about 40 degrees of freedom (DOF)) are used to parameterize fluctuations. This combined ENI/NMA method captures all intermediate conformations in the MD run with 1.5Angstrom RMSD on average. In addition, if we restrict attention to the time interval of the MD run between the two extreme conformations, the RMSD between the closest ENI/NMA pathway and the MD results is about 1Angstrom. These results may serve as a paradigm for reduced-DOF dynamic simulations of large biological macromolecules as well as a method for the reduced-parameter interpretation of massive amounts of MD data. C1 Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. NCI, Canc Res Ctr, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. RP Chirikjian, GS (reprint author), Johns Hopkins Univ, Dept Mech Engn, Baltimore, MD 21218 USA. RI Chirikjian, Gregory/A-3314-2010; kim, moon/H-2647-2012 NR 25 TC 20 Z9 21 U1 1 U2 4 PU ADENINE PRESS INC PI GUILDERLAND PA PO BOX 355/340, GUILDERLAND, NY 12084 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD DEC PY 2003 VL 21 IS 3 BP 395 EP 405 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 756AQ UT WOS:000187444000009 PM 14616035 ER PT J AU Nielsen, KL Allen, MR Bloomfield, SA Andersen, TL Chen, XD Poulsen, HS Young, MF Heegaard, AM AF Nielsen, KL Allen, MR Bloomfield, SA Andersen, TL Chen, XD Poulsen, HS Young, MF Heegaard, AM TI Biglycan deficiency interferes with ovariectomy-induced bone loss SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 20-24, 2002 CL SAN ANTONIO, TEXAS SP Amer Soc Bone Mineral Res DE biglycan; deficient mice; osteopenia; ovariectomy; bone turnover ID MICE LACKING; OSTEOCLAST DIFFERENTIATION; PROTEOGLYCANS BIGLYCAN; CHONDROITIN SULFATE; RICH PROTEOGLYCANS; OSTEOPROTEGERIN; OSTEOPOROSIS; MARROW; PROTEIN; DECORIN AB Introduction: Biglycan (bgn) is a small extracellular matrix proteoglycan enriched in skeletal tissues, and biglycan-deficient male mice have decreased trabecular bone mass and bone strength. The purpose of this study was to investigate the bone phenotype of the biglycan-deficient female mice and to investigate the effect of estrogen depletion by ovariectomy (OVX). Materials and Methods: OVX or sham operations were performed on 21-week-old mice that were divided into four groups: wt sham (n = 7), wt OVX (n = 9), bgn-deficient sham (n = 10) and bgn-deficient OVX (n = 10). The mice were killed 4 weeks after surgery. Bone mass and bone turnover were analyzed by peripheral quantitative computed tomography (pQCT), biochemical markers, and histomorphometry. Results and Conclusions: In contrast to the male mice, there were only few effects of bgn deficiency on bone metabolism in female mice, showing a clear gender difference. However, when stressed by OVX, the female bgn knockout (KO) mice were resistant to the OVX-induced trabecular bone loss. The wt mice showed a decrease in trabecular bone mineral density by pQCT measurements, a decrease in trabecular bone volume (BV/TV), and an increase in mineral apposition rate. In contrast, no significant changes were detected in bgn KO mice after OVX. In addition, analysis of the bone resorption marker deoxypyridinoline showed no significant increase in the bgn KO OVX mice compared with bgn KO sham mice. Measurements of serum osteoprotegerin (OPG) and RANKL revealed increased levels of OPG and decreased levels of RANKL in the bgn KO mice compared with wt mice. In conclusion, the bgn deficiency protects against increased trabecular bone turnover and bone loss in response to estrogen depletion, supporting the concept that bgn has dual roles in bone, where it may modulate both formation and resorption ultimately influencing the bone turnover process. C1 Nord Biosci AS, DK-2730 Herlev, Denmark. Natl Univ Hosp, Finsen Ctr, Dept Radiat Biol, Copenhagen, Denmark. Texas A&M Univ, Dept Hlth & Kinesiol, College Stn, TX USA. NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. RP Nielsen, KL (reprint author), Nord Biosci AS, Herlev Hovedgade 207, DK-2730 Herlev, Denmark. RI Allen, Matthew/A-8799-2015 OI Allen, Matthew/0000-0002-1174-9004 NR 41 TC 31 Z9 32 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2003 VL 18 IS 12 BP 2152 EP 2158 DI 10.1359/jbmr.2003.18.12.2152 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 745WB UT WOS:000186712700008 PM 14672350 ER PT J AU Reinlib, L Abraham, W AF Reinlib, L Abraham, W TI Recovery from heart failure with circulatory assist: A working group of the national, heart, lung, and blood institute SO JOURNAL OF CARDIAC FAILURE LA English DT Article DE heart failure; LVAD; circulatory assist; devices; mechanical circulatory support ID NECROSIS-FACTOR-ALPHA; LONG-TERM USE; DEVICE SUPPORT/; GENE-EXPRESSION; BRIDGE; TRANSPLANTATION; CARDIOMYOPATHY; IMPLANTATION; EXPERIENCE; THERAPY AB Background: Over the past decade, mechanical circulatory support has been beneficial as a bridge to cardiac transplantation, and anecdotal evidence suggests that heart failure patients fitted with mechanical assist devices experience direct cardiac benefits. Moreover, recent trials on limited numbers and subpopulations of patients-notably the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH)-support earlier observations of improved cardiac function and point towards the use of assist devices as destination therapy. Methods and Results: To investigate this phenomenon, on August 2-3, 2001, the National Heart, Lung, and Blood Institute convened the working group, "Recovery from Heart Failure with Circulatory Assist" in Bethesda, Maryland. The team included cardiac surgeons, cardiologists, and experts in experimental research. The goal was to prioritize recommendations to guide future programs in: (1) elucidating the mechanisms leading to reverse remodeling associated with a left ventricular assist device (LVAD); (2) exploring advanced treatments, including novel pharmacologies, tissue engineering, and cell therapies, to optimize recovery with LVAD therapy; and (3) identifying target genes, proteins, and cellular pathways to focus on for production of novel therapies for myocardial recovery and cardiovascular disease. Conclusions: The working group also made research and clinical recommendations to eventually translate findings into improved therapeutic strategies and device design: (1) support collaborations among clinical and basic scientists with an emphasis on clinical/translational research that might eventually lead to clinical trials; (2) identify candidate patients most likely to benefit from LVAD as a destination therapy; (3) explore potential biomarkers indicating when patients could most successfully be weaned from devices; and (4) promote clinical and experimental study of mechanically assisted organs and the tissue derived from them. C1 US Dept HHS, NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD USA. Ohio State Univ, Div Cardiol, Columbus, OH 43210 USA. RP Reinlib, L (reprint author), NIEHS, Div Extramural Res & Training, Susceptibil & Populat Hlth Branch, Room 3453,79 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 31 TC 15 Z9 17 U1 0 U2 3 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD DEC PY 2003 VL 9 IS 6 BP 459 EP 463 DI 10.1016/S1071-9164(03)00592-X PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 759AL UT WOS:000187715200006 PM 14966786 ER PT J AU Tatsumoto, T Sakata, H Dasso, M Miki, T AF Tatsumoto, T Sakata, H Dasso, M Miki, T TI Potential roles of the nucleotide exchange factor ECT2 and Cdc42 GTPase in spindle assembly in Xenopus egg cell-free extracts SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE exchange factor; Cdc42; mitosis; oncogene; phosphorylation ID EXPRESSION CDNA CLONING; RHO; MICROTUBULE; ONCOGENE; RAN; PROTEINS; FAMILY; ORGANIZATION; CYTOKINESIS; DYNAMICS AB The ECT2 protooncogene encodes a guanine nucleotide exchange factor for the Rho family of small GTPases. ECT2 contains motifs of cell cycle regulators at its N-terminal domain. We previously showed that ECT2 plays a critical role in cytokinesis. Here, we report a potential role of XECT2, the Xenopus homologue of the human ECT2, in spindle assembly in cell-free Xenopus egg extracts. Cloned XECT2 cDNA encodes a 100 kDa protein closely related to human ECT2. XECT2 is specifically phosphorylated in M phase extracts. Affinity-purified anti-XECT2 antibody strongly inhibited mitosis in Xenopus cell-free extracts. Instead of bipolar spindles, where chromosomes are aligned at the metaphase plane in control extracts, the addition of anti-XECT2 resulted in the appearance of abnormal spindles including monopolar and multipolar spindles as well as bipolar spindles with misaligned chromosomes. In these in vitro synthesized spindle structures, XECT2 was found to tightly associate with mitotic spindles. The N-terminal half of XECT2 lacking the catalytic domain also strongly inhibited spindle assembly in vitro, resulting in the formation of mitotic spindles with a low density. Among the representative Rho GTPases, a dominant-negative form of Cdc42 strongly inhibited spindle assembly in vitro. These results suggest that the Rho family GTPase Cdc42 and its exchange factor XECT2 are critical regulators of spindle assembly in Xenopus egg extracts. Published 2003 Wiley-Liss, Inc. C1 NCI, Mol Tumor Biol Sect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Miki, T (reprint author), NCI, Mol Tumor Biol Sect, Basic Res Lab, NIH, Bldg 37 1E24,37 Convent Dr, Bethesda, MD 20892 USA. NR 31 TC 17 Z9 17 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD DEC 1 PY 2003 VL 90 IS 5 BP 892 EP 900 DI 10.1002/jcb.10750 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 747UH UT WOS:000186822900003 PM 14624449 ER PT J AU Ren, ZG Kar, S Wang, ZQ Wang, MF Saavedra, JE Carr, BI AF Ren, ZG Kar, S Wang, ZQ Wang, MF Saavedra, JE Carr, BI TI JS-K, a novel non-ionic diazeniumdiolate derivative, inhibits Hep 3B hepatoma cell growth and induces c-Jun phosphorylation via multiple MAP kinase pathways SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; SIGNAL-REGULATED KINASE; NITRIC-OXIDE DONORS; INDUCED APOPTOSIS; NH2-TERMINAL KINASE; ERK PHOSPHORYLATION; PC12 CELLS; IN-VITRO; AP-1; DIFFERENTIATION AB JS-K, a non-ionic diazeniumdiolate derivative, is capable of arylating nucleophiles and spontaneously generating nitric oxide (NO) at physiological pH. This recently synthesized low molecular weight compound is shown here to be an inhibitor of cell growth with concomitant activation of mitogen-activated protein kinase (MAPK) members ERK, JNK, and p38 and their downstream effectors c-jun and AP-1. Inhibitors of these MAPK pathways abrogated the growth inhibitory actions of JS-K. In addition to the well-described actions of JNK as a kinase for c-jun, we show that c-jun is also an ERK target. Furthermore, JS-K generated NO in culture and NO inhibitors antagonized both MAPK induction and the growth inhibitory effects of JS-K. These results suggest two possible mechanisms for the mediation of JS-K growth inhibitory actions, namely NO-induction of MAPK pathway constituents as well as possible arylation reactions. The data support the idea that prolonged MAPK activation by JS-K action is important in mediating its growth-inhibitory actions. JS-K thus represents a promising platform for novel growth inhibitory analog synthesis. (C) 2003 Wiley-Liss, Inc. C1 Univ Pittsburgh, Liver Canc Ctr, Dept Surg, Pittsburgh, PA 15213 USA. NCI, Frederick Inc, SAIC, Basic Res Program, Frederick, MD USA. RP Carr, BI (reprint author), Univ Pittsburgh, Liver Canc Ctr, Dept Surg, E1552 Biomed Sci Tower,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [CA 82723]; PHS HHS [N01-C0-12400] NR 44 TC 36 Z9 39 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD DEC PY 2003 VL 197 IS 3 BP 426 EP 434 DI 10.1002/jcp.10380 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 737NU UT WOS:000186239300013 PM 14566972 ER PT J AU Nagineni, CN Samuel, W Nagineni, S Pardhasaradhi, K Wiggert, B Detrick, B Hooks, JJ AF Nagineni, CN Samuel, W Nagineni, S Pardhasaradhi, K Wiggert, B Detrick, B Hooks, JJ TI Transforming growth factor-beta induces expression of vascular endothelial growth factor in human retinal pigment epithelial cells: Involvement of mitogen-activated protein kinases SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID PROLIFERATIVE DIABETIC-RETINOPATHY; CHOROIDAL NEOVASCULAR MEMBRANES; KAPPA-B-ALPHA; MACULAR DEGENERATION; FACTOR VEGF; CROSS-TALK; MEDIATED EXPRESSION; MESSENGER-RNA; MAP KINASE; SMAD AB Vascular endothelial growth factor (VEGF) is a major agent in choroidal and retinal neovascularization, events associated with age-related macular degeneration (AMD) and diabetic retinopathy. Retinal pigment epithelium (RPE), strategically located between retina and choroid, plays a critical role in retinal disorders. We have examined the effects of various growth factors on the expression and secretion of VEGF by human retinal pigment epithelial cell cultures (HRPE). RT-PCR analyses revealed the presence of three isoforms of mRNA corresponding to VEGF 121, 165, and 189 that were up regulated by TGF-beta1. TGF-beta1, beta2, and beta3 were the potent inducers of VEGF secretion by HRPE cells whereas bFGF, PDGF, TGF-alpha, and GMCSF had no effects. TGF-beta receptor type 11 antibody significantly reversed induction of VEGF secretion by TGF-beta. In contrast activin, inhibin and BMP, members of TGF-beta super family, had no effects on VEGF expression in HRPE. VEGF mRNA levels and protein secretion induced by TGF-beta were significantly inhibited by SB203580 and U0126, inhibitors of MAP kinases, but not by staurosporine and PDTC, protein kinase C and NF-kappaB pathway inhibitors, respectively. TGF-beta also induced VEGF expression by fibroblasts derived from human choroid of eye. TGF-beta induction of VEGF secretion by RPE and choroid cells may play a significant role in choroidal neovascularization (CNV) in AMD. Since the secretion of VEGF by HRPE is regulated by MAP kinase pathways, MAP kinase inhibitors may have potential use as therapeutic agents for CNV in AMD. 2003. Published 2003 Wiley-Liss, lnc.(dagger). C1 NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Biochem, Washington, DC USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Hooks, JJ (reprint author), NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bldg 10,Room 6N 228, Bethesda, MD 20892 USA. NR 66 TC 96 Z9 106 U1 0 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD DEC PY 2003 VL 197 IS 3 BP 453 EP 462 DI 10.1002/jcp.10378 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 737NU UT WOS:000186239300016 PM 14566975 ER PT J AU Saporito, RA Donnelly, MA Hoffman, RL Garraffo, HM Daly, JW AF Saporito, RA Donnelly, MA Hoffman, RL Garraffo, HM Daly, JW TI A siphonotid millipede (Rhinotus) as the source of spiropyrrolizidine oximes of dendrobatid frogs SO JOURNAL OF CHEMICAL ECOLOGY LA English DT Article DE alkaloids; arthropods; frogs; dendrobatids; millipedes; pyrrolizidines ID ALKALOIDS; PUMILIOTOXINS; SKIN AB Poison frogs of the neotropical family Dendrobatidae contain a wide variety of lipophilic alkaloids, which are accumulated from alkaloid-containing arthropods. A small millipede, Rhinotus purpureus ( Siphonotidae), occurs microsympatrically with the dendrobatid frog Dendrobates pumilio on Isla Bastimentos, Bocas del Toro Province, Panama. Methanol extracts of this millipede contain the spiropyrrolizidine O- methyloxime 236, an alkaloid previously known only from skin extracts of poison frogs, including populations of D. pumilio. Thus, R. purpureus represents a likely dietary source of such alkaloids in dendrobatid frogs. C1 NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. Virginia Museum Nat Hist, Martinsville, VA 24112 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 11 TC 27 Z9 31 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0098-0331 J9 J CHEM ECOL JI J. Chem. Ecol. PD DEC PY 2003 VL 29 IS 12 BP 2781 EP 2786 DI 10.1023/B:JOEC.0000008065.28364.a0 PG 6 WC Biochemistry & Molecular Biology; Ecology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology GA 753ZK UT WOS:000187278100013 PM 14969363 ER PT J AU Bhangoo, RK Dell, ML Towbin, K Myers, FS Lowe, CH Pine, DS Leibenluft, E AF Bhangoo, RK Dell, ML Towbin, K Myers, FS Lowe, CH Pine, DS Leibenluft, E TI Clinical correlates of episodicity in juvenile mania SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID BIPOLAR DISORDER; CHILDREN; SYMPTOMS; ADHD; VALIDITY AB Objective: Researchers debate whether the diagnostic criteria for mania should differ between children and adults. Specifically, although the Diagnostic and Statistical Manual of Mental Disorders (fourth edition; DSM-IV) requires episodic mood changes, children commonly are diagnosed as manic on the basis of chronic irritability. In this preliminary study, children carrying a diagnosis of bipolar disorder (BPD) in the community were classified as having either episodic or chronic symptoms. We hypothesized that the episodic group would be more likely to have a history of psychosis and a parental history of BPD, whereas the chronic group would be more likely to have conduct disorder. Methods: Parents of children carrying the BPD diagnosis were interviewed on the telephone to obtain psychiatric and family histories. Children were considered episodic (n = 34) if they had a history of one or more DSM-IV manic/hypomanic episodes meeting full duration criteria and chronic (n = 53) if they had no discernable episodes. Results: The episodic group was more likely to have had psychosis, parental history of BPD, and to have experienced each manic symptom except for irritability and psychomotor agitation. Children in the episodic group were also more likely to have had a depressive episode meeting full DSM-IV criteria and were more likely to have made a suicide attempt. Children in the chronic group were not more likely to meet criteria for conduct disorder but were more likely to exhibit violence toward others. Conclusions: These preliminary data indicate that, among children being treated for BPD in the community, those with discrete episodes of mania may be more likely to have a lifetime history of psychosis and a parental history of BPD. The latter hypothesis should be tested in a sample where relatives are interviewed directly. C1 NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Safety Serv, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Safety Serv, Bethesda, MD 20892 USA. EM LEIBS@mail.nih.gov NR 18 TC 33 Z9 34 U1 1 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD WIN PY 2003 VL 13 IS 4 BP 507 EP 514 DI 10.1089/104454603322724896 PG 8 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 772QB UT WOS:000188851800036 PM 14977463 ER PT J AU Bhangoo, RK Lowe, CH Myers, FS Treland, J Curran, J Towbin, KE Leibenluft, E AF Bhangoo, RK Lowe, CH Myers, FS Treland, J Curran, J Towbin, KE Leibenluft, E TI Medication use in children and adolescents treated in the community for bipolar disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID SSRI-INDUCED MANIA; SEROTONIN REUPTAKE INHIBITORS; DOUBLE-BLIND; TRICYCLIC ANTIDEPRESSANTS; STIMULANT TREATMENT; LITHIUM; PLACEBO; SYMPTOMS; CARBAMAZEPINE; DIVALPROEX AB We assessed the use of mood stabilizers, stimulants, antipsychotic medication, and selective serotonin reuptake inhibitors in children being treated in the community for bipolar disorder (BPD). One hundred eleven patients were screened via parent phone interview for possible inclusion in a phenomenological study of BPD. Data were obtained on the patients' medication trials and side effects. The results of the study indicated that children and adolescents who carry a diagnosis of BPD are treated with a mean of 3.40 +/- 1.48 medications and have had a mean of 6.32 +/- 3.67 trials of psychotropic medication in the past. Ninety-eight percent have had a trial of a mood stabilizer or anticonvulsant, with the most common being valproate (79%), lithium (51%), and gabapentin (29%). C1 NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM leibs@mail.nih.gov NR 43 TC 35 Z9 37 U1 5 U2 5 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD WIN PY 2003 VL 13 IS 4 BP 515 EP 522 DI 10.1089/104454603322724904 PG 8 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 772QB UT WOS:000188851800037 PM 14977464 ER PT J AU Arnaldi, G Angeli, A Atkinson, AB Bertagna, X Cavagnini, F Chrousos, GP Fava, GA Findling, JW Gaillard, RC Grossman, AB Kola, B Lacroix, A Mancini, T Mantero, F Newell-Price, J Nieman, LK Sonino, N Vance, ML Giustina, A Boscaro, M AF Arnaldi, G Angeli, A Atkinson, AB Bertagna, X Cavagnini, F Chrousos, GP Fava, GA Findling, JW Gaillard, RC Grossman, AB Kola, B Lacroix, A Mancini, T Mantero, F Newell-Price, J Nieman, LK Sonino, N Vance, ML Giustina, A Boscaro, M TI Diagnosis and complications of Cushing's syndrome: A consensus statement SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GLUCOCORTICOID-INDUCED OSTEOPOROSIS; CORTICOTROPIN-RELEASING HORMONE; BONE-MINERAL DENSITY; DIFFERENTIAL-DIAGNOSIS; TRANSSPHENOIDAL SURGERY; POSTOPERATIVE EVALUATION; ADRENAL INCIDENTALOMA; PARATHYROID-HORMONE; SURGICAL-TREATMENT; METABOLIC SYNDROME AB In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized. C1 Univ Ancona, Dept Internal Med, Div Endocrinol, I-60100 Ancona, Italy. Univ Turin, Dept Clin & Biol Sci, Div Internal Med, I-10063 Turin, Italy. Royal Victoria Hosp, Reg Ctr Endocrinol & Diabet, Belfast BT12 6BA, Antrim, North Ireland. Queens Univ Belfast, Belfast BT12 6BA, Antrim, North Ireland. INSERM, U567, Inst Cochin, F-75014 Paris, France. Univ Paris 05, Dept Endocrinol, F-75014 Paris, France. Fac Cochin, F-75014 Paris, France. Univ Milan, Inst Ricovero & Cura Carattere Sci, Italian Auxol Inst,San Luca Hosp, Dept Endocrinol, I-20149 Milan, Italy. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Bologna, Dept Psychol, I-40127 Bologna, Italy. St Lukes Hosp, Endocrine Diabet Ctr, Milwaukee, WI 53215 USA. CHU Vaudois, Univ Hosp, Div Endocrinol Diabetol & Metab, CH-1011 Lausanne, Switzerland. St Bartholomews Hosp, Dept Endocrinol, London EC1A 7BE, England. Ctr Hosp Univ Montreal, Dept Med, Montreal, PQ H2W 1T7, Canada. Univ Padua, Dept Med & Surg Sci, Div Endocrinol, I-35128 Padua, Italy. Univ Sheffield, No Gen Hosp, Div Clin Sci, Sheffield 55 7AU, S Yorkshire, England. Univ Padua, Dept Mental Hlth, I-35128 Padua, Italy. Univ Padua, Dept Stat Sci, I-35128 Padua, Italy. Univ Virginia Hlth Syst, Charlottesville, VA 22908 USA. Univ Brescia, Dept Internal Med, Endocrine Sect, I-25125 Brescia, Italy. RP Arnaldi, G (reprint author), Azienda Osped Umberto I, Clin Endocrinol, Sede Torrette, I-60100 Ancona, Italy. EM g.arnaldi@aoumbertoprimo.marche.it OI BOSCARO, MARCO/0000-0003-2596-1652 NR 76 TC 602 Z9 637 U1 2 U2 21 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 DEC 1 PY 2003 VL 88 IS 12 BP 5593 EP 5602 DI 10.1210/jc.2003-030871 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 752TZ UT WOS:000187184400001 PM 14671138 ER PT J AU Haluzik, M Nedvidkova, J Bartak, V Dostalova, I Vlcek, P Racek, P Taus, M Svacina, S Alesci, S Pacak, K AF Haluzik, M Nedvidkova, J Bartak, V Dostalova, I Vlcek, P Racek, P Taus, M Svacina, S Alesci, S Pacak, K TI Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human subcutaneous abdominal adipose tissue assessed with microdialysis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACTIVATED PROTEIN-KINASE; HUMAN SKELETAL-MUSCLE; FATTY-ACID OXIDATION; THYROID-HORMONE; LIPOLYSIS; BROWN; RECEPTORS; GLUCOSE; METABOLISM; ADIPOCYTES AB Thyroid hormones play a major role in lipid metabolism. However, whether they directly affect lipolysis locally in the adipose tissue remains unknown. Therefore, we measured abdominal sc adipose tissue norepinephrine ( NE), basal, and isoprenaline-stimulated lipolysis in 12 hypothyroid patients ( HYPO), six hyperthyroid patients (HYPER), and 12 healthy controls by in vivo microdialysis. Adipose tissue NE was decreased in HYPO and increased in HYPER compared with controls (90.4 +/- 2.9 and 458.0 +/- 69.1 vs. 294.9 +/- 19.5 pmol/liter, P < 0.01). Similarly, basal lipolysis, assessed by glycerol assay, was lower in HYPO and higher in HYPER than in controls (88.2 +/- 9.9 and 566.0 +/- 42.0 vs. 214.3 +/- 5.1 mu mol/liter P < 0.01). The relative magnitude of isoprenaline-induced glycerol increase was smaller in HYPO (39 +/- 19.4%, P < 0.05 vs. basal) and higher in HYPER (277 +/- 30.4%, P < 0.01) than in controls (117 +/- 5.6%, P < 0.01). The corresponding changes in NE after isoprenaline stimulation were as follows: 120 +/- 9.2% ( P< 0.05), 503 +/- 113% ( P< 0.01), and 267 +/- 17.2 ( P < 0.01). In summary, by affecting local NE levels and adrenergic postreceptor signaling, thyroid hormones may influence the lipolysis rate in the abdominal sc adipose tissue. C1 NICHHD, Unit Clin Neuroendocrinol, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Fac Med 1, Dept Med 3, Prague, Czech Republic. Fac Med 2, Dept Nucl Med, Prague, Czech Republic. Outpatient Endocrine Clin, Prague, Czech Republic. Inst Endocrinol, Prague 11694, Czech Republic. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Unit Clin Neuroendocrinol, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr,MSC-1583, Bethesda, MD 20892 USA. EM karel@mail.nih.gov RI Svacina, Stepan/C-1962-2017 OI Svacina, Stepan/0000-0002-0894-4116 NR 29 TC 25 Z9 25 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 DEC 1 PY 2003 VL 88 IS 12 BP 5605 EP 5608 DI 10.1210/jc.2003-030576 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 752TZ UT WOS:000187184400003 PM 14671140 ER PT J AU Bakalov, VK Axelrod, L Baron, J Hanton, L Nelson, LM Reynolds, JC Hill, S Troendle, J Bondy, CA AF Bakalov, VK Axelrod, L Baron, J Hanton, L Nelson, LM Reynolds, JC Hill, S Troendle, J Bondy, CA TI Selective reduction in cortical bone mineral density in Turner syndrome independent of ovarian hormone deficiency SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-HORMONE; OSTEOPOROSIS; WOMEN; SIZE AB Women with Turner syndrome (TS) are at risk for osteoporosis from ovarian failure and possibly from haploinsufficiency for bone-related X-chromosome genes. To establish whether cortical or trabecular bone is predominantly affected, and to control for the ovarian failure, we studied forearm bone mineral density (BMD) in 41 women with TS ages 18 - 45 yr and in 35 age-matched women with karyotypically normal premature ovarian failure (POF). We measured BMD at the 1/3 distal radius (D-Rad(1/3); predominantly cortical bone) and at the ultradistal radius (UD-Rad; predominantly trabecular bone) by dual x-ray absorptiometry. Women with TS had lower cortical BMD compared with POF (D-Rad(1/3) Z-score = -1.5 +/- 0.8 for TS and 0.08 +/- 0.7 for POF; P< 0.0001). In contrast, the primarily trabecular UD-Rad BMD was normal in TS and not significantly different from POF (Z-score = - 0.62 +/- 1.1 for TS and - 0.34 +/- 1.0 for POF; P = 0.26). The difference in cortical BMD remained after adjustment for height, age of puberty, lifetime estrogen exposure, and serum 25-hydroxyvitamin D (P = 0.0013). Cortical BMD was independent of serum IGF-I and - II, PTH, and testosterone in TS. We conclude that there is a selective deficiency in forearm cortical bone in TS that appears independent of ovarian hormone exposure and is probably related to X-chromosome gene(s) haploinsufficiency. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Bakalov, VK (reprint author), NICHHD, Dev Endocrinol Branch, NIH, 10 Ctr Cr,Bldg 10-10N262, Bethesda, MD 20892 USA. EM bakalov@mail.nih.gov NR 14 TC 40 Z9 41 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 DEC 1 PY 2003 VL 88 IS 12 BP 5717 EP 5722 DI 10.1210/jc.2003-030913 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 752TZ UT WOS:000187184400022 PM 14671158 ER PT J AU Nunez, SB Calis, K Cutler, GB Jones, J Feuillan, PP AF Nunez, SB Calis, K Cutler, GB Jones, J Feuillan, PP TI Lack of efficacy of fadrozole in treating precocious puberty in girls with the McCune-Albright syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID NONSTEROIDAL AROMATASE INHIBITOR; LUTEINIZING-HORMONE; BREAST-CANCER; HYDROCHLORIDE; PLASMA; RADIOIMMUNOASSAY; CGS-16949A; SECRETION AB We administered the aromatase inhibitor fadrozole to 16 girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome. The girls' ages ranged from 3.2 - 9.7 yr, and their bone ages ranged from 5.75 - 14.25 yr. After baseline evaluations, fadrozole was started at a dose of 240 mug/kg . d (equivalent to the dose recommended for therapy of estrogen-dependent breast cancer) for 12 - 21 months and increased to 480 mug/ kg . d for an additional 12 months in 10 girls. During treatment, seven girls had evidence of central precocious puberty; hence, the GnRH agonist deslorelin (4 mug/kg . d sc) was added to their regimen. One girl was on a long-acting GnRH agonist from the start of treatment. Patients were evaluated at 2 - 6-month intervals throughout treatment. After the first 6 - 12 months of treatment, fadrozole showed some benefits in 10 girls, including decrease in frequency of menses and/or rates of linear growth and bone maturation; however, fadrozole had no significant benefit in the group as a whole. The seven girls with evidence of central precocious puberty had no slowing in the progression of their puberty during the combined fadrozole and GnRH analog treatment. Adverse effects of fadrozole included inhibition of cortisol and aldosterone biosynthesis at the dose of 480 mug/ kg . d, without clinical evidence of adrenal insufficiency. In addition, three patients complained of nonspecific abdominal pain during fadrozole treatment. In one patient, this resolved with a reduction in dose from 480 to 240 mug/kg . d; in two patients, it resolved spontaneously. One girl had muscle weakness and constipation on the 480 mug/kg . d. This resolved after discontinuation of the drug. We conclude that fadrozole is not sufficiently potent to block estrogen synthesis in most girls with gonadotropin-independent precocious puberty due to the McCune-Albright syndrome and may impair the adrenocortical stress response. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Feuillan, PP (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262,10 Ctr Dr,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pfeuill@helix.nih.gov NR 19 TC 16 Z9 17 U1 0 U2 2 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 DEC 1 PY 2003 VL 88 IS 12 BP 5730 EP 5733 DI 10.1210/jc.2003-030864 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 752TZ UT WOS:000187184400024 PM 14671160 ER PT J AU Hofseth, LJ Khan, MA Ambrose, M Nikolayeva, O Xu-Welliver, M Kartalou, M Hussain, SP Roth, RB Zhou, XL Mechanic, LE Zurer, I Rotter, V Samson, LD Harris, CC AF Hofseth, LJ Khan, MA Ambrose, M Nikolayeva, O Xu-Welliver, M Kartalou, M Hussain, SP Roth, RB Zhou, XL Mechanic, LE Zurer, I Rotter, V Samson, LD Harris, CC TI The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID OXIDATIVE DNA-DAMAGE; ULCERATIVE-COLITIS; NITRIC-OXIDE; MUTATOR PHENOTYPE; MISMATCH REPAIR; COLON-CANCER; FRAMESHIFT MUTATIONS; COLORECTAL CANCERS; AP-ENDONUCLEASE; POLYMERASE-BETA AB Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MST was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MST. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MST in patients with UC and may extend to chronic inflammatory or other diseases with MST of unknown etiology. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. MIT, Biol Engn Div, Cambridge, MA 02139 USA. MIT, Ctr Environm Hlth Sci, Cambridge, MA 02139 USA. Weizmann Inst Sci, Dept Mol Cell Biol, Rehovot, Israel. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 3608,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU NCI NIH HHS [CA55042, CA75576, R01 CA055042, R01 CA075576]; NIEHS NIH HHS [ES02109, P30 ES002109] NR 54 TC 147 Z9 151 U1 1 U2 5 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 DEC PY 2003 VL 112 IS 12 BP 1887 EP 1894 DI 10.1172/JCI200319757 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 754TT UT WOS:000187348300016 PM 14679184 ER PT J AU O'Sullivan, CE Kasai, M Francesconi, A Petraitis, V Petraitiene, R Kelaher, AM Sarafandi, AA Walsh, TJ AF O'Sullivan, CE Kasai, M Francesconi, A Petraitis, V Petraitiene, R Kelaher, AM Sarafandi, AA Walsh, TJ TI Development and validation of a quantitative real-time PCR assay using fluorescence resonance energy transfer technology for detection of Aspergillus fumigatus in experimental invasive pulmonary aspergillosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID BRONCHOALVEOLAR LAVAGE SAMPLES; POLYMERASE-CHAIN-REACTION; LINKED-IMMUNOSORBENT-ASSAY; IMMUNOCOMPROMISED PATIENTS; NEUTROPENIC PATIENTS; GALACTOMANNAN; DIAGNOSIS; RABBITS; DNA; GRANULOCYTOPENIA AB Invasive pulmonary aspergillosis (IPA) is a frequently fatal infection in immunocompromised patients that is difficult to diagnose. Present methods for detection of Aspergillus spp. in bronchoalveolar lavage (BAL) fluid and in tissue vary in sensitivity and specificity. We therefore developed an A. fumigatus-specific quantitative real-time PCR-based assay utilizing fluorescent resonance energy transfer (FRET) technology. We compared the assay to quantitative culture of BAL fluid and lung tissue in a rabbit model of experimental IPA. Using an enzymatic and high-speed mechanical cell wall disruption protocol, DNA was extracted from samples of BAIL fluid and lung tissues from noninfected and A. fumigatus-infected rabbits. A unique primer set amplified internal transcribed spacer regions (ITS) I and 2 of the rRNA operon. Amplicon was detected using FRET probes targeting a unique region of ITS1. Quantitation of A. fumigatus DNA was achieved by use of external standards. The presence of PCR inhibitors was determined by use of a unique control plasmid. The analytical sensitivity of the assay was less than or equal to10 copies of target DNA. No cross-reactivity occurred with other medically important filamentous fungi. The assay results correlated with pulmonary fungal burden as determined by quantitative culture (r = 0.72, Spearman rank correlation; P less than or equal to 0.0001). The mean number of genome equivalents detected in untreated animals was 3.86 log(10) (range, 0.86 to 6.39 log(10)) in tissue. There was a 3.53-log(10) mean reduction of A. fumigatus genome equivalents in animals treated with amphotericin B (AMB) (95% confidence interval, 3.38 to 3.69 log(10); P less than or equal to 0.0001), which correlated with the reduction of residual fungal burden in lung tissue measured in terms of log(10) CFU/gram. The enhanced quantitative sensitivity of the real-time PCR assay was evidenced by detection of A. fumigatus genome in infarcted culture-negative lobes, by a greater number of mean genome equivalents compared to the number of CFU per gram in tissue and BAL fluid, and by superior detection of therapeutic response to AMB in BAL fluid compared to culture. This real-time PCR assay using FRET technology is highly sensitive and specific in detecting A. fumigatus DNA from BAL fluid and lung tissue in experimental IPA. 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, Bldg 10,Rm 13N-240, Bethesda, MD 20892 USA. NR 26 TC 59 Z9 62 U1 1 U2 5 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 DEC PY 2003 VL 41 IS 12 BP 5676 EP 5682 DI 10.1128/JCM.41.12.5676-5682.2003 PG 7 WC Microbiology SC Microbiology GA 753JT UT WOS:000187228800050 PM 14662960 ER PT J AU Kerlikowske, K Miglioretti, DL Ballard-Barbash, R Weaver, DL Buist, DSM Barlow, WE Cutter, G Geller, BM Yankaskas, B Taplin, SH Carney, PA AF Kerlikowske, K Miglioretti, DL Ballard-Barbash, R Weaver, DL Buist, DSM Barlow, WE Cutter, G Geller, BM Yankaskas, B Taplin, SH Carney, PA TI Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; PLUS PROGESTIN; WOMENS HEALTH; COLLABORATIVE REANALYSIS; TUMOR CHARACTERISTICS; MENOPAUSAL ESTROGEN; FAMILY HISTORY; RISK; MAMMOGRAPHY; DENSITY AB Purpose: We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use. Methods: From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers. Results: Compared with nonusers, women using estrogen and progestin for greater than or equal to 5 years were at increased risk of breast tumors of stage O or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size less than or equal to 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or 2 (RR, 1.60; 95% CI, 1.44 to 1.77), grade 3 or 4 (RR, 1.54; 95% CI, 1.37 to 1.73), and estrogen receptor-positive (RR, 1.72; 95%a CI, 1.55 to 1.90). Estrogen-only users were slightly more likely to have estrogen receptor-positive breast cancer compared with nonusers (RR, 1.14; 95% CI, 1.06 to 1.23). Conclusion: Use of estrogen and progestin postmenopausal hormone therapy for five years or more increased the likelihood of developing breast cancer, including both tumors with favorable prognostic features and tumors with unfavorable prognostic features. (C) 2003 by American Society of Clinical Oncology. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Gen Internal Med Sect, Dept Vet Affairs, San Francisco, CA 94143 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. NCI, Appl Res Program, DCCPS, Bethesda, MD 20892 USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Nevada, Sch Med, Appl Res Facil, Ctr Res Design & Stat Methods, Reno, NV 89557 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Dept Community & Family Med, Dartmouth Med Sch, Lebanon, NH 03766 USA. RP Kerlikowske, K (reprint author), San Francisco Vet Affairs Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. FU NCI NIH HHS [U01CA70040, U01CA63731, U01CA63740, U01CA70013, U01CA86082, U01CA86076, U01CA69976, U01CA63736] NR 49 TC 93 Z9 97 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2003 VL 21 IS 23 BP 4314 EP 4321 DI 10.1200/JCO.2003.05.151 PG 8 WC Oncology SC Oncology GA 749HB UT WOS:000186912900012 PM 14645420 ER PT J AU Hussain, MM Kotz, H Minasian, L Premkumar, A Sarosy, G Reed, E Zhai, SP Steinberg, SM Raggio, M Oliver, VK Figg, WD Kohn, EC AF Hussain, MM Kotz, H Minasian, L Premkumar, A Sarosy, G Reed, E Zhai, SP Steinberg, SM Raggio, M Oliver, VK Figg, WD Kohn, EC TI Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CALCIUM INFLUX INHIBITOR; SIGNAL-TRANSDUCTION INHIBITOR; MICRONIZED FORMULATION; IV COLLAGEN; TRIAZOLE; PHARMACOKINETICS; ANGIOGENESIS; BIOAVAILABILITY; IDENTIFICATION AB Purpose: Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting greater than or equal to 6 months in patients with relapsed ovarian cancer. Patients and Methods: Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 mug/ml. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting greater than or equal to 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured. Results: Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the greater than or equal to 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed. Conclusion: CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease. 2003 by American Society of Clinical Oncology. C1 NCI, Med Oncol Clin Res Unit, Med Ovarian Canc Clin, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), 10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 46 TC 52 Z9 57 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2003 VL 21 IS 23 BP 4356 EP 4363 DI 10.1200/JCO.2003.04.136 PG 8 WC Oncology SC Oncology GA 749HB UT WOS:000186912900018 PM 14645425 ER PT J AU Glover, DA Byrne, J Mills, JL Robison, LL Nicholson, HS Meadows, A Zeltzer, LK AF Glover, DA Byrne, J Mills, JL Robison, LL Nicholson, HS Meadows, A Zeltzer, LK TI Impact of CNS treatment on mood in adult survivors of childhood leukemia: A report from the children's cancer group SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE LYMPHOCYTIC-LEUKEMIA; POSTTRAUMATIC-STRESS-DISORDER; CRANIAL RADIATION; NEUROPSYCHOLOGICAL PERFORMANCE; LIFE; IRRADIATION; ADOLESCENT; PREDICTORS AB Purpose: This study assessed the relationship between CNS treatment and psychologic mood using the Profile of Moods State (POMS), a standardized measure of affect, among a large sample of young adult survivors of childhood acute lymphoblastic leukemia (ALL; N = 555). Patients and Methods: Survivors of childhood ALL (ages 18 to 33 years at study entry) participated in a structured telephone interview eliciting demographic, health, and behavioral data and the POMS. Treatment data included total dose of CNS irradiation (CRT) and intrathecal methotrexate (MTX) obtained from medical records. Results: Mood disturbance was reported by 24% of survivors. High-dose CRT and MTX predicted disturbance rates modestly and primarily in combination with education variables. Interactions between educational achievement, a history of attendance in special education classes, and sex were better predictors than treatment type or dose. Non-white males, those younger than 12.5 years of age at diagnosis, and those with negative perceptions of current health and cancer's impact on employment were also at greater risk for mood disturbance (P <.01 to .001). Conclusion: Although most survivors are doing well psychologically, a subset of long-term survivors show potentially serious mood disturbance. Mood disturbance seems to be a function of interactions between preexisting individual difference variables (eg, sex, race/ethnicity), treatment factors, and posttreatment educational experiences. Prevention strategies aimed at childhood cancer survivors at greatest risk for mood disturbance may be improved by focus on posttreatment psychosocial and educational supports. (C) 2003 by American Society of Clinical Oncology. C1 Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Dept Psychiat & Biobehav Sci, Inst Neuropsychiat,Med Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Pediat, David Geffen Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Jonsson Canc Ctr, David Geffen Sch Med, Los Angeles, CA USA. Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. NICHHD, Epidemiol Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN USA. Oregon Hlth Sci Univ, Dept Hematol Oncol, Portland, OR 97201 USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. RP Glover, DA (reprint author), Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Dept Psychiat & Biobehav Sci, Inst Neuropsychiat,Med Ctr, 760 Westwood Plaza,68-237 NPl, Los Angeles, CA 90024 USA. FU NCRR NIH HHS [P41 RR013642-097342, P41 RR013642] NR 38 TC 36 Z9 36 U1 1 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 1 PY 2003 VL 21 IS 23 BP 4395 EP 4401 DI 10.1200/JCO.2003.04.089 PG 7 WC Oncology SC Oncology GA 749HB UT WOS:000186912900023 PM 14645430 ER PT J AU Kupka, RW Luckenbaugh, DA Post, RM Leverich, GS Nolen, WA AF Kupka, RW Luckenbaugh, DA Post, RM Leverich, GS Nolen, WA TI Rapid and non-rapid cycling bipolar disorder: A meta-analysis of clinical studies SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 3rd European-Stanley-Foundation Conference on Bipolar Disorder CY SEP 12-14, 2002 CL FREIBURG, GERMANY SP European Stanley Foundation ID THYROID-FUNCTION; AFFECTIVE-ILLNESS; ANTI-DEPRESSANTS; COURSE MODIFIER; FAMILY HISTORY; MOOD DISORDERS; DSM-IV; LITHIUM; HYPOTHYROIDISM; VALIDITY AB Background: Rapid cycling, defined as 4 or more mood episodes per year, is a course specifier of bipolar disorder associated with relative treatment resistance. Several risk factors have been suggested to be associated with rapid cycling. The purpose of this meta-analysis was to compare clinical studies for the evidence of discriminating factors between rapid and non-rapid cycling. Data Sources and Selection: We searched MEDLINE and reference lists of articles and book chapters and selected all of the clinical studies published from 1974 to 2002 comparing subjects with rapid and non-rapid cycling bipolar disorder. Prevalence rates and mean random effect sizes for 18 potential risk factors that were reported by at least 3 studies were calculated. In addition, we differentiated between current and lifetime diagnoses of rapid cycling. Data Synthesis: Twenty studies were identified. Rapid cycling was present in 16.3% of 2054 bipolar patients in 8 studies that included patients who were consecutively admitted to an inpatient or outpatient facility, without a priori selection of rapid cyclers and without matching the numbers of rapid cyclers to non-rapid cycling controls. Female gender and bipolar II subtype both had a small, but statistically significant, effect (p < .000 for female gender, p < .001 for bipolar 11 subtype). The further absence of recurrences with lithium prophylaxis was reported in 34% of rapid cyclers compared with 47% of non-rapid cyclers, a nearly significant difference, and a partial response was present in 59% and 65% of patients, respectively. The effect of hypothyroidism was significant (p < .01) in studies using current, but not lifetime, definitions of rapid cycling. In 46% of cases, a rapid cycling course was preceded by treatment with antidepressants, but systematic data on their causal role are lacking. Conclusion: Rapid cycling is slightly more prevalent in women and in patients with bipolar II subtype. In contrast to common opinion, lithium prophylaxis has at least partial efficacy in a considerable number of rapid cyclers, especially when antidepressants are avoided. Hypothyroidism may be associated with mood destabilization in vulnerable patients. C1 Altrecht Inst Mental Hlth Care, NL-3512 PG Utrecht, Netherlands. Univ Utrecht, Ctr Med, Utrecht, Netherlands. NIMH, Mood Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Kupka, RW (reprint author), Altrecht Inst Mental Hlth Care, Lange Nieuwstraat 119, NL-3512 PG Utrecht, Netherlands. RI Nolen, Willem/E-9006-2014 NR 65 TC 91 Z9 92 U1 2 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD DEC PY 2003 VL 64 IS 12 BP 1483 EP 1494 PG 12 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 758DK UT WOS:000187617300013 PM 14728111 ER PT J AU Daszak, P AF Daszak, P CA Consortium Conservation Med TI The NIH-FIC Henipavirus group: examining the role of anthropogenic changes in the ecology and emergence of Hendra and Nipah viruses SO JOURNAL OF CLINICAL VIROLOGY LA English DT Meeting Abstract CT 6th Asia Pacific Congress of Medical Virology CY DEC 07-10, 2003 CL KUALA LUMPUR, MALAYSIA SP Malaysian Soc Infect Dis, Chemotherapy Asia Pacific Soc Med Virol C1 NIH FIC Henipavirus Grp, Palisades, NY 10964 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 1386-6532 J9 J CLIN VIROL JI J. Clin. Virol. PD DEC PY 2003 VL 28 SU 1 BP S39 EP S40 PG 2 WC Virology SC Virology GA 758ZE UT WOS:000187711900054 ER PT J AU Lu, Z Xu, Z Buchser, WJ AF Lu, Z Xu, Z Buchser, WJ TI Acoustic response properties of lagenar nerve fibers in the sleeper goby, Dormitator latifrons SO JOURNAL OF COMPARATIVE PHYSIOLOGY A-NEUROETHOLOGY SENSORY NEURAL AND BEHAVIORAL PHYSIOLOGY LA English DT Article DE directional selectivity; ear; hearing; otolithic organ; tuning ID INNERVATING OTOLITH ORGANS; SACCULAR AFFERENTS; CARASSIUS-AURATUS; OPSANUS-TAU; TUNING PROPERTIES; SQUIRREL-MONKEY; PARTICLE MOTION; TELEOST FISH; VOCAL FISH; GOLDFISH AB Auditory and vestibular functions of otolithic organs vary among vertebrate taxa. The saccule has been considered a major hearing organ in many fishes. However, little is known about the auditory role of the lagena in fishes. In this study we analyzed directional and frequency responses from single lagenar fibers of Dormitator latifrons to linear accelerations that simulate underwater acoustic particle motion. Characteristic frequencies of the lagenar fibers fell into two groups: less than or equal to 50 Hz and 80-125 Hz. We observed various temporal response patterns: strong phase-locking, double phase-locking, phase-locked bursting, and non-phase-locked bursting. Some bursting responses have not been previously observed in vertebrate otolithic nerve fibers. Lagenar fibers could respond to accelerations as small as 1.1 mm s(-2). Like saccular fibers, lagenar fibers were directionally responsive and decreased directional selectivity with stimulus level. Best response axes of the lagenar fibers clustered around the lagenar longitudinal axis in the horizontal plane, but distributed in a diversity of axes in the mid-sagittal plane, which generally reflect morphological polarizations of hair cells in the lagena. We conclude that the lagena of D. latifrons plays a role in sound localization in elevation, particularly at high stimulus intensities where responses of most saccular fibers are saturated. C1 Univ Miami, Dept Biol, Coral Gables, FL 33146 USA. Univ Miami, Program Neurosci, Miami, FL 33101 USA. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, NIEHS, Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Lu, Z (reprint author), Univ Miami, Dept Biol, 1301 Mem Dr,Room 4, Coral Gables, FL 33146 USA. OI Buchser, William/0000-0002-6675-6359 FU NIDCD NIH HHS [R01 DC03275, R29 DC03275] NR 46 TC 28 Z9 31 U1 0 U2 7 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-7594 J9 J COMP PHYSIOL A JI J. Comp. Physiol. A -Neuroethol. Sens. Neural Behav. Physiol. PD DEC PY 2003 VL 189 IS 12 BP 889 EP 905 DI 10.1007/s00359-003-0462-7 PG 17 WC Behavioral Sciences; Neurosciences; Physiology; Zoology SC Behavioral Sciences; Neurosciences & Neurology; Physiology; Zoology GA 752JL UT WOS:000187157300004 PM 14586545 ER PT J AU Aframian, DJ Amit, D Shai, E Baum, BJ Panet, A Honigman, A Deutsch, D Palmon, A AF Aframian, DJ Amit, D Shai, E Baum, BJ Panet, A Honigman, A Deutsch, D Palmon, A TI Enhancement of functional firefly luciferase secretion from salivary epithelial cells. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract CT 4th General Session of the International-Association-for-Dental-Research CY SEP 04-05, 2002 CL Sichuan Province, PEOPLES R CHINA C1 Hebrew Univ Jerusalem, IL-91905 Jerusalem, Israel. NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2003 VL 82 SI C BP 379 EP 379 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 775UD UT WOS:000189078302416 ER PT J AU Nagano, K Read, EK Masuda, T Murakami, Y Noguchi, T Yoshimura, F AF Nagano, K Read, EK Masuda, T Murakami, Y Noguchi, T Yoshimura, F TI The trimeric structure of ompa homologs in porphyromonas gingivalis SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract CT 4th General Session of the International-Association-for-Dental-Research CY SEP 04-05, 2002 CL Sichuan Province, PEOPLES R CHINA C1 Aichi Gakuin Univ, Sch Dent, Dept Microbiol, Nagoya, Aichi 464, Japan. Aichi Gakuin Univ, Sch Dent, Dept Periodontol, Nagoya, Aichi 464, Japan. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2003 VL 82 SI C BP 423 EP 423 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 775UD UT WOS:000189078302634 ER PT J AU Goldberg, M Septier, D Khoobarry, K Butler, WT Oldberg, A Fisher, L Young, M Ameye, L AF Goldberg, M Septier, D Khoobarry, K Butler, WT Oldberg, A Fisher, L Young, M Ameye, L TI Light and electron immunovisualization of fibromodulin and DSP in the tooth germs normal and fibromodulin deficient mice. SO JOURNAL OF DENTAL RESEARCH LA English DT Meeting Abstract CT 1st Annual Meeting of the International-Association-for-Dental-Research CY SEP 18, 2002 CL Cardiff, WALES C1 Univ Paris 05, F-75270 Paris 06, France. Lund Univ, S-22100 Lund, Sweden. NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2003 VL 82 SI C BP 489 EP 489 PG 1 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 775UD UT WOS:000189078302956 ER PT J AU Batouli, S Miura, M Brahim, J Tsutsui, TW Fisher, LW Gronthos, S Robey, PG Shi, S AF Batouli, S Miura, M Brahim, J Tsutsui, TW Fisher, LW Gronthos, S Robey, PG Shi, S TI Comparison of stem-cell-mediated osteogenesis and dentinogenesis SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE bone marrow stromal stem cell; dental pulp stem cell; osteoblast; odontoblast; transplantation ID MARROW STROMAL CELLS; DENTIN-PULP COMPLEX; IN-VITRO; BONE; STIMULATION; RESPONSES; MIGRATION; REPAIR; VIVO AB The difference between stem-cell-mediated bone and dentin regeneration is not yet well-understood. Here we use an in vivo stem cell transplantation system to investigate differential regulation mechanisms of bone marrow stromal stem cells (BMSSCs) and dental pulp stem cells (DPSCs). Elevated expression of basic fibroblast growth factor (bFGF) and matrix metalloproteinase 9 (MMP-9, gelatinase B) was found to be associated with the formation of hematopoietic marrow in BMSSC transplants, but not in the connective tissue of DPSC transplants. The expression of dentin sialoprotein (DSP) specifically marked dentin synthesis in DPSC transplants. Moreover, DPSCs were found to be able to generate reparative dentin-like tissue on the surface of human dentin in vivo. This study provided direct evidence to suggest that osteogenesis and dentinogenesis mediated by BMSSCs and DPSCs, respectively, may be regulated by distinct mechanisms, leading to the different organization of the mineralized and non-mineralized tissues. C1 NIDCR, NIH, Dept Hlth & Human Serv, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. NIDCR, NIH, Clin Res Core, Bethesda, MD 20892 USA. Mesenchymal Stem Cell Grp, Div Haematol, Inst Med & Vet Sci, Adelaide, SA 5000, Australia. RP Shi, S (reprint author), NIDCR, NIH, Dept Hlth & Human Serv, Craniofacial & Skeletal Dis Branch, Bldg 30,Room 222,30 Covent Dr,MSC-4320, Bethesda, MD 20892 USA. RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 22 TC 198 Z9 213 U1 2 U2 30 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD DEC PY 2003 VL 82 IS 12 BP 976 EP 981 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 747RL UT WOS:000186818500008 PM 14630898 ER PT J AU Avichezer, D Grajewski, RS Chan, CC Mattapallil, MJ Silver, PB Raber, JA Liou, GI Wiggert, B Lewis, GM Donoso, LA Caspi, RR AF Avichezer, D Grajewski, RS Chan, CC Mattapallil, MJ Silver, PB Raber, JA Liou, GI Wiggert, B Lewis, GM Donoso, LA Caspi, RR TI An immunologically privileged retinal antigen elicits tolerance: Major role for central selection mechanisms SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE gene knockout mice; interphotoreceptor retinoid-binding protein; thymic selection; uveitis; autoimmunity ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; REGULATORY T-CELLS; PROMISCUOUS GENE-EXPRESSION; THYMIC EPITHELIAL-CELLS; MYELIN BASIC-PROTEIN; BINDING-PROTEIN; CUTTING EDGE; HUMAN IRBP; MICE; UVEITIS AB Immunologically privileged retinal antigens can serve as targets of experimental autoimmune uveitis (EAU), a model for human uveitis. The tolerance status of susceptible strains, whose target antigen is not expressed in the thymus at detectable levels, is unclear. Here, we address this issue directly by analyzing the consequences of genetic deficiency versus sufficiency of a uveitogenic retinal antigen, interphotoreceptor retinoid-binding protein (IRBP). IRBP-knockout (KO) and wild-type (WT) mice on a highly EAU-susceptible background were challenged with IRBP. The KO mice had greatly elevated responses to IRBP, an altered recognition of IRBP epitopes, and their primed T cells induced exacerbated disease in WT recipients. Ultrasensitive immunohistochemical staining visualized sparse IRBP-positive cells, undetectable by conventional assays, in thymi of WT (but not of KO) mice. IRBP message was PCR, amplified from these cells after microdissection. Thymus transplantation between KO and WT hosts demonstrated that this level of expression is functionally relevant and sets the threshold of immune (and autoimmune) reactivity. Namely, KO recipients of WT thymi generated reduced IRBP-specific responses, and WT recipients of KO thymi developed enhanced responses and a highly exacerbated disease. Repertoire culling and thymus-dependent CD25(+) T cells were implicated in this effect. Thus, uveitis-susceptible individuals display a detectable and functionally significant tolerance to their target antigen, in which central mechanisms play a prominent role. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. Med Coll Georgia, Dept Ophthalmol, Augusta, GA 30912 USA. Wills Eye Hosp & Res Inst, Philadelphia, PA 19107 USA. NEI, Vet Resources Sect, NIH, Bethesda, MD 20892 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N222, Bethesda, MD 20892 USA. OI Caspi, Rachel/0000-0002-7140-7671 FU NEI NIH HHS [EY03829] NR 41 TC 54 Z9 58 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 1 PY 2003 VL 198 IS 11 BP 1665 EP 1676 DI 10.1084/jem.20030413 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 750KR UT WOS:000186990300007 PM 14657219 ER PT J AU Terabe, M Matsui, S Park, JM Mamura, M Noben-Trauth, N Donaldson, DD Chen, WJ Wahl, SM Ledbetter, S Pratt, B Letterio, JJ Paul, WE Berzofsky, JA AF Terabe, M Matsui, S Park, JM Mamura, M Noben-Trauth, N Donaldson, DD Chen, WJ Wahl, SM Ledbetter, S Pratt, B Letterio, JJ Paul, WE Berzofsky, JA TI Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: Abrogation prevents tumor recurrence SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE TGF-beta; NKT cells; immunologic surveillance; myeloid cells; IL-13 ID NITRIC-OXIDE; STAT6-DEFICIENT MICE; MONOCLONAL-ANTIBODIES; IMMUNE SUPPRESSION; HEPATIC-FIBROSIS; IL-13 INHIBITOR; IFN-GAMMA; CANCER; GENERATION; INDUCTION AB Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-niediated tumor immunosurveillance of the 15-12PM tumor could be suppressed by a CD1d-restricted lymphocyte, most likely a natural killer (NK) T cell, which produces interleukin (IL)-13. Here we present evidence for the effector elements in this suppressive pathway. T cell-reconstituted recombination activating gene (RAG)2 knockout (KO) and RAG2/IL-4 receptor alpha double KO mice showed that inhibition of immunosurveillance requires IL-13 responsiveness by a non-T non-B cell. Such nonlymphoid splenocytes from tumor-bearing mice produced more transforming growth factor (TGF)-beta, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-beta production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-beta production was also abrogated by depleting either CD11b(+) or Gr-1(+) cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-beta or depleting Gr-1(+) cells in vivo prevented the tumor recurrence, implying that TGF-beta made by a CD11b(+) Gr-1(+) myeloid cell, in an IL-13 and CD1d-restricted T cell-dependent mechanism, is necessary for down-regulation of tumor immunosurveillance. Identification of this stepwise regulation of immunosurveillance, involving CD1-restricted T cells, IL-13, myeloid cells, and TGF-beta, explains previous observations on myeloid suppressor cells or TGF-beta and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-beta and IL-13. C1 NCI, Mol Immunogenet & Vaccine Res Sect, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Immunol, Washington, DC 20037 USA. Wyeth Res, Cambridge, MA 02140 USA. Genzyme Corp, Framingham, MA 01701 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, NIH, Bldg 10,Room 6B-12,MSC 1578,10 Ctr Dr, Bethesda, MD 20892 USA. OI Mamura, Mizuko/0000-0003-4531-0144 NR 47 TC 353 Z9 369 U1 2 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 1 PY 2003 VL 198 IS 11 BP 1741 EP 1752 DI 10.1084/jem.20022227 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 750KR UT WOS:000186990300014 PM 14657224 ER PT J AU Ludlow, CL Loucks, T AF Ludlow, CL Loucks, T TI Stuttering: a dynamic motor control disorder SO JOURNAL OF FLUENCY DISORDERS LA English DT Review DE brain lesions; dystonia; task specific; spasmodic dysphonia ID ADDUCTOR SPASMODIC DYSPHONIA; MUSCLE AFFERENT BLOCK; POSITRON EMISSION TOMOGRAPHY; MANUAL REACTION-TIMES; HUMAN AUDITORY-CORTEX; LA-TOURETTE SYNDROME; CEREBRAL BLOOD-FLOW; WRITERS CRAMP; INTRACORTICAL EXCITABILITY; DISCONNEXION SYNDROMES AB The purpose of this review is to determine what neural mechanisms may be dysfunctional in stuttering. Three sources of evidence are reviewed. First, studies of dynamic inter-relationships among brain regions during normal speech and in persons who stutter (PWS) suggest that the timing of neural activity in different regions may be abnormal in PWS. Second, the brain lesions associated with acquired stuttering are reviewed. These indicate that in a high percentage of cases, the primary speech and language regions are not affected but lesions involve other structures, such as the basal ganglia, which may modulate the primary speech and language regions. Third, to characterize the motor control disorder in stuttering, similarities and differences from focal dystonias such as spasmodic dysphonia (SD) and Tourette's syndrome (TS) are reviewed. This review indicates that the central control abnormalities in stuttering are not due to disturbance in one particular brain region but rather a system dysfunction that interferes with rapid and dynamic speech processing for production. Educational objectives: The reader will be able to describe: (1) the similarities and differences between stuttering and other speech motor control disorders, (2) which brain lesions are most likely to produce acquired stuttering in adults, and (3) what type of brain abnormality most likely underlies stuttering. (C) 2003 Elsevier Inc. All rights reserved. C1 NINDS, Laryngeal & Speech Sect, Clin Neurosci Program, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Clin Neurosci Program, 10 Ctr Dr,MSC 1416,Bldg 10,Rm 5D38, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 NR 132 TC 81 Z9 86 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0094-730X J9 J FLUENCY DISORD JI J. Fluency Disord. PD WIN PY 2003 VL 28 IS 4 BP 273 EP 295 DI 10.1016/j.jfludis.2003.07.001 PG 23 WC Audiology & Speech-Language Pathology; Education, Special; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Education & Educational Research; Linguistics; Rehabilitation GA 754TD UT WOS:000187346900003 PM 14643066 ER PT J AU Stager, SV Jeffries, KJ Braun, AR AF Stager, SV Jeffries, KJ Braun, AR TI Common features of fluency-evoking conditions studied in stuttering subjects and controls: an (H2OPET)-O-15 study SO JOURNAL OF FLUENCY DISORDERS LA English DT Article DE brain activity patterns; stuttering and nonstuttering speakers; paced speech and singing ID CEREBRAL-ACTIVITY; AUDITORY FUNCTION; SPEECH; VARIABLES; PET; IDENTIFICATION; HETEROGENEITY; ACTIVATION; PATTERNS; DURATION AB We used (H2O)-O-15 PET to characterize the common features of two successful but markedly different fluency-evoking conditions - paced speech and singing - in order to identify brain mechanisms that enable fluent speech in people who stutter. To do so, we compared responses under fluency-evoking conditions with responses elicited by tasks that typically elicit dysfluent speech (quantifying the degree of stuttering and using this measure as a confounding covariate in our analyses). We evaluated task-related activations in both stuttering subjects and age- and gender-matched controls. Areas that were either uniquely activated during fluency-evoking conditions, or in which the magnitude of activation was significantly greater during fluency-evoking than dysfluency-evoking tasks included auditory association areas that process speech and voice and motor regions related to control of the larynx and oral articulators. This suggests that a common fluency-evoking mechanism might relate to more effective coupling of auditory and motor systems - that is, more efficient self-monitoring, allowing motor areas to more effectively modify speech. These effects were seen in both PWS and controls, suggesting that they are due to the sensorimotor or cognitive demands of the fluency-evoking tasks themselves. While responses seen in both groups were bilateral, however, the fluency-evoking tasks elicited more robust activation of auditory and motor regions within the left hemisphere of stuttering subjects, suggesting a role for the left hemisphere in compensatory processes that enable fluency. Educational objectives: The reader will learn about and be able to: (1) compare brain activation patterns under fluency- and dysfluency-evoking conditions in stuttering and control subjects; (2) appraise the common features, both central and peripheral, of fluency-evoking conditions; and (3) discuss ways in which neuroimaging methods can be used to understand the pathophysiology of stuttering. (C) 2003 Published by Elsevier Inc. C1 Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD 20892 USA. RP Braun, AR (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bldg 10,Room 5N118A, Bethesda, MD 20892 USA. OI Stager, Sheila/0000-0002-4294-2114 NR 32 TC 28 Z9 28 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0094-730X J9 J FLUENCY DISORD JI J. Fluency Disord. PD WIN PY 2003 VL 28 IS 4 BP 319 EP 336 DI 10.1016/j.jfludis.2003.08.004 PG 18 WC Audiology & Speech-Language Pathology; Education, Special; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Education & Educational Research; Linguistics; Rehabilitation GA 754TD UT WOS:000187346900005 PM 14643068 ER PT J AU Thiem, VD Hossain, MM Son, ND Hoa, NT Rao, MR Canh, DG Naficy, A Ke, NT Acosta, CJ Deen, JL Clemens, JD Trach, DD AF Thiem, VD Hossain, MM Son, ND Hoa, NT Rao, MR Canh, DG Naficy, A Ke, NT Acosta, CJ Deen, JL Clemens, JD Trach, DD TI Coverage and costs of mass immunization of an oral cholera vaccine in Vietnam SO JOURNAL OF HEALTH POPULATION AND NUTRITION LA English DT Article DE cholera; cholera vaccine; immunization; immunization programmes; costs and cost analysis; Vietnam ID FIELD TRIAL; FOLLOW-UP; BANGLADESH; NAM AB The objective of this study was to describe a mass-immunization campaign of a locally-produced oral, killed whole-cell cholera vaccine in Hue city, Vietnam. Mass immunization with a 2-dose regimen of the vaccine was conducted in 13 communes in early 1998. The total, age- and sex-specific vaccine coverage was calculated using data from the vaccination records and the government census. The number of vaccine doses procured, administered, wasted, and left over, and the human and other resources required to prepare and conduct the vaccination campaign were systematically recorded. Government expenditure for planning, procurement, and delivery of the vaccine were documented. In total, 118,555 (79%) of the 49,557 targeted population were fully vaccinated during the mass-vaccination campaign. The total expenditure for the project was US$ 105,447, resulting in a cost per fully-vaccinated person of US$ 0.89. Mass immunization with this locally-produced oral, killed cholera vaccine was found to be feasible and affordable with attainment of high vaccination coverage. C1 Int Vaccine Inst, Seoul 151600, South Korea. Inst Vaccines & Other Biol Subst, Nha Trang, Vietnam. NICHHD, Bethesda, MD 20892 USA. Hue Prov Hlth Serv, Hue, Vietnam. Natl Inst Hyg & Epidemiol, Hanoi, Vietnam. RP Deen, JL (reprint author), Int Vaccine Inst, Kwanak POB 14, Seoul 151600, South Korea. EM ideen@ivi.int NR 8 TC 13 Z9 13 U1 1 U2 3 PU ICDDR B PI DHAKA PA MOHAKHALI, 1212 DHAKA, BANGLADESH SN 1606-0997 EI 2072-1315 J9 J HEALTH POPUL NUTR JI J. Heatlh Popul. Nutr. PD DEC PY 2003 VL 21 IS 4 BP 304 EP 308 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 809OL UT WOS:000220645900002 ER PT J AU Limke, TL Rao, MS AF Limke, TL Rao, MS TI Neural stem cell therapy in the aging brain: Pitfalls and possibilities SO JOURNAL OF HEMATOTHERAPY & STEM CELL RESEARCH LA English DT Review ID AMYLOID PROTEIN-PRECURSOR; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; NEUROTROPHIC FACTOR; PARKINSONS-DISEASE; DENTATE GYRUS; GROWTH-FACTOR; SUBVENTRICULAR ZONE; MESSENGER-RNA; SUBSTANTIA-NIGRA AB As aging progresses, there is a decline in the brain's capacity to produce new neurons in the two neurogenic regions, the subventricular zone surrounding the lateral ventricles and the subgranular layer of the hippocampal dentate gyrus. The underlying cause of the declining neurogenesis is unknown, but is presumably related to age-related changes that occur during normal aging of the brain. It is exacerbated by age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Stem cell-based therapy to replace lost and/or damaged cells in the aging brain is currently the focus of intense research. The two most promising approaches involve transplantation of exogenous tissue and promoting proliferation of endogenous cells. However, age-related changes in the brain environment, including elevated oxidative stress and accumulation of protein and lipid by-products, present several unique challenges that must be addressed before cell-based therapy can be used as a viable option. Although progress has been made toward replacement of lost cells and recovery of lost function, there are fundamental issues that need to be addressed for stem cell therapy to be successful in the aging brain. In this review, we focus on recent progresses made toward understand the biology of neural stem cells in the aging brain, as well as progress toward using stem cells to replace cells lost during disease. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Limke, TL (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM limketo@grc.nia.nih.gov NR 81 TC 24 Z9 27 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1525-8165 J9 J HEMATOTH STEM CELL JI J. Hematother. Stem Cell Res. PD DEC PY 2003 VL 12 IS 6 BP 615 EP 623 DI 10.1089/15258160360732641 PG 9 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 764YQ UT WOS:000188239100005 PM 14977471 ER PT J AU Berlier, JE Rothe, A Buller, G Bradford, J Gray, DR Filanoski, BJ Telford, WG Yue, S Liu, JX Cheung, CY Chang, W Hirsch, JD Beechem, JM Haugland, RP Haugland, RP AF Berlier, JE Rothe, A Buller, G Bradford, J Gray, DR Filanoski, BJ Telford, WG Yue, S Liu, JX Cheung, CY Chang, W Hirsch, JD Beechem, JM Haugland, RP Haugland, RP TI Quantitative comparison of long-wavelength Alexa Fluor dyes to Cy dyes: Fluorescence of the dyes and their bioconjugates SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE Alexa Fluor dyes; Cy dyes; long-wavelength dyes; fluorescent bioconjugates; photostability; immunofluorescence; FRET; flow cytometry; microscopy ID SUCCINIMIDYL ESTERS; LABELING REAGENTS; ANTIGEN-DETECTION; FLOW-CYTOMETRY; PROBES; FLUOROCHROMES; PROTEINS; BINDING; BRIGHT; AVIDIN AB Amine-reactive N-hydroxysuccinimidyl esters of Alexa Fluor fluorescent dyes with principal absorption maxima at about 555 nm, 633 nm, 647 nm, 660 nm, 680 nm, 700 nm, and 750 nm were conjugated to antibodies and other selected proteins. These conjugates were compared with spectrally similar protein conjugates of the Cy3, Cy5, Cy5.5, Cy7, DY-630, DY-635, DY-680, and Atto 565 dyes. As N-hydroxysuccinimidyl ester dyes, the Alexa Fluor 555 dye was similar to the Cy3 dye, and the Alexa Fluor 647 dye was similar to the Cy5 dye with respect to absorption maxima, emission maxima, Stokes shifts, and extinction coefficients. However, both Alexa Fluor dyes were significantly more resistant to photobleaching than were their Cy dye counterparts. Absorption spectra of protein conjugates prepared from these dyes showed prominent blue-shifted shoulder peaks for conjugates of the Cy dyes but only minor shoulder peaks for conjugates of the Alexa Fluor dyes. The anomalous peaks, previously observed for protein conjugates of the Cy5 dye, are presumably due to the formation of dye aggregates. Absorption of light by the dye aggregates does not result in fluorescence, thereby diminishing the fluorescence of the conjugates. The Alexa Fluor 555 and the Alexa Fluor 647 dyes in protein conjugates exhibited significantly less of this self-quenching, and therefore the protein conjugates of Alexa Fluor dyes were significantly more fluorescent than those of the Cy dyes, especially at high degrees of labeling. The results from our flow cytometry, immunocytochemistry, and immunohistochemistry experiments demonstrate that protein-conjugated, long-wavelength Alexa Fluor dyes have advantages compared to the Cy dyes and other long-wavelength dyes in typical fluorescence-based cell labeling applications. C1 Mol Probes Inc, Eugene, OR 97402 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Hirsch, JD (reprint author), Mol Probes Inc, 29851 Willow Creek Rd, Eugene, OR 97402 USA. NR 22 TC 188 Z9 195 U1 18 U2 134 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD DEC PY 2003 VL 51 IS 12 BP 1699 EP 1712 PG 14 WC Cell Biology SC Cell Biology GA 748UA UT WOS:000186878400014 PM 14623938 ER PT J AU Scuteri, A Lakatta, EG Anderson, DE Fleg, JL AF Scuteri, A Lakatta, EG Anderson, DE Fleg, JL TI Transdermal 17 beta-oestradiol reduces salt sensitivity of blood pressure in postmenopausal women SO JOURNAL OF HYPERTENSION LA English DT Letter ID NITRIC-OXIDE INHIBITION C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. INRCA, UO Geriatr, Rome, Italy. RP Scuteri, A (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM scuteria@grc.nia.nih.gov NR 3 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD DEC PY 2003 VL 21 IS 12 BP 2419 EP 2420 DI 10.1097/01.hjh.0000098169.70956.22 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 912MO UT WOS:000228083000030 PM 14654763 ER PT J AU Zhang, MY Shu, YU Phogat, S Xiao, XD Cham, F Bouma, P Choudhary, A Feng, YR Sanz, I Rybak, S Broder, CC Quinnan, GV Evans, T Dimitrov, DS AF Zhang, MY Shu, YU Phogat, S Xiao, XD Cham, F Bouma, P Choudhary, A Feng, YR Sanz, I Rybak, S Broder, CC Quinnan, GV Evans, T Dimitrov, DS TI Broadly cross-reactive HIV neutralizing human monoclonal antibody Fab selected by sequential antigen panning of a phage display library SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE HIV; antibody; phage display; gp120; inhibitors; vaccines ID IMMUNODEFICIENCY-VIRUS TYPE-1; GP120; GLYCOPROTEIN; EPITOPE; GP41; 2G12; IDENTIFICATION; BINDING AB Identification of broadly cross-reactive human monoclonal antibodies (mAbs) has major implications for development of vaccines, inhibitors and research tools. Here we describe a sequential antigen panning (SAP) methodology that may facilitate the selection of such antibodies. An HIV-specific antibody Fab (m18) was selected from a human Fab phage-display library by SAP against several recombinant soluble HIV envelope glycoproteins (Envs) and Env-sCD4 complexes. This Fab bound to a variety of recombinant soluble Envs (gp140s) from primary HIV isolates representing different clades, and inhibited cell fusion and virus entry mediated by Envs of primary HIV isolates. The methodology and the results may have implications for development of HIV vaccines and inhibitors, as well as for identification of antibodies to conserved epitopes on rapidly mutating viruses and cells. Published by Elsevier B.V. C1 NCI, Human Immunovirol Grp, Lab Expt & Computat Biol, CCR,NIH, Frederick, MD 21702 USA. SAIC Frederick Inc, BRP, NCI, Frederick, MD 21702 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Univ Rochester, Dept Med, Rochester, NY 14642 USA. NCI Frederick, Biol Testing Branch, NIH, Frederick, MD 21702 USA. Univ Calif Davis, Davis, CA 95616 USA. RP Dimitrov, DS (reprint author), NCI, Human Immunovirol Grp, Lab Expt & Computat Biol, CCR,NIH, Bldg 469 ,Rm 246,POB B,Miller Dr, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 19 TC 52 Z9 57 U1 0 U2 3 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 DEC PY 2003 VL 283 IS 1-2 BP 17 EP 25 DI 10.1016/j.jim.2003.07.003 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 754UK UT WOS:000187349900003 PM 14659896 ER PT J AU van den Broeke, LT Daschbach, E Thomas, EK Andringa, G Berzofsky, JA AF van den Broeke, LT Daschbach, E Thomas, EK Andringa, G Berzofsky, JA TI Dendritic cell-induced activation of adaptive and innate antitumor immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC-T-LYMPHOCYTES; NATURAL-KILLER-CELLS; GROWTH-FACTOR-BETA; MURINE NK CELLS; IN-VIVO; BONE-MARROW; CD40 LIGAND; INTERFERON-GAMMA; TUMOR-IMMUNITY; RESPONSES AB While studying Ag-pulsed syngeneic dendritic cell (DC) immunization, we discovered that surprisingly, unpulsed DCs induced protection against tumor lung metastases resulting from i.v. injection of a syngeneic BALB/c colon carcinoma CT26 or a syngeneic C57BL/6 lung carcinoma LL/2. Splenocytes or immature splenic DCs did not protect. The protection was mediated by NK cells, in that it was abrogated by treatment with anti-asialo-GM1 but not anti-CD8, and was induced by CD1(-/-) DCs unable to stimulate NKT cells, but did not occur in beige mice lacking NK cells. Protection correlated with increased NK activity, and increased infiltration of NK but not CD8(+) cells in lungs of tumor-bearing mice. Protection depended on the presence of costimulatory molecules CD80, CD86, and CD40 on the DCs, but surprisingly did not require DCs that could make IL-12 or IL-15. Unexpectedly, protection sensitive to anti-asialo-GM1 and increased NK activity were still present 14 mo after DC injection. As NK cells lack memory, we found by depletion that CD4(+) not CD8(+) T cells were required for induction of the NK antitumor response. The role of DCs and CD4(+) T cells provides a novel mechanism for NK cell induction and innate immunity against cancer that may have potential in preventing clinical metastases. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bldg 10,Room 6B-12,Mail Stop Code 1578, Bethesda, MD 20892 USA. NR 59 TC 78 Z9 80 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 DEC 1 PY 2003 VL 171 IS 11 BP 5842 EP 5852 PG 11 WC Immunology SC Immunology GA 746UZ UT WOS:000186767200027 PM 14634094 ER PT J AU Vial, D Oliver, C Jamur, MC Pastor, MVD Trindade, ED Berenstein, E Zhang, J Siraganian, RP AF Vial, D Oliver, C Jamur, MC Pastor, MVD Trindade, ED Berenstein, E Zhang, J Siraganian, RP TI Alterations in granule matrix and cell surface of focal adhesion kinase-deficient mast cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-TYROSINE KINASES; JUN NH2-TERMINAL KINASE; C-KIT LIGAND; ACIDIC MUCOPOLYSACCHARIDES; SIGNAL-TRANSDUCTION; GROWTH-FACTOR; BINDING-SITE; PHOSPHORYLATION; INTEGRIN; FAK AB Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that plays an important role in many cellular processes and is tyrosine phosphorylated after FcepsilonRI aggregation in mast cells. In mice, null mutation of the fak gene results in a lethal phenotype in which the embryos fail to develop past day 8.5 of gestation. To study the role of FAK in these mast cells, 8.5-day embryos were isolated and placed in culture with IL-3 and stem cell factor (SCF). Although FAK was not required for the development of mast cells in culture, the FAK(-/-) embryo-derived mast cells had several distinct characteristics. Compared with the controls, the mast cells that lack FAK were less metachromatic and by electron microscopy had granules that appeared largely electron lucid, although their histamine content was unchanged. The FAK-deficient mast cells had a reduction in the content of chondroitin/dermatan sulfate, the major glycosaminoglycan component of the granular matrix. The FAK-deficient cells had fewer microvilli that were fused with each other, giving the cell surface a ruffled appearance. There was also a Mold increase in the number of cells highly expressing beta(7) integrin. However, signal transduction from the high affinity IgE receptor for the secretion of histamine was similar in the wild-type, heterozygote, and the FAK-deficient cells. The FcepsilonRI-induced tyrosine phosphorylation of paxillin, Crk-associated tyrosine kinase substrate (CAS), and mitogen-activated protein kinase proteins was independent of FAK. These results indicate that FAK plays a role in regulating the glycosaminoglycan content of the secretory granules and influences the cell surface morphology of mast cells. C1 NIDR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol & Bioagentes Patogen, Ribeirao Preto, Brazil. Univ Fed Sao Paulo, Escola Paulista Med, Dept Bioquim, Sao Paulo, Brazil. RP Siraganian, RP (reprint author), NIDR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bldg 10,Room 1N106, Bethesda, MD 20892 USA. RI Jamur, Maria Celia/L-5520-2016 OI Jamur, Maria Celia/0000-0001-7065-8543 NR 58 TC 9 Z9 10 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 DEC 1 PY 2003 VL 171 IS 11 BP 6178 EP 6186 PG 9 WC Immunology SC Immunology GA 746UZ UT WOS:000186767200067 PM 14634134 ER PT J AU Bray, M Mahanty, S AF Bray, M Mahanty, S TI Ebola hemorrhagic fever and septic shock SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID DISSEMINATED INTRAVASCULAR COAGULATION; VIRUS-INFECTED PATIENTS; TISSUE FACTOR; DENDRITIC CELLS; ADAPTIVE IMMUNITY; MARBURG VIRUSES; SEVERE SEPSIS; IN-VITRO; APOPTOSIS; MONOCYTES C1 NIAID, Biodef Clin Res Branch, Off Clin Res, Off Director,NIH, Bethesda, MD 20892 USA. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, Off Clin Res, Off Director,NIH, 6700A Rockledge Dr,Rm 5132, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov OI Mahanty, Siddhartha/0000-0003-1068-0524 NR 44 TC 53 Z9 58 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 DEC 1 PY 2003 VL 188 IS 11 BP 1613 EP 1617 DI 10.1086/379727 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 756QV UT WOS:000187493200001 PM 14639530 ER PT J AU Geisbert, TW Young, HA Jahrling, PB Davis, KJ Kagan, E Hensley, LE AF Geisbert, TW Young, HA Jahrling, PB Davis, KJ Kagan, E Hensley, LE TI Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: Overexpression of tissue factor in primate monocytes/macrophages is a key event SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 12th International Congress of Virology CY JUL 27-AUG 01, 2002 CL PARIS, FRANCE ID DISSEMINATED INTRAVASCULAR COAGULATION; MARBURG-VIRUS DISEASE; ACTIVATED PROTEIN-C; PROCOAGULANT ACTIVITY; ELECTRON-MICROSCOPY; FACTOR PATHWAY; SEPTIC SHOCK; SEPSIS; INFECTION; MONKEYS AB Disseminated intravascular coagulation is a prominent manifestation of Ebola virus (EBOV) infection. Here, we report that tissue factor l plays an important role in triggering the hemorrhagic complications that characterize EBOV infections. Analysis of samples obtained from 25 macaques showed increased levels of TF associated with lymphoid macrophages, whereas analysis of peripheral blood-cell RNA showed increased levels of TF transcripts by day 3. Plasma from macaques contained increased numbers of TF-expressing membrane microparticles. Dysregulation of the fibrinolytic system developed during the course of infection, including a rapid decrease in plasma levels of protein C. Infection of primary human monocytes/macrophages (PHMs) was used to further evaluate the role of TF in EBOV infections. Analysis of PHM RNA at 1-48 h showed increased TF transcripts, whereas levels of TF protein were dramatically increased by day 2. Thus, chemotherapeutic strategies aimed at controlling overexpression of TF may ameliorate the effects of EBOV hemorrhagic fever. C1 USA, Div Virol, Med Res Inst Infect Dis, MCMR UIV, Ft Detrick, MD 21702 USA. USA, Headquarters, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21701 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Geisbert, TW (reprint author), USA, Div Virol, Med Res Inst Infect Dis, MCMR UIV, 1425 Porter St, Ft Detrick, MD 21702 USA. EM tom.geisbert@amedd.army.mil NR 51 TC 184 Z9 199 U1 0 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 1 PY 2003 VL 188 IS 11 BP 1618 EP 1629 DI 10.1086/379724 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 756QV UT WOS:000187493200002 PM 14639531 ER PT J AU Yamada, N Matsushima, H Tagaya, Y Shimada, S Katz, SI AF Yamada, N Matsushima, H Tagaya, Y Shimada, S Katz, SI TI Generation of a large number of connective tissue type mast cells by culture of murine fetal skin cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE chemokine; cytokine; fetus; mast cells; skin ID C-KIT LIGAND; SECRETORY GRANULE PROTEASES; 3T3 FIBROBLASTS; IN-VITRO; MOUSE; EXPRESSION; COCULTURE; RECEPTOR; EXOCYTOSIS; ACTIVATION AB We describe a novel culture system for generating large numbers of murine skin-associated mast cells and distinguish their characteristics from bone marrow-derived cultured mast cells. Culture of day 16 fetal skin single cell suspensions in the presence of interleukin-3 and stem cell factor allowed expansion and maturation of mast cells in the presence of stromal cells. The average yield of mast cells after 2 wk was 7.3 million cells per fetus at a purity of 96%. These fetal skin-derived cultured mast cells increased their histamine content in a time-dependent manner to 3.6 pg per cell after 2 wk and 6.7 pg per cell after 4 wk. Phenotypic analyses revealed much greater expression of CD49b and CD81 and lesser expression of CD77 and CD102 on fetal skin-derived cultured mast cells as compared with bone marrow-derived cultured mast cells. These findings suggest a close similarity between fetal skin-derived cultured mast cells and freshly isolated cutaneous mast cells. Connective tissue mast cell characteristics of fetal skin-derived cultured mast cells were evidenced by: (1) their greater histamine content than bone marrow-derived cultured mast cells; (2) the presence of heparin; and (3) their degranulation in response to compound 48/80 and substance P. Importantly, fetal skin-derived cultured mast cells secreted greater amounts of interleukin-13 but much less MIP-1beta and interleukin-6 than bone marrow-derived cultured mast cells in response to ionomycin. Thus fetal skin-derived cultured mast cells have many characteristics distinct from bone marrow-derived cultured mast cells and can be used as a model of cutaneous mast cells to discern their functions. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Yamanashi, Fac Med, Dept Dermatol, Yamanashi, Japan. RP Katz, SI (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Rm 12 N238, Bethesda, MD 20892 USA. NR 36 TC 40 Z9 40 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD DEC PY 2003 VL 121 IS 6 BP 1425 EP 1432 DI 10.1046/j.1523-1747.2003.12613.x PG 8 WC Dermatology SC Dermatology GA 752UB UT WOS:000187184600029 PM 14675193 ER PT J AU Kutkat, L Hodge, JG Jeffry, T Bonta, DM AF Kutkat, L Hodge, JG Jeffry, T Bonta, DM TI The HIPAA privacy rule: Reviewing the post-compliance impact on public health practice and research SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article; Proceedings Paper CT 2nd Annual Partnership Conference on Public Health Law CY JUN 16-18, 2003 CL ATLANTA, GEORGIA C1 NIH, Off Sci Policy & Planning, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Law & Publ Hlth, Baltimore, MD USA. Davis Wright Tremaine, Los Angeles, CA USA. Dept Hlth Serv, Sacramento, CA USA. RP Kutkat, L (reprint author), NIH, Off Sci Policy & Planning, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC LAW MEDICINE ETHICS PI BOSTON PA 765 COMMONWEALTH AVE, SUITE 1634, BOSTON, MA 02215 USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD WIN PY 2003 VL 31 IS 4 SU S BP 70 EP 72 DI 10.1111/j.1748-720X.2003.tb00758.x PG 3 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 770LH UT WOS:000188731900023 PM 14968632 ER PT J AU Szabo, I Wetzel, MA Zhang, N Steele, AD Kaminsky, DE Chen, CG Liu-Chen, LY Bednar, F Henderson, EE Howard, OMZ Oppenheim, JJ Rogers, TJ AF Szabo, I Wetzel, MA Zhang, N Steele, AD Kaminsky, DE Chen, CG Liu-Chen, LY Bednar, F Henderson, EE Howard, OMZ Oppenheim, JJ Rogers, TJ TI Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE chemokines; neuroimmunology; cell trafficking; AIDS ID CHEMOKINE RECEPTOR CCR5; TUMOR-NECROSIS-FACTOR; DOWN-REGULATION; HUMAN-MONOCYTES; CROSS-DESENSITIZATION; MOLECULAR-CLONING; GENE-EXPRESSION; BETA-ENDORPHIN; IL-8 RECEPTOR; CUTTING EDGE AB The opiates are well-established immunomodulatory factors, and recent evidence suggests that mu- and delta-opioid receptor ligands alter chemokine-driven chemotactic responses through the process of heterologous desensitization. In the present report, we sought to examine the capacity of mu- and delta-opioids to modulate the function of chemokine receptors CCR5 and CXCR4, the two major human immunodeficiency virus (HIV) coreceptors. We found that the chemotactic responses to the CCR1/5 ligand CCL5/regulated on activation, normal T expressed and secreted, but not the CXCR4 ligand stromal cell-derived factor-1a/CXCL12 were inhibited following opioid pretreatment. Studies were performed with primary monocytes and Chinese hamster ovary cells transfected with CCR5 and the mu-opioid receptor to determine whether cross-desensitization of CCR5 was a result of receptor internalization. Using radiolabeled-binding analysis, flow cytometry, and confocal microscopy, we found that the heterologous desensitization of CCR5 was not associated with a significant degree of receptor internalization. Despite this, we found that the cross-desensitization of CCR5 by opioids was associated with a decrease in susceptibility to R5 but not X4 strains of HIV-1. Our findings are consistent with the notion that impairment of the normal signaling activity of CCR5 inhibits HIV-1 coreceptor function. These results have significant implications for our understanding of the effect of opioids on the regulation of leukocyte trafficking in inflammatory disease states and the process of coreceptor-dependent HIV-1 infection. The interference with HIV-1 uptake by heterologous desensitization of CCR5 suggests that HIV-1 interaction with this receptor is not passive but involves a signal transduction process. C1 Temple Univ, Sch Med, Dept Microbiol & Immunol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Ctr Subst Abuse Res, Philadelphia, PA 19140 USA. Temple Univ, Sch Med, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. NCI, Mol Immunoregulat Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Bethesda, MD 20892 USA. RP Rogers, TJ (reprint author), Temple Univ, Sch Med, Dept Microbiol & Immunol, 3400 N Broad St, Philadelphia, PA 19140 USA. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NIAID NIH HHS [T32 AI-07101]; NIDA NIH HHS [DA-04745, DA-06650, DA-11130, DA-11263, DA-14230, F31 DA-05894, P30 DA-13429, T32 DA-07237] NR 55 TC 52 Z9 53 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD DEC PY 2003 VL 74 IS 6 BP 1074 EP 1082 DI 10.1189/jlb.0203067 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 755FJ UT WOS:000187392600015 PM 12972507 ER PT J AU Mueller, GA Kirby, TW DeRose, EF London, RE AF Mueller, GA Kirby, TW DeRose, EF London, RE TI NMR assignment of protein side chains using residue-correlated labeling and NOE spectra SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article ID STAPHYLOCOCCAL NUCLEASE; SECONDARY STRUCTURE; C-13 MAGNETIZATION; LARGER PROTEINS; AMINO-ACIDS; RESONANCE; SPECTROSCOPY; H-1; CALMODULIN; INTERLEUKIN-1-BETA AB A new approach for the isotopic labeling of proteins is proposed that aims to facilitate side chain resonance assignments. Residue-correlated (RC) labeling is achieved by the expression of a protein on a medium containing a mixture of labeled, e.g., [U-C-13,N-15]amino acids, and NMR silent, [U-H-2]amino acids. De novo synthesis of amino acids was suppressed by feedback inhibition by the amino acids in the growth medium and by the addition of beta-chloro-L-alanine, a transaminase inhibitor. Incorporation of these amino acids into synthesized proteins results in a relative diminution of inter-residue NOE interactions and a relative enhancement of intra-residue NOEs. Comparison of the resulting NOE spectra with those obtained from a uniformly labeled sample allows identification of intra-residue NOE peaks. Thus, this approach provides direct information for sidechain assignments in the NOE spectra, which are subsequently used for structural analysis. We have demonstrated the feasibility of this strategy for the 143 amino acid nuclease inhibitor NuiA, both at 35 degreesC, corresponding to a rotational correlation time of 9.5 ns, and at 5 degreesC, corresponding to a rotational correlation time of 22 ns. (C) 2003 Elsevier Inc. All rights reserved. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, 111 Alexander Dr,POB 12233,MD MR-01, Res Triangle Pk, NC 27709 USA. NR 39 TC 2 Z9 2 U1 1 U2 7 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 DEC PY 2003 VL 165 IS 2 BP 237 EP 247 DI 10.1016/j.jmr.2003.08.006 PG 11 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 750UV UT WOS:000187017600006 PM 14643705 ER PT J AU Chen, KC Ford, RM Cummings, PT AF Chen, KC Ford, RM Cummings, PT TI Cell balance equation for chemotactic bacteria with a biphasic tumbling frequency SO JOURNAL OF MATHEMATICAL BIOLOGY LA English DT Article DE chemotaxis; random motility; series expansion; perturbation theory ID TRANSPORT-EQUATIONS; ESCHERICHIA-COLI; RANDOM MOTILITY; NUMERICAL-SOLUTION; FLAGELLAR MOTOR; POROUS-MEDIA; MIGRATION; MODEL; POPULATIONS; COEFFICIENTS AB Alt's three-dimensional cell balance equation characterizing the chemotactic bacteria was analyzed under the presence of one-dimensional spatial chemoattractant gradients. Our work differs from that of others who have developed rather general models for chemotaxis in the use of a non-smooth anisotropic tumbling frequency function that responds biphasically to the combined temporal and spatial chemoattractant gradients. General three-dimensional expressions for the bacterial transport parameters were derived for chemotactic bacteria, followed by a perturbation analysis under the planar geometry. The bacterial random motility and chemotaxis were summarized by a motility tensor and a chemotactic velocity vector, respectively. The consequence of invoking the diffusion-approximation assumption and using intrinsic one-dimensional models with modified cellular swimming speeds was investigated by numerical simulations. Characterizing the bacterial random orientation after tumbles by a turn angle probability distribution function, we found that only the first-order angular moment of this turn angle probability distribution is important in influencing the bacterial long-term transport. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Chem Engn, Charlottesville, VA 22904 USA. Vanderbilt Univ, Dept Chem Engn, Nashville, TN 37235 USA. Oak Ridge Natl Lab, Nanomat Theory Inst, Oak Ridge, TN 37831 USA. RP Chen, KC (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Cummings, Peter/B-8762-2013 OI Cummings, Peter/0000-0002-9766-2216 NR 42 TC 16 Z9 17 U1 1 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0303-6812 J9 J MATH BIOL JI J. Math. Biol. PD DEC PY 2003 VL 47 IS 6 BP 518 EP 546 DI 10.1007/s00285-003-0216-8 PG 29 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 756RJ UT WOS:000187494500002 PM 14618378 ER PT J AU Hart, TC Hart, PS Gorry, MC Michalec, MD Ryu, OH Uygur, C Ozdemir, D Firatli, S Aren, G Firatli, E AF Hart, TC Hart, PS Gorry, MC Michalec, MD Ryu, OH Uygur, C Ozdemir, D Firatli, S Aren, G Firatli, E TI Novel ENAM mutation responsible for autosomal recessive amelogenesis imperfecta and localised enamel defects SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID PORCINE SECRETORY ENAMEL; OPEN BITE DEFORMITY; DECIDUOUS TEETH; PRIMARY CANINE; FAMILIAL HYPERCHOLESTEROLEMIA; MATRIX PROTEINS; GREAT APES; HYPOPLASIA; GENE; DOMINANT AB The genetic basis of non-syndromic autosomal recessive forms of amelogenesis imperfecta ( AI) is unknown. To evaluate five candidate genes for an aetiological role in AI. In this study 20 consanguineous families with AI were identified in whom probands suggested autosomal recessive transmission. Family members were genotyped for genetic markers spanning five candidate genes: AMBN and ENAM (4q13.3), TUFT1 (1q21), MMP20 (11q22.3- q23), and KLK4 (19q13). Genotype data were evaluated to identify homozygosity in affected individuals. Mutational analysis was by genomic sequencing. Homozygosity linkage studies were consistent for localisation of an AI locus in three families to the chromosome 4q region containing the ENAM gene. ENAM sequence analysis in families identified a 2 bp insertion mutation that introduced a premature stop codon in exon 10. All three probands were homozygous for the same g. 13185_13186insAG mutation. These probands presented with a generalised hypoplastic AI phenotype and a class II openbite malocclusion. All heterozygous carriers of the g. 13185_13186insAG mutation had localised hypoplastic enamel pitting defects, but none had AI or openbite. The phenotype associated with the g. 13185_13186insAG ENAM mutation is dose dependent such that ARAI with openbite malocclusion segregates as a recessive trait, and enamel pitting as a dominant trait. C1 Univ Pittsburgh, Sch Dent Med, Dept Oral Med & Pathol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. Univ Istanbul, Sch Dent, Dept Periodontol, Istanbul, Turkey. Univ Istanbul, Sch Dent, Dept Pedodont, Istanbul, Turkey. Univ Istanbul, Sch Dent, Dept Orthodont, Istanbul, Turkey. RP Hart, TC (reprint author), NIDCR, NIH, Bldg 10,Room 1N-117,10 Ctr Dr, Bethesda, MD 20892 USA. RI FIRATLI, Erhan/E-4241-2013 OI FIRATLI, Erhan/0000-0002-4154-6929 FU NIDCR NIH HHS [R-01DE12920] NR 66 TC 68 Z9 72 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1468-6244 J9 J MED GENET JI J. Med. Genet. PD DEC PY 2003 VL 40 IS 12 BP 900 EP 906 DI 10.1136/jmg.40.12.900 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 755KM UT WOS:000187402100007 PM 14684688 ER PT J AU Shelton, DR Van Kessel, JAS Wachtel, MR Belt, KT Karns, JS AF Shelton, DR Van Kessel, JAS Wachtel, MR Belt, KT Karns, JS TI Evaluation of parameters affecting quantitative detection of Escherichia coli O157 in enriched water samples using immunomagnetic electrochemiluminescence SO JOURNAL OF MICROBIOLOGICAL METHODS LA English DT Article DE electrochemiluminescence; enterohemorrhagic; E. coli O157; immunological; immunomagnetic separation ID EVANESCENT-WAVE BIOSENSOR; HEMORRHAGIC COLITIS; CYTOMETRY; CATTLE; ASSAY AB We report here the use of immunomagnetic (IM) electrochemiluminescence (ECL) for quantitative detection of Esherichia coli O157:H7 in water samples following enrichment in minimal lactose broth (MLB). IM beads prepared in-house with four commercial anti-O157 monoclonal antibodies were compared for efficiency of cell capture. IM-ECL responses for E. coli O157:H7 (strain SEA13B88) were similar for all four commercial anti-O157 LPS monoclonal antibodies. The ECL signal was linearly correlated with E. coli O157:H7 cell concentration, indicating a constant ECL response per cell. Twenty-two strains of E. coli O157:H7 or O157:NM gave comparable ECL signals using IM beads prepared in-house. To assess the potential for interference from background bacteria in MLB-enriched water samples, 104 cells of E. coli O157:H7 (strain SEA13B88) were added to enriched samples prior to analysis. There was considerable variability in recovery of E. coli O157:H7 cells; net ECL signals ranged from 1% to 100% of expected values (i.e., percent inhibition from 0% to 99%). Cultures of Klebsiella pneumoniae, Klebsiella oxytoca, and Enterobacter cloacae, subsequently isolated from MLB-enriched water samples via IM separation (IMS), were observed to interfere with the binding of E. coli O157:H7 cells to IM beads. Recoveries of 10(4) E. coli O157:H7 cells were less than or equal to10% in the presence of ca. 10(8) K. pneumoniae, K. oxytoca, or E. cloacae cells. None of these strains gave a positive IM-ECL signal. Although competitive binding decreased sensitivity, there still was a linear correlation between ECL signal and higher E. coli O15TH7 cell concentrations. These studies indicate that IM-ECL in conjunction with MLB enrichment is capable of quantitatively detecting as few as 10(3) to 10(5) E. coli O15TH7 cells ml(-1), depending on percent recoveries, in enriched samples that contain ca. 10(9) total lactose-fermenting bacteria ml(-1). Assuming comparable growth rates for E. coli O157:H7 and other lactose-fermenting bacteria in MLB, it may be possible to detect as few as one E. coli O157:H7 in 100 ml of raw water containing as many as 10(4) to 10(6) lactose-fermenting bacteria (i.e., total coliforms). Published by Elsevier B.V. C1 USDA, Environm Microbial Safety Lab, Beltsville, MD 20705 USA. NIH, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Forest Serv, Baltimore Ecosyst Study LTER, USDA, Baltimore, MD 21227 USA. RP Shelton, DR (reprint author), USDA, Environm Microbial Safety Lab, ARS Bldg 173,BARC E,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM sheltond@ba.ars.usda.gov NR 22 TC 11 Z9 12 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7012 J9 J MICROBIOL METH JI J. Microbiol. Methods PD DEC PY 2003 VL 55 IS 3 BP 717 EP 725 DI 10.1016/j.mimet.2003.07.004 PG 9 WC Biochemical Research Methods; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 747UP UT WOS:000186823500017 PM 14607414 ER PT J AU Fijnvandraat, AC van Ginneken, ACG Schumacher, CA Boheler, KR Deprez, RHL Christoffels, VM Moorman, AFM AF Fijnvandraat, AC van Ginneken, ACG Schumacher, CA Boheler, KR Deprez, RHL Christoffels, VM Moorman, AFM TI Cardiomyocytes purified from differentiated embryonic stem cells exhibit characteristics of early chamber myocardium SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE embryonic stem cells; in vitro differentiation; transcription factors; chamber formation; genetic selection; Ncx1; ANEPPS ID MESSENGER-RNA; MAMMALIAN HEART; HPRT LOCUS; IN-VITRO; SARCOPLASMIC-RETICULUM; DEVELOPMENTAL-CHANGES; GENE-EXPRESSION; RAT; EXCHANGER; TISSUE AB Mouse embryonic stem (ES) cells easily differentiate towards the cardiac lineage making them suitable as an in vitro model to study cardiogenesis and as a potential source of transplantable cells. In this study, we show by in situ hybridisation that about 30% of the volume of cultures of differentiating ES cells consists of cardiomyocytes. RT-PCR analyses showed that the transcription factors Nkx2.5, Gata4, Mef2c and Irx4 were expressed at levels in the same order of magnitude as the levels observed in embryonic, neonatal and adult hearts. Atrial natriuretic factor and Connexin 40, associated with chamber formation in vivo, are expressed at relatively low levels, similar to those observed at early heart development in vivo. To facilitate the isolation of ES cell-derived cardiomyocytes, a cell line was constructed by stable transfection of the aminoglycoside phosphotransferase cDNA driven by the cardiac-specific distant upstream part of the Na+/Ca2+ exchanger promoter. To accomplish single-copy integration, the construct was inserted into the hypoxanthine phosphoribosyltransferase locus of HMI ES cells by homologous recombination. Cardiac-specific resistance to G418-sulphate (neomycin) allowed isolation of a pure population of cardiomyocytes. Genetically selected and unselected cell populations were characterised electrophysiologically using patch clamp. To explore whether clusters of cells have a similar differentiation profile, action potentials (APs) were measured in aggregates of differentiating ES cells, using a new method based on the voltage-dependent fluorescent dye di-4-ANEPPS. Both whole-cell recordings using patch-clamp and optical measurements with di-4-ANEPPS of the AP showed that upstroke velocity increases and AP duration decreases with differentiation time, accompanied by a decrease in AP interval, suggesting the initiation of the developmental programme underlying the formation of chamber myocardium. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Amsterdam, Dept Anat & Embryol, Acad Med Ctr, Expt & Mol Cardiol Grp, NL-1105 AZ Amsterdam, Netherlands. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Moorman, AFM (reprint author), Univ Amsterdam, Dept Anat & Embryol, Acad Med Ctr, Expt & Mol Cardiol Grp, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands. EM a.f.moorman@amc.uva.nl NR 47 TC 60 Z9 65 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD DEC PY 2003 VL 35 IS 12 BP 1461 EP 1472 DI 10.1016/j.yjmcc.2003.09.011 PG 12 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 758GF UT WOS:000187625100009 PM 14654372 ER PT J AU Contreras, MA Rapoport, SI AF Contreras, MA Rapoport, SI TI Interactions between n-3 and n-6 polyunsaturated fatty acids in brain of n-3 deficient rats SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE animal models; arachidonic acid; brain; lipid metabolism; phospholipids C1 Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 9 EP 9 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200027 ER PT J AU Ingram, D AF Ingram, D TI Slowing brain aging by calorie restriction and calorie restriction mimetics SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE 2-deoxyglucose; dopamine; glucose; insulin; metformin C1 NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 13 EP 13 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200042 ER PT J AU Klee, C Wang, X Ren, H Ghosh, M Samouilov, A Zweier, J AF Klee, C Wang, X Ren, H Ghosh, M Samouilov, A Zweier, J TI Calcineurin: a protein phosphatase under the control of Ca2+ and reactive oxygen species SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE calcineurin C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21224 USA. RI Samouilov, Alexandre/E-4010-2011; Samouilov, Alexandre/B-5824-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 14 EP 14 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200046 ER PT J AU Qu, Y Chang, L Klaff, J Seemann, R Rapoport, SI AF Qu, Y Chang, L Klaff, J Seemann, R Rapoport, SI TI Chronic administration of the antidepressant, fluoxetine, enhances phospholipase a2 signaling involving the release of the second SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE antidepressant drugs; arachidonic acid; G-protein coupled receptors; serotonin; signal transduction C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 20 EP 20 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200068 ER PT J AU Sheng, ZH AF Sheng, ZH TI Syntabulin: a novel syntaxin-binding and microtubule-associated protein involved in syntaxin-cargo transport SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE syntaxin; transport; synaptic vesicles; microtubules; neurotransmitter release C1 Natl Inst Neurol Disorders & Stroke, Synapt Funct Unit, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 20 EP 20 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200069 ER PT J AU Mattson, MP Zhang, P Fu, W AF Mattson, MP Zhang, P Fu, W TI Telomerase in neuronal development and death SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 26 EP 26 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200088 ER PT J AU Zhu, JPQ Cadet, JL Angulo, JA AF Zhu, JPQ Cadet, JL Angulo, JA TI Substance P involvement in methamphetamine-induced cell death of striatal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE cell death; methamphetamine; striatum; substance P C1 CUNY Hunter Coll, Dept Biol Sci, New York, NY 10021 USA. NIDA, Mol Neuropsychiat Sect, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 70 EP 70 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200240 ER PT J AU Leenders, AGM Lin, L Huang, LD Lu, PH Sheng, ZH AF Leenders, AGM Lin, L Huang, LD Lu, PH Sheng, ZH TI Light-chains of microtubule-associated proteins: a possible link between Ca2+-channels and the cytoskeleton SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE calcium channel; cytoskeletal proteins; microtubule proteins; synapse; synaptosomal membrane C1 NINDS, Synapt Funct Unit, NIH, Bethesda, MD 20892 USA. Shanghai Med Univ 2, Neurobiol Lab, Shanghai, Peoples R China. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 112 EP 112 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200396 ER PT J AU Pant, HC Li, BS AF Pant, HC Li, BS TI Cdk5: role in nervous system function SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE cdk5; kinase cross talk; neuronal survival; phosphorylation C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 121 EP 121 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200428 ER PT J AU d'Hellencourt, CL Harry, GJ AF d'Hellencourt, CL Harry, GJ TI Pyramidal and dentate granule cells genes expression in chemically induced neurodegeneration SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE hippocampus; laser capture microdissection; microarray; neurodegeneration; trimethyltin C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 138 EP 138 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200496 ER PT J AU Dambinova, S Izykenova, G Gappoeva, M Wang, Y Hoffer, B AF Dambinova, S Izykenova, G Gappoeva, M Wang, Y Hoffer, B TI NMDA receptors expression and immunoreactivity in experimental cerebral ischemia and hemorrhage SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT Joint Meeting of the International-Society-for-Neurochemistry/Asian-Pacific-Society-for-Neuro chemistry CY AUG 03-08, 2003 CL WANCHAI, PEOPLES R CHINA SP Int soc Neurochem, Asian Pacific Soc Neurochem DE glutamate receptor; hemorrhage; immunoassay ischemia C1 Emory Univ, Atlanta, GA 30322 USA. State Med Univ, St Petersburg, Russia. NIDA Ctr, Baltimore, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 SU 1 BP 144 EP 144 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 753PR UT WOS:000187240200517 ER PT J AU Gilman, CP Perry, T Furukawa, K Grieg, NH Egan, JM Mattson, MP AF Gilman, CP Perry, T Furukawa, K Grieg, NH Egan, JM Mattson, MP TI Glucagon-like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE calcium channels; cyclic AMP; cyclic AMP response element-binding protein; diabetes; excitotoxicity; synaptic plasticity ID PANCREATIC BETA-CELLS; DEPENDENT PROTEIN-KINASE; INSULIN-SECRETION; RAT-BRAIN; CULTURED HIPPOCAMPAL; SYNAPTIC PLASTICITY; INTRACELLULAR CA2+; GENE-EXPRESSION; BINDING-SITES; CYCLIC-AMP AB Glucagon-like peptide 1 (GLP-1) activates receptors coupled to cAMP production and calcium influx in pancreatic cells, resulting in enhanced glucose sensitivity and insulin secretion. Despite evidence that the GLP-1 receptor is present and active in neurons, little is known of the roles of GLP-1 in neuronal physiology. As GLP-1 modulates calcium homeostasis in pancreatic beta cells, and because calcium plays important roles in neuronal plasticity and neurodegenerative processes, we examined the effects of GLP-1 on calcium regulation in cultured rat hippocampal neurons. When neurons were pre-treated with GLP-1, calcium responses to glutamate and membrane depolarization were attenuated. Whole-cell patch clamp analyses showed that glutamate-induced currents and currents through voltage-dependent calcium channels were significantly decreased in neurons pre-treated with GLP-1. Pre-treatment of neurons with GLP-1 significantly decreased their vulnerability to death induced by glutamate. Acute application of GLP-1 resulted in a transient elevation of intracellular calcium levels, consistent with the established effects of GLP-1 on cAMP production and activation of cAMP response element-binding protein. Collectively, our findings suggest that, by modulating calcium responses to glutamate and membrane depolarization, GLP-1 may play important roles in regulating neuronal plasticity and cell survival. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 68 TC 52 Z9 59 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 IS 5 BP 1137 EP 1144 DI 10.1046/j.1471-4159.2003.02073.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 742TB UT WOS:000186533200008 PM 14622093 ER PT J AU Schutz, B Damadzic, R Weihe, E Eiden, LE AF Schutz, B Damadzic, R Weihe, E Eiden, LE TI Identification of a region from the human cholinergic gene locus that targets expression of the vesicular acetylcholine transporter to a subset of neurons in the medial habenular nucleus in transgenic mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE choline acetyltransferase; cholinergic gene locus; gene regulation; vesicular acetylcholine transporter ID CENTRAL-NERVOUS-SYSTEM; ACETYLTRANSFERASE GENE; IMMUNOHISTOCHEMISTRY; PRODUCTS; VACHT; CHAT AB We use a transgenic mouse model system to elucidate the regulatory regions within the human cholinergic gene locus responsible for vesicular acetylcholine transporter gene expression in vivo. In this report we characterized two transgenes for their ability to confer cholinergic-specific expression of the encoded vesicular acetylcholine transporter. An 11.2 kb transgene (named hV11.2) that spanned from about 5 kb upstream of the start of vesicular acetylcholine transporter translation down to the first choline acetyltransferase coding exon gave expression in the somatomotor neurons and a subpopulation of cholinergic neurons in the medial habenular nucleus. The second transgene (named hV6.7), a 5-prime truncated version of hV11.2 that was devoid of 4.5 kb of gene-regulatory sequences completely lacked vesicular acetylcholine transporter expression in vivo. Our data indicate that vesicular acetylcholine transporter expression in somatomotor neurons and in the medial habenular nucleus is uniquely specified within the cholinergic gene locus, and separable from cholinergic expression elsewhere. The identification of these two subdivisions of the cholinergic nervous system suggests that other cholinergic neurons in the CNS and PNS are similarly regulated by additional discrete domains within the cholinergic gene locus. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. Univ Marburg, Dept Mol Neurosci, Inst Anat & Cell Biol, Marburg, Germany. RP Schutz, B (reprint author), Univ Bonn, Mol Neurobiol Lab, Clin Psychiat & Psychotherapy, Clin Ctr, Siegmund Freud Str 25, D-53127 Bonn, Germany. OI Eiden, Lee/0000-0001-7524-944X NR 28 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 IS 5 BP 1174 EP 1183 DI 10.1046/j.1471-4159.2003.02095.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 742TB UT WOS:000186533200012 PM 14622097 ER PT J AU Xi, ZX Shen, H Baker, DA Kalivas, PW AF Xi, ZX Shen, H Baker, DA Kalivas, PW TI Inhibition of non-vesicular glutamate release by group III metabotropic glutamate receptors in the nucleus accumbens SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE L(+)-2-amino-4-phosphonobutyric acid; glutamate; metabotropic glutamate receptors; microdialysis; non-vesicular release; nucleus accumbens ID EXCITATORY SYNAPTIC-TRANSMISSION; IN-VIVO; DEVELOPMENTAL REGULATION; CORTICAL CULTURES; CALCIUM CURRENTS; NERVE-TERMINALS; RAT HIPPOCAMPUS; DORSAL STRIATUM; MESSENGER-RNAS; CA2+ CHANNELS AB Previous in vitro studies have shown that group III metabotropic glutamate receptors (mGluRs) regulate synaptic glutamate release. The present study used microdialysis to characterize this regulation in vivo in rat nucleus accumbens. Reverse dialysis of the group III mGluR agonist L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) decreased, whereas the antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP) increased the extracellular level of glutamate. The decrease by L-AP4 or the increase by MSOP was antagonized by co-administration of MSOP or L-AP4, respectively. Activation of mGluR4a by (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid or mGluR6 by 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid had no effect on extracellular glutamate. (R,S)-4-Phosphonophenylglycine (PPG), another group III agonist with high affinity for mGluR4/6/8, reduced extracellular glutamate only at high concentrations capable of binding to mGluR7. The increase in extracellular glutamate by MSOP was tetrodotoxin-independent, and resistant to both the L-type and N-type Ca-2 channel blockers. L-AP4 failed to block 30 mM K+-induced vesicular glutamate release. Blockade of glutamate uptake by D,L-threo-beta-benzyloxyaspartate caused a Ca-2-independent elevation in extracellular glutamate that was reversed by L-AP4. Finally, (S)-4-carboxyphenylglycine, an inhibitor of cystine-glutamate antiporters, attenuated the L-AP4-induced reduction in extracellular glutamate. Together, these data indicate that group III mGluRs regulate in vivo extracellular glutamate in the nucleus accumbens by inhibiting non-vesicular glutamate release. C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. RP Xi, ZX (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Baker, David/I-6955-2013 OI Baker, David/0000-0002-0664-6780 FU NIDA NIH HHS [DA 03906]; NIMH NIH HHS [MH 40817] NR 46 TC 32 Z9 34 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 IS 5 BP 1204 EP 1212 DI 10.1046/j.1471-4159.2003.02093.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 742TB UT WOS:000186533200015 PM 14622100 ER PT J AU Vinade, L Chang, M Schlief, ML Petersen, JD Reese, TS Tao-Cheng, JH Dosemeci, A AF Vinade, L Chang, M Schlief, ML Petersen, JD Reese, TS Tao-Cheng, JH Dosemeci, A TI Affinity purification of PSD-95-containing postsynaptic complexes SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE affinity purification; anchoring proteins; glutamate receptors; postsynaptic density; PSD-95 ID AMPA RECEPTOR; SYNAPTIC DISTRIBUTION; DENSITY FRACTION; PROTEIN; PSD-95; CORTEX; IMMUNOCYTOCHEMISTRY; SYNAPSES; SUBUNIT; BINDING AB A widely used method for the preparation of postsynaptic density (PSD) fractions consists of treatment of synaptosomal membranes with Triton X-100 and further purification by density gradient centrifugation. In the present study, the purity of this preparation was assessed by electron microscopic analysis. Thin-section and rotary shadow immuno-electron microscopy of the Triton X-100-derived PSD fraction shows many PSD-95-positive structures that resemble in situ PSDs in shape and size. However, the fraction also includes contaminants such as CaMKII clusters, spectrin filaments and neurofilaments. We used magnetic beads coated with an antibody against PSD-95 to further purify PSD-95-containing complexes from the Triton-derived PSD fraction. Biochemical analysis of the affinity-purified material shows a substantial reduction in the astrocytic marker glial fibrillary acidic protein and electron microscopic analysis shows mostly individual PSDs attached to magnetic beads. This preparation was used to assess the association of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors with the PSD-95-containing complex. AMPA receptors are demonstrated by immunoblotting to be present in the complex, although they do not co-purify exclusively with PSD-95, suggesting the existence of two pools of receptors, one associated with the PSD-95 scaffold and the other not. Of the AMPA receptor-anchoring proteins tested, SAP-97 is present in the affinity-purified preparation whereas GRIP is found only in trace amounts. These results imply that a subpopulation of AMPA receptors is anchored to the PSD-95-containing scaffold through interaction of GluR1 with SAP-97. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Electron Microscopy Facil, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Program Mol Physiol, Woods Hole, MA 02543 USA. RP Vinade, L (reprint author), NINDS, Neurobiol Lab, NIH, 9000 Rockville Pike,Bldg 36-2A21, Bethesda, MD 20892 USA. EM vinade@codon.nih.gov OI Petersen, Jennifer/0000-0003-1107-8535 NR 24 TC 19 Z9 19 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 IS 5 BP 1255 EP 1261 DI 10.1046/j.1471-4159.2003.02091.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 742TB UT WOS:000186533200020 PM 14622105 ER PT J AU Bosetti, F Weerasinghe, GR AF Bosetti, F Weerasinghe, GR TI The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A(2) knockout mouse SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachidonic acid; brain; cyclooxygenase; phospholipase A(2); prostaglandin ID PLATELET-ACTIVATING-FACTOR; RAT-BRAIN; ARACHIDONIC-ACID; CHRONIC LITHIUM; MICE DEFICIENT; GENE; INHIBITORS; SYNTHASE; CELLS; MACROPHAGES AB We examined brain phospholipase A(2) (PLA(2)) activity and the expression of enzymes metabolizing arachidonic acid (AA) in cytosolic PLA(2) knockout (cPLA(2)(-/-)) mice to see if other brain PLA(2) can compensate for the absence of cPLA(2) alpha and if cPLA(2) couples with specific downstream enzymes in the eicosanoid biosynthetic pathway. We found that the rate of formation of prostaglandin E-2 (PGE(2)), an index of net cyclooxygenase (COX) activity, was decreased by 62% in the cPLA(2)(-/-) compared with the control mouse brain. The decrease was accompanied by a 50-60% decrease in mRNA and protein levels of COX-2, but no change in these levels in COX-1 or in PGE synthase. Brain 5-lipoxygenase (5-LO) and cytochrome P450 epoxygenase (cyp2C11) protein levels were also unaltered. Total and Ca2+-dependent PLA(2) activities did not differ significantly between cPLA(2)(-/-) and control mice, and protein levels of type VI iPLA(2) and type V sPLA(2), normalized to actin, were unchanged. These results show that type V sPLA(2) and type VI iPLA(2) do not compensate for the loss of brain cPLA(2) alpha, and that this loss has significant downstream effects on COX-2 expression and PGE(2) formation, sparing other AA oxidative enzymes. This suggests that cPLA(2) is critical for COX-2-derived eicosanoid production in mouse brain. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 10,Rm 6 N202, Bethesda, MD 20892 USA. NR 42 TC 47 Z9 48 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2003 VL 87 IS 6 BP 1471 EP 1477 DI 10.1046/j.1471-4159.2003.02118.x PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 749GU UT WOS:000186912100015 PM 14713302 ER PT J AU Hendler, T Pianka, P Sigal, M Kafri, M Ben-Bashat, D Constantini, S Graif, M Fried, I Assaf, Y AF Hendler, T Pianka, P Sigal, M Kafri, M Ben-Bashat, D Constantini, S Graif, M Fried, I Assaf, Y TI Delineating gray and white matter involvement in brain lesions: three-dimensional alignment of functional magnetic resonance and diffusion-tensor imaging SO JOURNAL OF NEUROSURGERY LA English DT Article DE functional magnetic resonance imaging; diffusion-tensor imaging; diffusion; brain tumor ID FMRI; TUMORS; MRI; STIMULATION; TRACKING; LANGUAGE; ANATOMY; TRACTS; SIGNAL AB Object. The role of functional magnetic resonance (fMR) imaging has become increasingly important in the presurgical mapping of gray matter. Neurosurgical interventions often involve fiber bundles that connect critical functional areas. Recently, diffusion-tensor (DT) imaging has enabled the visualization of fiber bundle direction and integrity, thus providing the ability to delineate clearly white matter from gray matter tissue. The main objective of this study was to improve the presurgical assessment of critical functionality in the vicinity of brain lesions by combining DT and fMR imaging methodologies. Methods. Twenty patients with various space-occupying brain lesions underwent imaging for presurgical evaluation of motor and/or somatosensory functions. The authors focus on five patients with diverse space-occupying brain lesions. Diffusion tensor-based fiber tracking and fMR imaging activation maps were superimposed in three dimensions to visualize pyramidal tracts corresponding to motor and somatosensory regional activation. Conclusions. The combination of DT and fMR imaging for presurgical functional brain mapping provides valuable information that cannot be extracted using either method alone. The validity and sensitivity of noninvasive functional mapping for surgical guidance could be improved by considering results obtained with both methods. Furthermore, the use of three-dimensional visualization seems crucial and unique for viewing and understanding the complicated spatial relationship among the lesion, gray matter activation, and white matter fiber bundles. C1 Tel Aviv Sourasky Med Ctr, Dept Radiol, Funct Brain Imaging Unit, Wohl Inst Adv Imaging, IL-64239 Tel Aviv, Israel. Tel Aviv Univ, Sch Chem, Tel Aviv, Israel. Tel Aviv Med Ctr & Sch Med, Dana Childrens Hosp, Dept Pediat Neurosurg, IL-64239 Tel Aviv, Israel. Univ Calif Los Angeles, Div Neurosurg, Ctr Hlth Sci, Los Angeles, CA 90024 USA. NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. RP Assaf, Y (reprint author), Tel Aviv Sourasky Med Ctr, Dept Radiol, Funct Brain Imaging Unit, Wohl Inst Adv Imaging, 6 Weizman St, IL-64239 Tel Aviv, Israel. RI hendler, talma/C-7677-2012 NR 28 TC 69 Z9 75 U1 0 U2 4 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2003 VL 99 IS 6 BP 1018 EP 1027 DI 10.3171/jns.2003.99.6.1018 PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 751VX UT WOS:000187111700013 PM 14705730 ER PT J AU Zhang, W Nwagwu, C Le, DM Yong, VW Song, H Couldwell, WT AF Zhang, W Nwagwu, C Le, DM Yong, VW Song, H Couldwell, WT TI Increased invasive capacity of connexin43-overexpressing malignant glioma cells SO JOURNAL OF NEUROSURGERY LA English DT Article DE connexin; glioma; Matrigel; matrix metalloproteinase ID PROTEIN-KINASE-C; CENTRAL-NERVOUS-SYSTEM; GAP-JUNCTION PROTEIN; IN-VITRO; BRAIN-TUMOR; RAT-BRAIN; GLIOBLASTOMA-MULTIFORME; IV COLLAGENASE; MIGRATION; EXPRESSION AB Object. Malignant glioma cells, similar to astrocytes, express connexin43 (Cx43) universally but at widely varied levels. Data from previous studies have demonstrated that malignant glioma cells form functional gap junction channels among themselves as well as with astrocytes and that such a communication has the potential to modulate the phenotypic characteristics of astrocytes. Recently, gap junctions have been demonstrated to play a role in the invasive phenotype of malignant gliomas. In this study, the authors have further investigated the motility and invasion ability of Cx43-overexpressing and Cx43-deficient malignant glioma cells. Methods. Using a standard invasion system of a Matrigel transwell invasion chamber, the authors found that the number of Cx43-transfected C6 glioma cells (C6-Cx43 cells) migrating through the Matrigel-coated membrane was similar to that of mock-transfected control cells (C6-mock cells) during the first 24 hours, but increased significantly thereafter. When these cells were cocultured with astrocytes, the number of invading C6-Cx43 cells was more than threefold greater than the number of invading C6-mock cells. Results of an in vitro cell motility assay also demonstrated that C6-Cx43 cells were more motile and scatter-active than C6-mock cells. Furthermore, zymographic analysis of MMPs, an important determinant in glioma invasion, demonstrated that the amounts of MMP-2 and MMP-9 in culture medium collected from C6-Cx43 cells were orders of magnitude higher than those from C6-mock cells. In addition, BB-94, a synthetic MMP inhibitor, significantly inhibited C6-Cx43 cell invasion. Conclusions. The overexpression of gap junction proteins in glioma cells and the intercellular communication between tumor and nontumor glia cells may play important roles in the facilitation of glioma cell invasion. C1 Univ Utah, Dept Neurosurg, Salt Lake City, UT 84132 USA. New York Med Coll, Dept Neurosurg, Valhalla, NY 10595 USA. New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. Univ Calgary, Dept Oncol, Calgary, AB T2N 1N4, Canada. Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 1N4, Canada. RP Couldwell, WT (reprint author), Univ Utah, Dept Neurosurg, 30 North 1900 East,Suite 3B409, Salt Lake City, UT 84132 USA. FU NINDS NIH HHS [NS01672] NR 34 TC 46 Z9 50 U1 1 U2 8 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD DEC PY 2003 VL 99 IS 6 BP 1039 EP 1046 DI 10.3171/jns.2003.99.6.1039 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 751VX UT WOS:000187111700015 PM 14705732 ER PT J AU Balder, HF Virtanen, M Brants, HAM Krogh, V Dixon, LB Tan, F Mannisto, S Bellocco, R Pietinen, P Wolk, A Berrino, F Van den Brandt, PA Hartman, AM Goldbohm, RA AF Balder, HF Virtanen, M Brants, HAM Krogh, V Dixon, LB Tan, F Mannisto, S Bellocco, R Pietinen, P Wolk, A Berrino, F Van den Brandt, PA Hartman, AM Goldbohm, RA TI Common and country-specific dietary patterns in four European cohort studies SO JOURNAL OF NUTRITION LA English DT Article DE dietary patterns; factor analysis; principal components analysis; cohort studies; cancer ID SCALE PROSPECTIVE COHORT; EATING PATTERNS; FOOD USE; NUTRITIONAL EPIDEMIOLOGY; COLORECTAL-CANCER; NUTRIENT INTAKE; BREAST-CANCER; COLON-CANCER; PORTION SIZE; RISK AB The association between diet and cancer, predominantly investigated univariately, has often been inconsistent, possibly because of the large number of candidate risk factors and their high intercorrelations. Analysis of dietary patterns is expected to give,more insight than analysis of single nutrients or foods. This study aimed to develop and apply a common methodological approach to determine dietary patterns in four cohort studies originating in Finland, the Netherlands, Sweden and Italy. Food items on each of the food frequency questionnaires were aggregated into 51 food groups, defined on the basis of their position in the diet pattern and possible relevance to cancer etiology. Exploratory factor analysis was used to analyze dietary patterns. Using a standardized approach, 3-5 stable dietary patterns were identified, explaining 20-29% of total variance in consumption of the food groups. Two dietary patterns, which explained most of the variance, were consistent across the studies. The first pattern was characterized by high consumption of (salad) vegetables, the second by high consumption of pork, processed meat and potatoes. In addition, a few specifically national food patterns were identified. Sensitivity analyses showed that the identified patterns were robust for number of factors extracted, distribution of input variables and energy adjustment. Our findings suggest that some important eating patterns are shared by the four populations under study, whereas other eating patterns are population specific. C1 TNO, Nutr & Food Res, Dept Nutr Epidemiol, NL-3700 AJ Zeist, Netherlands. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. Natl Publ Hlth Inst, Dept Nutr, Helsinki, Finland. Natl Canc Inst, Epidemiol Unit, I-20133 Milan, Italy. NYU, Dept Nutr Food Studies & Publ Hlth, New York, NY USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Masstricht Univ, Dept Methodol & Stat, Maastricht, Netherlands. Karolinska Inst, Inst Environm Epidemiol, Stockholm, Sweden. RP Balder, HF (reprint author), TNO, Nutr & Food Res, Dept Nutr Epidemiol, NL-3700 AJ Zeist, Netherlands. RI Krogh, Vittorio/K-2628-2016 OI Krogh, Vittorio/0000-0003-0122-8624 NR 38 TC 60 Z9 61 U1 0 U2 4 PU AMER INST NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD DEC PY 2003 VL 133 IS 12 BP 4246 EP 4251 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 753CU UT WOS:000187214900034 PM 14652380 ER PT J AU Warburton, G Childs, RC Charles, M Brahim, JS AF Warburton, G Childs, RC Charles, M Brahim, JS TI Hodgkin's lymphoma: A case report involving the mandible SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Editorial Material ID MALIGNANT-LYMPHOMA; PROGNOSTIC SCORE; DISEASE; BONE; ABVD; MOPP; CHEMOTHERAPY; ORGANIZATION C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Bethesda, MD 20892 USA. RP Brahim, JS (reprint author), NIDCR, Room 1N117,10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. NR 26 TC 3 Z9 3 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD DEC PY 2003 VL 61 IS 12 BP 1492 EP 1496 DI 10.1016/j.joms.2002.09.002 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 745WM UT WOS:000186714000019 PM 14663818 ER PT J AU Zylicz, Z Krajnik, M van Sorge, AA Costantini, M AF Zylicz, Z Krajnik, M van Sorge, AA Costantini, M TI Paroxetine in the treatment of severe non-dermatological pruritus: A randomized, controlled trial SO JOURNAL OF PAIN AND SYMPTOM MANAGEMENT LA English DT Article DE Pruritus; itch; paroxetine; paraneoplastic phenomenon; chemotherapy; induced itch ID POLYCYTHEMIA-VERA; UREMIC PRURITUS; DOUBLE-BLIND; ONDANSETRON; RELIEF; ITCH; ANTAGONISTS; CIMETIDINE; MANAGEMENT; HISTAMINE AB Severe pruritus may be an idiopathic phenomenon or associated with advanced systemic disease. It is one of the most distressing and difficult to treat symptoms. Uncontrolled studies have suggested that, in patients experiencing severe pruritus, paroxetine appeared to have a rapid anti-pruritic effect. This study was a prospective double-blind, randomized within patient comparison of paroxetine and placebo. The intensity of pruritus was measured subjectively with a numerical analogue scale. The primary endpoint of the trial was the mean pruritus score, measured for seven days after randomization and after cross-over. The secondary endpoint was individual global response to the treatment. Response was defined as at least 50% reduction of intensity of pruritus in the last three days of the treatment period vs. baseline. Adverse effects and Patient satisfaction and preferences were also recorded. Twenty-six patients were included in the study; 17 of them had solid tumors, 4 had hematological malignancies and 5 had various nonmalignant or idiopathic conditions. Eight patients had drug-induced pruritus (none opioid-induced), 7 patients had paraneoplastic pruritus and 3 had cholestatic pruritus. After a run-in period, patients were randomly assigned to treatment with 20 mg paroxetine or placebo. The crossover took place after 7 days. Two patients discontinued treatment because of adverse effects of paroxetine. Twenty-four patients treated with paroxetine had lower pruritus intensity scores over the 7 treatment periods (mean +/- SE = 5.2 +/- 0.32) as compared to placebo (mean +/- SE = 6.0 +/- 0.32). Mean difference between placebo and paroxetine was 0.78 (95% CI = 0.37-1.19). Nine of twenty-four patients (37.5%) fulfilled criteria of response. The onset of anti-pruritic action was observed usually after 2-3 days, irrespective of the order of treatment. The outcome of this study indicates that paroxetine is effective in the treatment of severe pruritus of non-dermatological origin. (C) 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. C1 Hospice Rozenheuvel, NL-6891 DD Rozendaal, Netherlands. Ludwik Rdygier Univ Med Sci, Palliat Care Dept, Bydgoszcz, Poland. Rijnstate Hosp, Dept Pharm, Arnhem, Netherlands. Natl Canc Inst, Unit Clin Epidemiol & Trials, Genoa, Italy. RP Zylicz, Z (reprint author), Hospice Rozenheuvel, Rosendaalselaan 20, NL-6891 DD Rozendaal, Netherlands. RI costantini, massimo/G-1443-2012; Krajnik, Malgorzata/G-8923-2014; OI costantini, massimo/0000-0002-5293-7079 NR 31 TC 83 Z9 84 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0885-3924 J9 J PAIN SYMPTOM MANAG JI J. Pain Symptom Manage. PD DEC PY 2003 VL 26 IS 6 BP 1105 EP 1112 DI 10.1016/j.jpainsymman.2003.05.004 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal; Clinical Neurology SC Health Care Sciences & Services; General & Internal Medicine; Neurosciences & Neurology GA 753ZC UT WOS:000187277400009 PM 14654262 ER PT J AU Chanock, S AF Chanock, S TI The etiology of childhood immune thrombocytopenic purpura: How complex is it? SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article; Proceedings Paper CT Meeting of the Intercontinental-Childhood-Study-Group (CIS) CY SEP 23-25, 2003 CL BUERGENSTOCK, SWITZERLAND SP Intercontinental Childhood Study Grp DE platelet; immune regulation; genetic variation; pediatrics ID PLATELET-ASSOCIATED IGG; SICKLE-CELL-DISEASE; FC-GAMMA RECEPTORS; STROKE; POLYMORPHISMS; ANTIBODY; CHILDREN; FUTURE; STATES; ANEMIA AB Recent developments in genomics and basic immunology have provided a new set of tools for investigation into the etiology and treatment of childhood immune thrombocytopenia purpura (ITP). The genomic revolution is generating a catalog of germ-line common genetic variants, some of which could influence the susceptibility or outcome of ITP. Similarly, in vitro analyses and animal models have been employed to probe the basic alterations underlying ITP. The emergence of a more refined understanding of complex diseases such as ITP has important implications for-prevention, therapy, and follow-up. The relative contribution of the genetic component and its interaction with the strong environmental stimulus, such as an acute, antecedent viral infection, remains to be determined. C1 NCI, Ctr Adv Technol, Pediat Oncol Branch, Sect Genom Variat,Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Core Genotyping Facil, NIH, Bethesda, MD 20892 USA. RP Chanock, S (reprint author), NCI, Ctr Adv Technol, Pediat Oncol Branch, Sect Genom Variat,Ctr Canc Res,NIH, 8717 Grovemont Circle, Bethesda, MD 20892 USA. NR 33 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD DEC PY 2003 VL 25 SU 1 BP S7 EP S10 DI 10.1097/00043426-200312001-00002 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 754RV UT WOS:000187346100002 PM 14668631 ER PT J AU Mizoguchi, H Wu, HE Narita, M Sora, I Hall, FS Uhl, GR Loh, HH Nagase, H Tseng, LF AF Mizoguchi, H Wu, HE Narita, M Sora, I Hall, FS Uhl, GR Loh, HH Nagase, H Tseng, LF TI Lack of mu-opioid receptor-mediated G-protein activation in the spinal cord of mice lacking exon 1 or exons 2 and 3 of the MOR-1 gene SO JOURNAL OF PHARMACOLOGICAL SCIENCES LA English DT Article DE mu-opioid receptor; exon; knockout mice; G-protein activation; spinal cord ID MORPHINE-INDUCED ANALGESIA; BETA-ENDORPHIN; KNOCKOUT MICE; GUANOSINE-5'-O-(3-THIO)TRIPHOSPHATE BINDING; DIFFERENTIAL MECHANISM; MOUSE PONS/MEDULLA; OPIATE RECEPTOR; ENDOMORPHIN; STIMULATION; EXPRESSION AB The G-protein activation induced by mu-opioid receptor agonists was determined in spinal cord membranes from two types of mu-opioid receptor knockout mice: mice with a disruption of exon 1 (MOR (Exon 1)-KO) or exons 2 and 3 (MOR (Exons 2 and 3)-KO) of the mu-opioid receptor gene. The G-protein activation induced by the opioid agonists was measured by monitoring the increases of guanosine-5'-O-(3- [S-35]thio)triphosphate ([S-35]GTPgammaS) binding. The mu-opioid receptor agonists (D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin, endomorphin-1, endomorphin-2, morphine, morphine-6beta-glucuronide, and fentanyl produced concentration-dependent increases of [S-35]GTPgammaS binding to spinal cord membranes in wild-type mice, but not in MOR (Exon 1)-KO mice or MOR (Exons 2 and 3)-KO mice. On the other hand, the delta-opioid receptor agonist [D-Pen(2,5)]enkephalin, the kappa-opioid receptor agonist (-)U50,488H, or the ORL1-receptor agonist nociception increased [S-35]GTPgammaS binding in the spinal cord membranes from both MOR (Exon 1)-KO mice and MOR (Exons 2 and 3)-KO mice to the same extent as in the corresponding wild-type mice. The results provide further information about the important roles of the sequences encoded within exon 1 and exons 2 and 3 of mu-opioid receptor gene for the activation of G-proteins by mu-opioid receptor agonists in the mouse spinal cord. C1 Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. Hoshi Univ, Sch Pharm, Dept Toxicol, Tokyo 1428501, Japan. Tokyo Inst Psychiat, Dept Psychopharmacol, Tokyo 1568585, Japan. NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA. Toray Industries Ltd, Pharmaceut Res Lab, Kamakura, Kanagawa 2488555, Japan. RP Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. EM ltseng@mcw.edu RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU NIDA NIH HHS [DA 03811] NR 22 TC 18 Z9 19 U1 0 U2 1 PU JAPANESE PHARMACOLOGICAL SOC PI KYOTO PA EDITORIAL OFF, KANTOHYA BLDG GOKOMACHI-EBISUGAWA NAKAGYO-KU, KYOTO, 604, JAPAN SN 1347-8613 EI 1347-8648 J9 J PHARMACOL SCI JI J. Pharmacol. Sci. PD DEC PY 2003 VL 93 IS 4 BP 423 EP 429 DI 10.1254/jphs.93.423 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 757MN UT WOS:000187566200007 PM 14737012 ER PT J AU Luellen, BA Miller, DB Chisnell, AC Murphy, DL O'Callaghan, JP Andrews, AM AF Luellen, BA Miller, DB Chisnell, AC Murphy, DL O'Callaghan, JP Andrews, AM TI Neuronal and astroglial responses to the serotonin and norepinephrine neurotoxin: 1-methyl-4-(2 '-aminophenyl)-1,2,3,6-tetrahydropyridine SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID FIBRILLARY ACIDIC PROTEIN; SUPEROXIDE-DISMUTASE ACTIVITY; DOPAMINERGIC NEUROTOXICITY; MONOAMINE-OXIDASE; MPTP 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE; HIPPOCAMPAL SEROTONIN; STRIATAL DOPAMINE; UPTAKE INHIBITORS; TRANSGENIC MICE; SPINAL-CORD AB 1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2MPTP) causes long-term loss of forebrain serotonin (5-HT) and norepinephrine (NE) and consequently, is unlike 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine ( MPTP) and its other 2'-analogs that primarily deplete striatal dopamine (DA). In the present investigation into the acute effects of 2'-NH2-MPTP in mice, profound decreases in cortical and hippocampal 5-HT and NE to 10 to 40% of control were observed as early as 30 min post-treatment and lasted throughout the ensuing 21 days. Striatal DA was decreased to 60 to 80% of control during the first 48 h but returned to normal by 72 h. Reactive gliosis, which occurs in response to neurodegeneration was not evident by immunocytochemistry but was detected by enzyme-linked immunosorbent assay, where glial fibrillary acidic protein (GFAP) was increased to 130% of control in cortex, hippocampus, and brain stem 48 to 72 h post-treatment. To explore the possibility that 5-HT modulates the astrocytic response to injury, 2'-NH2-MPTP was used to damage 5-HT axons 2 weeks before administration of the potent DA neurotoxin 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3MPTP). Despite a 90% decrement in striatal DA in 2'-NH2-MPTP/ 2'- CH3-MPTP-treated mice, increases in GFAP were attenuated compared to mice treated with 2'-CH3-MPTP alone. Thus, 2'-NH2-MPTP causes severe and immediate decrements in 5-HT and NE in frontal cortex and hippocampus, yet induces a modest GFAP response compared with other MPTP analogs that have their primary effect on DA. These results demonstrate the importance of obtaining quantitative assessments of GFAP to detect astroglial responses associated with selective damage to neurotransmitter systems with low-density innervation and suggest that serotonin may facilitate the astrocytic response to striatal injury. C1 Penn State Univ, Davey Lab 152, Dept Chem, University Pk, PA 16802 USA. Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA. Ctr Dis Control & Prevent, Lab Neurotoxicol, NIEHS, Morgantown, WV USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Andrews, AM (reprint author), Penn State Univ, Davey Lab 152, Dept Chem, University Pk, PA 16802 USA. RI Andrews, Anne/B-4442-2011; O'Callaghan, James/O-2958-2013 OI Andrews, Anne/0000-0002-1961-4833; FU NIMH NIH HHS [R03 MH 067713-01] NR 40 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2003 VL 307 IS 3 BP 923 EP 931 DI 10.1124/jpet.103.055749 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748WB UT WOS:000186883100011 PM 14561848 ER PT J AU Mager, DE Mascelli, MA Kleiman, NS Fitzgerald, DJ Abernethy, DR AF Mager, DE Mascelli, MA Kleiman, NS Fitzgerald, DJ Abernethy, DR TI Simultaneous modeling of abciximab plasma concentrations and ex vivo pharmacodynamics in patients undergoing coronary angioplasty SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID MEDIATED DRUG DISPOSITION; MONOCLONAL-ANTIBODIES; PLATELET INHIBITION; GPIIB-IIIA; RECEPTOR; PHARMACOKINETICS; BINDING; ANTAGONISTS; QUANTIFICATION; VOLUNTEERS AB An integrated structural pharmacokinetic/pharmacodynamic (PK/PD) model was developed for the glycoprotein IIb/IIIa antagonist abciximab administered to patients undergoing percutaneous transluminal coronary angioplasty. PK/PD data, in the form of plasma abciximab concentrations and ex vivo platelet aggregation in the presence of 20 muM adenosine diphosphate, were obtained from two previously conducted clinical studies. Study 1 consisted of patients who were given abciximab as a single intravenous injection of 0.25 mg/kg ( n = 32). Patients in study 2 received an identical bolus dose, followed by a 36-h infusion at 0.125 mug/kg/min ( n = 15). The PK component of the final model included drug-receptor binding, nonspecific distribution, and linear systemic clearance, whereas the PD module assumed that ex vivo dynamics were controlled by free plasma drug concentration. Mean PK/PD data from both studies were fitted simultaneously using nonlinear regression. PK profiles from both studies show rapidly decreasing plasma abciximab concentrations at early time points, but with extended terminal disposition phases. The maximum effect (E-max = 83.6%) was achieved rapidly and gradually returned to baseline values, although inhibition could be measured long after abciximab concentrations dropped below the detection limit. The final model well described the resulting PK/PD profiles and allowed for parameter estimation with relatively small coefficients of variation. Simulations were conducted to assess predicted receptor-occupancy and effects of selected parameters on PK/PD profiles. Models such as the one developed in this study demonstrate how drug binding to pharmacological targets may influence the PK of certain drugs and also provide a suitable paradigm for defining the PK/PD relationships of similar compounds. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Centocor Inc, Malvern, PA 19355 USA. Baylor Coll Med, Div Cardiol, Houston, TX 77030 USA. Royal Coll Surgeons Ireland, Ctr Cardiovasc Sci, Dublin 2, Ireland. RP Abernethy, DR (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 26 Z9 26 U1 1 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2003 VL 307 IS 3 BP 969 EP 976 DI 10.1124/jpet.103.057299 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748WB UT WOS:000186883100017 PM 14534354 ER PT J AU Justinova, Z Ferre, S Segal, PN Antoniou, K Solinas, M Pappas, LA Highkin, JL Hockemeyer, O Munzar, P Goldberg, SR AF Justinova, Z Ferre, S Segal, PN Antoniou, K Solinas, M Pappas, LA Highkin, JL Hockemeyer, O Munzar, P Goldberg, SR TI Involvement of adenosine A(1) and A(2A) receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID STRIATAL MEMBRANES; GLUTAMATE RELEASE; CEREBRAL-CORTEX; DOPAMINE; ANTAGONISTS; AGONISTS; BINDING; STIMULATION; MONOAMINE; BRAIN AB Adenosine, by acting on adenosine A(1) and A(2A) receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that nonselective adenosine receptor antagonists ( caffeine and 3,7-dimethyl-1-propargylxanthine) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A(1) and A(2A) receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A(1) receptor agonist N-6-cyclopentyladenosine (CPA; 0.01 - 0.1 mg/ kg) and antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.3-23.7 mg/ kg) and the A(2A) receptor agonist 2-p-(2-carboxyethyl) phenethylamino-5'- N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; 0.03-0.18 mg/kg) and antagonist 3-(3-hydroxypropyl)-8-(3-methoxystyryl)7- methyl-1-propargylxanthin phosphate disodium salt (MSX-3; 1-56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A(1) and A(2A) receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A(2A) receptor agonist CGS 21680 also produced drug-appropriate responding ( although at lower levels) when substituted for the cocaine-training stimulus, and both CGS 21680 and the A(1) receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast, both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetamine-training stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A(1) and A(2A) receptors appear to play important but differential roles in the modulation of the discriminative-stimulus effects of methamphetamine and cocaine. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch,NIH, US Dept HHS, Baltimore, MD 21224 USA. Univ Athens, Dept Pharmacol, Sch Med, Goudi, Greece. Univ Bonn, Inst Pharmaceut, D-5300 Bonn, Germany. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch,NIH, US Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Justinova, Zuzana/A-9109-2011; Ferre, Sergi/K-6115-2014; Solinas, Marcello/M-3500-2016 OI Justinova, Zuzana/0000-0001-5793-7484; Ferre, Sergi/0000-0002-1747-1779; Solinas, Marcello/0000-0002-0664-5964 NR 40 TC 36 Z9 36 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2003 VL 307 IS 3 BP 977 EP 986 DI 10.1124/jpet.103.056762 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748WB UT WOS:000186883100018 PM 14557381 ER PT J AU Stevenson, GW Folk, JE Linsenmayer, DC Rice, KC Negus, SS AF Stevenson, GW Folk, JE Linsenmayer, DC Rice, KC Negus, SS TI Opioid interactions in rhesus monkeys: Effects of delta plus mu and delta plus kappa agonists on schedule-controlled responding and thermal nociception SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID TAIL-WITHDRAWAL PROCEDURE; SQUIRREL-MONKEY; RECEPTOR; ANTINOCICEPTION; MORPHINE; MODULATION; ENKEPHALIN; ANALGESIA; CLONING; BRAIN AB Agonists at delta, mu, and kappa opioid receptors produce interacting effects in rodents and nonhuman primates. To further evaluate the determinants of these interactions, this study examined the effects of mixtures of delta + mu and delta + kappa agonists in rhesus monkeys (n = 4-5) using two behavioral procedures, an assay of schedule-controlled responding for food reinforcement and an assay of thermal nociception. Results were analyzed using dose-addition analysis. In the assay of schedule-controlled responding, the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl-benzamide (SNC80); the mu agonists methadone, fentanyl, morphine, and nalbuphine; and the kappa agonists (5alpha, 7alpha, 8beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide (U69,593) and bremazocine all dose dependently decreased rates of food-maintained responding when administered alone. Fixed ratio mixtures of SNC80 + mu agonists produced additive or subadditive effects, whereas SNC80 + kappa agonist mixtures produced only additive effects. In the assay of thermal nociception, SNC80 produced no measurable effects when administered alone, whereas mu and kappa agonists produced dose-dependent antinociception. SNC80 + mu agonist mixtures produced superadditive effects manifested as leftward shifts in mu agonist dose-effect curves. This synergism was antagonized by the delta-selective antagonist naltrindole, suggesting that SNC80-induced enhancement of mu agonist antinociception was delta receptor-mediated. SNC80 did not enhance the antinociceptive effects of the highly selective kappa agonist U69,593, and it produced only a marginal enhancement of antinociception produced by the less selective kappa agonist bremazocine. These results suggest that delta agonists may selectively enhance the antinociceptive effects of mu agonists in rhesus monkeys. These results also confirm that opioid agonist interactions may depend on the receptor selectivity and relative doses of the agonists and on the experimental endpoint. C1 Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. NIDDKD, Med Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Negus, SS (reprint author), Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, 115 Mill St, Belmont, MA 02478 USA. EM negus@mclean.harvard.edu FU NIDA NIH HHS [R01-DA11460, P01-DA14528, T32-DA07252] NR 45 TC 35 Z9 35 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2003 VL 307 IS 3 BP 1054 EP 1064 DI 10.1124/jpet.103.056515 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748WB UT WOS:000186883100028 PM 14557380 ER PT J AU Scheidweiler, KB Plessinger, MA Shojaie, J Wood, RW Kwong, TC AF Scheidweiler, KB Plessinger, MA Shojaie, J Wood, RW Kwong, TC TI Pharmacokinetics and pharmacodynamics of methylecgonidine, a crack cocaine pyrolyzate SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ANHYDROECGONINE METHYL-ESTER; CHROMATOGRAPHY-MASS-SPECTROMETRY; PYROLYSIS PRODUCTS; NITRIC-OXIDE; URINE; IDENTIFICATION; METABOLITES; ECGONIDINE; SMOKING; PLASMA AB Methylecgonidine is formed from cocaine base when smoked and has been identified in biological fluids of crack smokers. Ecgonidine, a metabolite of methylecgonidine formed via esterase activity, also has been identified in similar samples collected from crack smokers. Methylecgonidine and ecgonidine can be used as biomarkers to differentiate smoking from cocaine use via other routes of administration. We determined the pharmacokinetic properties of methylecgonidine and ecgonidine in sheep after intravenous administration of methylecgonidine at doses of 3.0, 5.6, and 10.0 mg/kg using gas chromatography-mass spectro-metric assays. Methylecgonidine clears quickly from blood with a half-life of 18 to 21 min, whereas ecgonidine has a longer half-life of 94 to 137 min. Because ecgonidine clears more slowly, it may be a more effective biomarker of cocaine smoking. The cardiovascular stimulant effects of cocaine contrast with reported in vitro muscarinic agonist effects of methylecgonidine, decreasing contractility and stimulating nitric oxide production in cardiac cells and tissues. To test the hypothesis that methylecgonidine produces cardiovascular effects in vivo consistent with muscarinic agonism, methylecgonidine was administered to sheep intravenously (0.1-3.0 mg/kg) while monitoring heart rate and blood pressure. Significant hypotension and tachycardia occurred in all three sheep. Two of the three sheep demonstrated mild bradycardia 3 to 5 min after methylecgonidine injection. Intravenous pretreatment with atropine methyl bromide (15 mug/kg) antagonized methylecgonidine-induced hypotension in all three sheep, supporting the hypothesis that methylecgonidine acts as a muscarinic agonist in vivo. C1 Univ Rochester, Sch Med, Dept Pathol & Lab Med, Rochester, NY USA. Univ Rochester, Dept Obstet & Gynecol, Rochester, NY USA. RP Scheidweiler, KB (reprint author), NIDA, Chem & Drug Metab Sect, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIDA NIH HHS [DA 05080, DA 07232] NR 38 TC 13 Z9 14 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD DEC 1 PY 2003 VL 307 IS 3 BP 1179 EP 1187 DI 10.1124/jpet.103.055434 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748WB UT WOS:000186883100044 PM 14561847 ER PT J AU Ward, MM Kuzis, S AF Ward, MM Kuzis, S TI Ceiling effects and the Schober test SO JOURNAL OF RHEUMATOLOGY LA English DT Letter ID ANKYLOSING-SPONDYLITIS; FUNCTIONAL DISABILITY; SPINAL MOBILITY C1 NIAMSD, Intramural Res Program, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Camino Med Grp, Sunnyvale, CA USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, US Dept Hlth & Human Serv, Bldg 10,Room 9S205,10 Ctr Dr MSC 1828, Bethesda, MD 20892 USA. NR 7 TC 3 Z9 3 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD DEC PY 2003 VL 30 IS 12 BP 2732 EP 2733 PG 2 WC Rheumatology SC Rheumatology GA 755ZR UT WOS:000187441800047 PM 14719230 ER PT J AU Heymann, JAW Hirai, T Shi, D Subramaniam, S AF Heymann, JAW Hirai, T Shi, D Subramaniam, S TI Projection structure of the bacterial oxalate transporter OxlT at 3.4 angstrom resolution SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE electron cryo-microscopy; major facilitator superfamily; membrane transporter; two-dimensional crystallization ID MAJOR FACILITATOR SUPERFAMILY; OXALOBACTER-FORMIGENES; ESCHERICHIA-COLI; GLYCEROL-3-PHOSPHATE TRANSPORTER; 3-DIMENSIONAL STRUCTURE; LACTOSE PERMEASE; PROTEIN; MECHANISM; EXCHANGE; FEATURES AB OxlT is a bacterial transporter protein with 12 transmembrane segments that belongs to the Major Facilitator Superfamily of transporters. It facilitates the exchange of oxalate and formate across the membrane of the Gram-negative bacterium Oxalobacter formigenes. From an electron crystallographic analysis of two-dimensional, tube-like crystals of OxlT, we have previously determined the three-dimensional structure of this transporter at 6.5 Angstrom resolution. Here, we report conditions to obtain crystalline, two-dimensional sheets of OxlT with diameters exceeding 2 mum. Images of the crystalline sheets were recorded at liquid nitrogen temperatures on a transmission electron microscope equipped with a field-emission gun, operated at 300kV. Computed optical diffraction patterns from the best images display measurable reflections to about 3.4 Angstrom, and electron diffraction patterns show spots to about 3.2 Angstrom resolution in the best cases. As in the case of the tube-like crystals, the new crystalline sheets also belong to the p22(l)2(l) symmetry group. However, the unit cell dimensions of 102.7 Angstrom x 67.3 Angstrom are significantly smaller in one direction than those previously observed with the tube-like crystals that display unit cell dimensions of 100.3 Angstrom x 79.0 Angstrom. Different regions of OxlT are involved in intermolecular contacts in the two types of crystals, and the improved resolution of the sheet crystals appears to be mainly attributable to this tighter packing of the monomers within the unit cell. Published by Elsevier Inc. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RI Hirai, Teruhisa/G-2105-2015 OI Hirai, Teruhisa/0000-0002-2114-8149 NR 23 TC 20 Z9 23 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD DEC PY 2003 VL 144 IS 3 BP 320 EP 326 DI 10.1016/j.jsb.2003.09.002 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 750XH UT WOS:000187023400007 PM 14643200 ER PT J AU Li, XK Jones, M Wang, HF Davies, CH Swanson, JC Hashimoto, I Rusk, RA Schindera, ST Barber, BJ Sahn, DJ AF Li, XK Jones, M Wang, HF Davies, CH Swanson, JC Hashimoto, I Rusk, RA Schindera, ST Barber, BJ Sahn, DJ TI Strain rate acceleration yields a better index for evaluating left ventricular contractile function as compared with tissue velocity acceleration during isovolumic contraction time: An in vivo study SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID REGIONAL MYOCARDIAL-FUNCTION; ANIMAL-MODEL; WALL-MOTION; DOPPLER-ECHOCARDIOGRAPHY; NONINVASIVE ASSESSMENT; PRESSURE-VOLUME; VALIDATION; RELAXATION; INDICATOR; GRADIENT AB Objective: Our study aimed to investigate whether strain rate acceleration (SRA) during isovolumic contraction time (IVCT) could serve as a sensitive indicator of myocardial function. Methods: A total of 8 sheep underwent occlusion of left anterior descending coronary artery or diagonal branches and 2 sheep underwent left circumflex coronary artery occlusion to create septal, apical, or basal segment myocardial ischemia. 19 to 27 weeks before the study. Baseline, volume-loading, dobutamine, and metoprolol infusion were used to produce 4 hemodynamic stages for each sheep. Doppler tissue imaging was acquired using a 5-MHz probe (GE/VingMed Vivid Five, GE Medical Systems, Milwaukee, Wis) on open-chest animals using the liver as a standoff at the apex. Using software (EchoPac, GE Medical Systems), SRA during IVCT was calculated and compared with tissue velocity acceleration (TVA) during IVCT from areas located in die normal and ischemic zones. Also, invasively monitored left ventricle dP/dt was measured as reference contractile function. Results: Both TVA and SEA during IVCT showed higher values for normal tissue than for ischemic area (P < .0001). SRA for normal wall segments changed significantly during the 4 stages (P = .01) with corresponding changes on high-fidelity left ventricular pressure catheters (r = 0.92). TVA over normal segments showed no significant change (P = .29) in the 4 hemodynamic stages. Both TVA and SRA of the ischemic segments showed no significant change with pharmacologic maneuvers or loading conditions. Conclusions. SRA and TVA during IVCT are both useful indicators for detecting abnormal heart wall motion. However, SRA tends to be more sensitive than TVA for differentiating the response to stress conditions. C1 Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, Portland, OR 97239 USA. NHLBI, Bethesda, MD 20892 USA. RP Sahn, DJ (reprint author), Oregon Hlth Sci Univ, Clin Care Ctr Congenital Heart Dis, 3181 SW Sam Jackson Pk Rd,L608, Portland, OR 97239 USA. NR 29 TC 14 Z9 14 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD DEC PY 2003 VL 16 IS 12 BP 1211 EP 1216 DI 10.1067/j.echo.2003.07.006 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 750VL UT WOS:000187019100002 PM 14652598 ER PT J AU Cheung, AK Levin, NW Greene, T Agodoa, L Bailey, J Beck, G Clark, W Levey, AS Leypoldt, JK Ornt, DB Rocco, MV Schulman, G Schwab, S Teehan, B Eknoyan, G AF Cheung, AK Levin, NW Greene, T Agodoa, L Bailey, J Beck, G Clark, W Levey, AS Leypoldt, JK Ornt, DB Rocco, MV Schulman, G Schwab, S Teehan, B Eknoyan, G CA HEMO Study Grp TI Effects of high-flux Hemodialysis on clinical outcomes: Results of the HEMO study SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID POLYSULFONE DIALYZERS; ALBUMIN LEVELS; AMINO-ACID; DIALYSIS; MORTALITY; MEMBRANES; LOSSES; UREA; BETA(2)-MICROGLOBULIN; CLEARANCE AB Among the 1846 patients in the HEMO Study, chronic high-flux dialysis did not significantly affect the primary outcome of the all-cause mortality (ACM) rate or the main secondary composite outcomes, including the rates of first cardiac hospitalization or ACM, first infectious hospitalization or ACM, first 15% decrease in serum albumin levels or ACM, or all non-vascular access-related hospitalizations. The high-flux intervention, however, seemed to be associated with reduced risks of specific cardiac-related events. The relative risks (RR) for the high-flux arm, compared with the low-flux ann, were 0.80 [95% confidence interval (CI), 0.65 to 0.99] for cardiac death and 0.87 (95% CI, 0.76 to 1.00) for the composite of first cardiac hospitalization or cardiac death. Also, the effect of high-flux dialysis on ACM seemed to vary, depending on the duration of prior dialysis. This report presents secondary analyses to further explore the relationship between the flux intervention and the duration of dialysis with respect to various outcomes. The patients were stratified into a short-duration group and a long-duration group, on the basis of the mean duration of dialysis of 3.7 yr before randomization. In the subgroup that had been on dialysis for >3.7 yr, randomization to high-flux dialysis was associated with lower risks of ACM (RR, 0.68; 95% Cl, 0.53 to 0.86; P = 0.001), the composite of first albumin level decrease or ACM (RR, 0.74; 95 % CI, 0.60 to 0.91; P= 0.005), and cardiac deaths (RR, 0.63; 95% CI, 0.43 to 0.92; P= 0.016), compared with low-flux dialysis. No significant differences were observed in outcomes related to infection for either duration subgroup, however, and the trends for beneficial effects of high-flux dialysis on ACM rates were considerably weakened when the years of dialysis during the follow-up phase were combined with the prestudy years of dialysis in the analysis. For the subgroup of patients with <3.7 yr of dialysis before the study, assignment to high-flux dialysis had no significant effect on any of the examined clinical outcomes. These data suggest that high-flux dialysis might have a beneficial effect on cardiac outcomes. Because these results are derived from multiple statistical comparisons, however, they must be interpreted with caution. The subgroup results that demonstrate that patients with different durations of dialysis are affected differently by high-flux dialysis are interesting and require further study for confirmation. C1 Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Lankenau Hosp, Dept Med, Philadelphia, PA USA. Duke Univ, Dept Med, Durham, NC USA. Vanderbilt Univ, Dept Med, Nashville, TN USA. Wake Forest Univ, Dept Med, Winston Salem, NC 27109 USA. Univ Rochester, Dept Med, Rochester, NY USA. Tufts Univ, New England Med Ctr, Dept Med, Boston, MA 02111 USA. Baxter Healthcare Corp, Mcgaw Pk, IL USA. Emory Univ, Dept Med, Atlanta, GA 30322 USA. NIDDK, NIH, Bethesda, MD USA. Cleveland Clin Fdn, Dept Epidemiol & Biostat, Cleveland, OH 44195 USA. Renal Res Inst, New York, NY USA. Vet Affairs Salt Lake City Healthcare Syst, Salt Lake City, UT USA. Univ Utah, Dialysis Program, Dept Med, Salt Lake City, UT 84112 USA. RP Cheung, AK (reprint author), Univ Utah, Dialysis Program, Dept Med, 85 N Med Dr E, Salt Lake City, UT 84112 USA. NR 35 TC 160 Z9 169 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD DEC PY 2003 VL 14 IS 12 BP 3251 EP 3263 DI 10.1097/01.ASN.0000096373.13406.94 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 746RP UT WOS:000186761700026 PM 14638924 ER PT J AU Berger, AR Bradley, WG Brannagan, TH Busis, NA Cros, DP Dalakas, MC Danon, MJ Donofrio, PD Engel, WK England, JD Feldman, EL Freeman, RL Kinsella, LJ Lacomis, D Latov, N Menkes, DL Sander, HW Thomas, FP Triggs, WJ Windebank, AJ Wolfe, GI AF Berger, AR Bradley, WG Brannagan, TH Busis, NA Cros, DP Dalakas, MC Danon, MJ Donofrio, PD Engel, WK England, JD Feldman, EL Freeman, RL Kinsella, LJ Lacomis, D Latov, N Menkes, DL Sander, HW Thomas, FP Triggs, WJ Windebank, AJ Wolfe, GI CA Neuropathy Assoc Med Advisory Comm TI Guidelines for the diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Article ID CLINICAL-FEATURES; RESEARCH CRITERIA; CIDP; POLYRADICULONEUROPATHY; NEUROPATHY; SPECTRUM C1 Cornell Univ, Weill Med Coll, Peripheral Neuropathy Ctr, New York, NY 10022 USA. Univ Florida, Dept Neurol, Shands Jacksonville, FL USA. Univ Florida, Inst Neurosci, Shands Jacksonville, FL USA. Univ Miami, Sch Med, Dept Neurol, Miami, FL 33152 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, EMG Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Peripheral Neuropathy Ctr, Boston, MA 02114 USA. NINDS, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Univ So Calif, Sch Med, Los Angeles, CA 90089 USA. Beaconess Billings Clin, Billings, MT USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Ctr Auton & Peripheral Nerve Disorders, Boston, MA 02215 USA. St Louis Univ, St Louis, MO 63103 USA. Tenet Forest Pk Hosp, St Louis, MO USA. Neuropathy Assoc, New York, NY USA. Univ Tennessee, Hlth Sci Ctr, Knoxville, TN 37996 USA. St Louis Univ, St Louis, MO 63103 USA. Univ Florida, Inst Brain, Gainesville, FL 32611 USA. Peripheral Nerve Soc, Rochester, MN USA. Mayo Clin & Mayo Fdn, Mayo Med Sch, Rochester, MN 55905 USA. Univ Texas, SW Med Ctr, Peripheral Neuropathy Ctr, Dallas, TX 75230 USA. RP Latov, N (reprint author), Cornell Univ, Weill Med Coll, Peripheral Neuropathy Ctr, 635 Madison Ave,Suite 400, New York, NY 10022 USA. NR 21 TC 29 Z9 30 U1 0 U2 3 PU WOODLAND PUBLICATIONS, INC PI NEW YORK PA 69 MURRAY ST, NEW YORK, NY 10007 USA SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD DEC PY 2003 VL 8 IS 4 BP 282 EP 284 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 755UF UT WOS:000187429300010 PM 14641652 ER PT J AU Venkateswarlu, D Duke, RE Perera, L Darden, TA Pedersen, LG AF Venkateswarlu, D Duke, RE Perera, L Darden, TA Pedersen, LG TI An all-atom solution-equilibrated model for human extrinsic blood coagulation complex (sTF-VIIa-Xa): a protein-protein docking and molecular dynamics refinement study SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE blood coagulation; extrinsic Xase pathway; molecular dynamics simulations; protein-protein docking; ternary complex ID FACTOR PATHWAY INHIBITOR; TISSUE FACTOR REGION; SUBSTRATE FACTOR-X; FACTOR-IX; PROTHROMBIN FRAGMENT-1; SHAPE COMPLEMENTARITY; KUNITZ DOMAIN; GEOMETRIC FIT; BINDING SITE; ACTIVE-SITE AB Tissue factor (TF)-bound factor (F)VIIa plays a critical role in activating FX, an event that rapidly results in blood coaLulation. Despite recent advances in the structural information about soluble TF (sTF)-bound VIIa and Xa individually. the atomic details of the temary complex are not known. As part of our long-term goal to provide a structural understanding of the extrinsic blood coagulation pathway, we built an all atom solution-equilibrated model of the human sTF-VIIa-Xa ternary complex using protein-protein docking and molecular dynamics (MD) simulations. The starting structural coordinates of sTF-VIIa and Xa were derived from dynamically equilibrated solution structures. Due to the flexible nature of the light-chain of the Xa molecule, a three-stage docking approach was employed in which SP (Arg195-Lys448)/EGF2 (Arg86-Arg139), EGF1 (Asp46-Thr85) and GLA (Ala1-Lys45) domains were docked in a sequential manner. The rigid-body docking approach of the FTDOCK method in conjunction with filtering based on biochemical knowledge from experimental site-specific mutagenesis studies provided the strategy. The best complex obtained from the docking experiments was further refined using MD simulations for 3 ns in explicit water. In addition to explaining most of the known experimental site-specific mutagenesis data pertaining to sTF-VIIa, our model also characterizes likely enzyme-binding exosites on FVIIa and Xa that may be involved in the temary complex formation. According to the equilibrated model, the 140s loop of VIIa serves as the key recognition motif for complex formation. Stable interactions occur between the FVIIa 140s loop and the FXa beta-strand B2 region near the sodium-binding domain, the 160 s loop and the N-terminal activation loop regions. The helical-hydrophobic stack region that connects the GLA and EGF1 domains of VIIa and Xa appears to play a potential role in the membrane binding region of the ternary complex. The proposed model may serve as a reasonable structural basis for understanding the exosite-mediated substrate recognition of sTF-VIIa and to advance understanding of the TFPI-mediated regulatory pathway of the extrinsic blood coagulation cascade. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013; Venkateswarlu, Divi/K-1815-2014 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861; Venkateswarlu, Divi/0000-0003-2481-7480 FU NHLBI NIH HHS [HL-06350, P01 HL006350] NR 54 TC 15 Z9 15 U1 1 U2 5 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD DEC PY 2003 VL 1 IS 12 BP 2577 EP 2588 DI 10.1111/j.1538-7836.2003.00421.x PG 12 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 755RZ UT WOS:000187426400019 PM 14750502 ER PT J AU Normand, JL Lambert, EY Vlahov, D AF Normand, JL Lambert, EY Vlahov, D TI Understanding the dynamics of sexual transmission of HIV among drug-using populations: An integration of biological, behavioral, and environmental perspectives SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Editorial Material C1 NIDA, CAMCODA, Bethesda, MD 20892 USA. New York Acad Med, Ctr Urban Epidemiol Studies, New York, NY USA. RP Lambert, EY (reprint author), NIDA, CAMCODA, 6001 Execut Blvd, Rm 5180, MSC 9593, Bethesda, MD 20892 USA. NR 7 TC 7 Z9 7 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD DEC PY 2003 VL 80 IS 4 SU 3 BP 1 EP 6 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 763HZ UT WOS:000188080300001 ER PT J AU Linehan, WM Walther, MM Zbar, B AF Linehan, WM Walther, MM Zbar, B TI The genetic basis of cancer of the kidney SO JOURNAL OF UROLOGY LA English DT Review DE kidney; kidney neoplasms; gene expression; epithelium ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; HIPPEL-LINDAU-DISEASE; PARENCHYMAL SPARING SURGERY; FAMILIAL CUTANEOUS LEIOMYOMATOSIS; MET PROTOONCOGENE; TYROSINE KINASE; INTRAOPERATIVE ULTRASOUND; SPONTANEOUS PNEUMOTHORAX AB Purpose: The types of epithelial renal tumors are clear cell, types I and II papillary, chromophobe and oncocytoma. We identified the genetic basis of these different types of kidney cancer to provide better methods for early diagnosis of this disease as well as provide the foundation for the development of molecular therapeutic approaches. Materials and Methods: To identify the genetic basis of kidney cancer we studied families with an inherited predisposition to kidney cancer. Families in which 2 or more individuals had kidney cancer underwent a comprehensive evaluation to determine whether they were affected with a hereditary form of renal carcinoma. Genetic linkage analysis was performed to identify the gene for inherited forms of renal carcinoma. Results: The gene for the inherited form of clear cell renal carcinoma associated with von Hippel-Lindau gene was identified. This gene has been found to be a tumor suppressor gene. A new form of inherited renal carcinoma, hereditary papillary renal carcinoma, was identified. The gene for this condition was identified and found to be the proto-oncogene c-Met. A previously unidentified form of familial renal oncocytoma was found. A familial form of chromophobe renal carcinoma and oncocytoma associated with Birt Hogg Dube syndrome was found. The gene for this condition was localized on the short arm of chromosome 17 and it has been identified. We studied families with cutaneous leiomyomas, uterine leiomyomas and papillary renal carcinoma. We identified mutations in the fumarate hydratase gene in patients affected with this disorder, namely hereditary leiomyoma renal cell carcinoma. Conclusions: Kidney cancer used to be considered a single disease. It is now known that there are a number of different types of cancers of the kidney with different histological patterns and different clinical courses that appear to respond differently to therapy. These different types of kidney cancer are caused by different genes, ie they each have a distinct genetic basis. Understanding the molecular pathways of these cancer genes should provide insight into their varying clinical courses and responses to treatment as well as provide the foundation for the development of disease specific molecular therapeutic strategies. C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10,Room 2B47, Bethesda, MD 20892 USA. NR 64 TC 272 Z9 295 U1 0 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD DEC PY 2003 VL 170 IS 6 BP 2163 EP 2172 DI 10.1097/01.ju.0000096060.92397.ed PN 1 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 742QG UT WOS:000186529000001 PM 14634372 ER PT J AU Diehn, FE Neeman, Z Hvizda, JL Wood, BJ AF Diehn, FE Neeman, Z Hvizda, JL Wood, BJ TI Remote thermometry to avoid complications in radiofrequency ablation SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; TUMOR ABLATION; SPINAL-CORD; HYPERTHERMIA; OPPORTUNITIES; ULTRASOUND; CHALLENGES; CANCER AB Percutaneous image-guided radiofrequency ablation (RFA) of tumors has the potential risk for thermal damage to nearby normal collateral tissues. Thus, the goal of creating a sufficient area of tumor necrosis must be weighed against the risk for injury to collateral tissues. In this study, remote thermistors were used to monitor temperatures near collateral structures during tumor RFA. Four unique cases are described. When temperature-sensitive structures are near the target lesion, remote thermometry could further increase the safety of this evolving minimally invasive procedure. C1 Mayo Clin & Mayo Fdn, Mayo Med Sch, Rochester, MN 55905 USA. NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Wood, BJ (reprint author), Mayo Clin & Mayo Fdn, Mayo Med Sch, Rochester, MN 55905 USA. EM bwood@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 20 TC 24 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD DEC PY 2003 VL 14 IS 12 BP 1569 EP 1576 DI 10.1097/01.RVI.0000096769.74047.5 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 800IL UT WOS:000220021900013 PM 14654495 ER PT J AU Neeman, Z Auerbach, A Wood, BJ AF Neeman, Z Auerbach, A Wood, BJ TI Metastatic involvement of a retrieved inferior vena cava filter SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter ID PULMONARY-EMBOLISM; PREVENTION C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Neeman, Z (reprint author), NIH, Ctr Clin, Bldg 10,Room 1C387, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 5 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD DEC PY 2003 VL 14 IS 12 BP 1585 EP 1585 DI 10.1016/S1051-0443(07)60319-4 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 800IL UT WOS:000220021900016 PM 14654498 ER PT J AU Smith, RH Ding, CT Kotin, RM AF Smith, RH Ding, CT Kotin, RM TI Serum-free production and column purification of adeno-associated virus type 5 SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE AAV; adeno-associated virus; AAV-5 ID ION-EXCHANGE CHROMATOGRAPHY; HUMAN PARVOVIRUS; AAV SEROTYPES; VIRAL VECTORS; GENE-TRANSFER; HELPER; TRANSDUCTION; CLONING; DNA AB Viral vectors derived from adeno-associated virus (AAV) are rapidly becoming the vehicles of choice for gene therapy applications. AAV-2 is the adeno-associated virus serotype most commonly employed in AAV-mediated gene therapy studies; however, recently developed vectors derived from alternative serotypes of AAV, such as AAV-5, are receiving special attention due to their disparate tissue tropisms and potential for serial administration. In this report, we describe a rapid and efficient method for the serum-free production and column purification of recombinant AAV-5 particles. This method utilizes a combination of anion-exchange chromatography and gel filtration chromatography to purify recombinant AAV particles to near homogeneity. Importantly, viral particles are captured directly from cellular extracts with high efficiency, and vector purification is achieved in less than one working day with a minimal amount of sample manipulation. The method described in this report does not require partial purification by density centrifugation, detergent treatment, or solvent extraction to achieve efficient levels of column binding and vector purification. (C) 2003 Elsevier B.V. All rights reserved. C1 NHLBI, Lab Biochem Genet, Bethesda, MD 20892 USA. RP Kotin, RM (reprint author), NHLBI, Lab Biochem Genet, Bldg 10,Rm 7N-264,9000 Rockville Pike, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 23 TC 41 Z9 43 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD DEC PY 2003 VL 114 IS 2 BP 115 EP 124 DI 10.1016/j.jviromet.2003.098.002 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 750KM UT WOS:000186989900001 PM 14625046 ER PT J AU Tang, SX Murakami, T Cheng, NQ Steven, AC Freed, EO Levin, JG AF Tang, SX Murakami, T Cheng, NQ Steven, AC Freed, EO Levin, JG TI Human immunodeficiency virus type 1 N-terminal capsid mutants containing cores with abnormally high levels of capsid protein and virtually no reverse transcriptase SO JOURNAL OF VIROLOGY LA English DT Article ID CYCLOPHILIN-A INCORPORATION; AMINO-ACID SUBSTITUTIONS; IN-VITRO; GAG PROTEINS; LIFE-CYCLE; POSTTRANSLATIONAL MODIFICATIONS; PREINTEGRATION COMPLEX; PARTICLE MATURATION; CYCLOSPORINE-A; HIV-1 VIRIONS AB We previously described the phenotype associated with three alanine substitution mutations in conserved residues (Trp23, Phe40, and Asp51) in the N-terminal domain of human immunodeficiency virus type I capsid protein (CA). All of the mutants produce noninfectious virions that lack conical cores and, despite having a functional reverse transcriptase (RT), are unable to initiate reverse transcription in vivo. Here, we have focused on elucidating the mechanism by which these CA mutations disrupt virus infectivity. We also report that cyclophilin A packaging is severely reduced in W23A and F40A virions, even though these residues are distant from the cyclophilin A binding loop. To correlate loss of infectivity with a possible defect in an early event preceding reverse transcription, we modeled disassembly by generating viral cores from particles treated with mild nonionic detergent; cores were isolated by sedimentation in sucrose density gradients. In general, fractions containing mutant cores exhibited a normal protein profile. However, there were two striking differences from the wild-type pattern: mutant core fractions displayed a marked deficiency in RT protein and enzymatic activity (<5% of total RT in gradient fractions) and a substantial increase in the retention of CA. The high level of core-associated CA suggests that mutant cores may be unable to undergo proper disassembly. Thus, taken together with the almost complete absence of RT in mutant cores, these findings can account for the failure of the three CA mutants to synthesize viral DNA following virus entry into cells. C1 NICHD, Lab Mol Genet, NIH, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, Bethesda, MD 20892 USA. Natl Inst Arthritis & Musculoskeletal & Skin Dis, Lab Struct Biol Res, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), NICHD, Lab Mol Genet, NIH, Bldg 6B,Rm 216, Bethesda, MD 20892 USA. NR 73 TC 41 Z9 43 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 DEC PY 2003 VL 77 IS 23 BP 12592 EP 12602 DI 10.1128/JVI.77.23.12592-12602.2003 PG 11 WC Virology SC Virology GA 744DM UT WOS:000186612700021 PM 14610182 ER PT J AU Dimcheff, DE Askovic, S Baker, AH Johnson-Fowler, C Portis, JL AF Dimcheff, DE Askovic, S Baker, AH Johnson-Fowler, C Portis, JL TI Endoplasmic reticulum stress is a determinant of retrovirus-induced spongiform neurodegeneration SO JOURNAL OF VIROLOGY LA English DT Article ID UNFOLDED PROTEIN RESPONSE; MURINE LEUKEMIA-VIRUS; C RNA VIRUS; ECOTROPIC RETROVIRUS; ENVELOPE PROTEIN; GENE-EXPRESSION; MUTANT MICE; CELL-DEATH; WILD MICE; DISEASE AB FrCaSE is a mouse retrovirus that causes a fatal noninflammatory spongiform neurodegenerative disease with pathological features strikingly similar to those induced by transmissible spongiform encephalopathy (TSE) agents. Neurovirulence is determined by the sequence of the viral envelope protein, though the specific role of this protein in disease pathogenesis is not known. In the present study, we compared host gene expression in the brain stems of mice infected with either FrCas(E) or the avirulent virus F43, differing from FrCas(E) in the sequence of the envelope gene. Four of the 12 disease-specific transcripts up-regulated during the preclinical period represent responses linked to the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Among these genes was CHOP/GADD153, which is induced in response to conditions that perturb endoplasmic reticulum function. In vitro studies with NIH 3T3 cells revealed up-regulation of CHOP as well as BiP, calreticulin, and Grp58/ERp57 in cells infected with FrCaSE but not with F43. Immunoblot analysis of infected NIH 3T3 cells demonstrated the accumulation of uncleaved envelope precursor protein in FrCas(E)- but not F43-infected cells, consistent with ER retention. These results suggest that retrovirus-induced spongiform neurodegeneration represents a protein-folding disease and thus may provide a useful tool for exploring the causal link between protein misfolding and the cytopathology that it causes. C1 NIAID, Rocky Mt Lab, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. RP Portis, JL (reprint author), NIAID, Rocky Mt Lab, Lab Persistent Viral Dis, 903 S 4th St, Hamilton, MT 59840 USA. NR 61 TC 64 Z9 65 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 DEC PY 2003 VL 77 IS 23 BP 12617 EP 12629 DI 10.1128/JVI.77.23.12617-12629.2003 PG 13 WC Virology SC Virology GA 744DM UT WOS:000186612700023 PM 14610184 ER PT J AU Teterina, NL Rinaudo, MS Ehrenfeld, E AF Teterina, NL Rinaudo, MS Ehrenfeld, E TI Strand-specific RNA synthesis defects in a poliovirus with a mutation in protein 3A SO JOURNAL OF VIROLOGY LA English DT Article ID POLYMERASE 3D(POL); VIRAL-RNA; IN-VITRO; ENDOPLASMIC-RETICULUM; HUMAN RHINOVIRUS; POSITIVE-STRAND; 2C PROTEIN; REPLICATION COMPLEXES; MEMBRANE-BINDING; GENETIC-ANALYSIS AB Substitution of a methionine residue at position 79 in poliovirus protein 3A with valine or threonine caused defective viral RNA synthesis, manifested as delayed onset and reduced yield of viral RNA, in HeLa cells transfected with a luciferase-containing replicon. Viruses containing these same mutations produced small or minute plaques that generated revertants upon further passage, with either wild-type 3A sequences or additional nearby compensating mutations. Translation and polyprotein processing were not affected by the mutations, and 3AB proteins containing the altered amino acids at position 79 showed no detectable loss of membrane-binding activity. Analysis of individual steps of viral RNA synthesis in HeLa cell extracts that support translation and replication of viral RNA showed that VPg uridylylation and negative-strand RNA synthesis occurred normally from mutant viral RNA; however, positive-strand RNA synthesis was specifically reduced. The data suggest that a function of viral protein 3A is required for positive-strand RNA synthesis but not for production of negative strands. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Ehrenfeld, E (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6120,9000 Rockville, Bethesda, MD 20892 USA. NR 86 TC 19 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 DEC PY 2003 VL 77 IS 23 BP 12679 EP 12691 DI 10.1128/JVI.77.23.12679-12691.2003 PG 13 WC Virology SC Virology GA 744DM UT WOS:000186612700029 PM 14610190 ER PT J AU Trubey, CM Chertova, E Coren, LV Hilburn, JM Hixson, CV Nagashima, K Lifson, JD Ott, DE AF Trubey, CM Chertova, E Coren, LV Hilburn, JM Hixson, CV Nagashima, K Lifson, JD Ott, DE TI Quantitation of HLA class II protein incorporated into human immunodeficiency type 1 virions purified by anti-CD45 immunoaffinity depletion of microvesicles SO JOURNAL OF VIROLOGY LA English DT Article ID CELL LEUKEMIA-VIRUS; HUMAN T-CELLS; GAG PROTEINS; MN STRAIN; HIV-1; PATHOGENESIS; ENVELOPE; ANTIBODY; HISTOCOMPATIBILITY; RETROVIRUSES AB Among the many host cell-derived proteins found in human immunodeficiency virus type 1 (HIV-1), HLA class 11 (HLA-II) appears to be selectively incorporated onto virions and may contribute to mechanisms of indirect imunopathogenesis in HIV infection and AIDS. However, the amount of HLA-II on the surface of HIV-1 particles has not been reliably determined due to contamination of virus preparations by microvesicles containing host cell proteins, including HLA-II. Even rigorous sucrose density centrifugation is unable to completely separate HIV-1 from microvesicles. CD45, a leukocyte integral membrane protein, is found on microvesicles, yet appears to be excluded from HIV-1 particles. Exploiting this observation, we have developed a CD45-based immunoaffinity depletion method for removing CD45-containing microvesicles that yields highly purified preparations of virions. Examination of CD45-depleted HIV-1(MN) by high-pressure liquid chromatography, protein sequencing, and amino acid analyses determined a molar ratio of HLA-II to Gag of 0.04 to 0.05 in the purified virions, corresponding to an estimated average of 50 to 63 native HLA-II complexes (i.e., a dimer of alpha and beta heterodimers) per virion. These values are approximately 5- to 10-fold lower than those previously determined for other virion preparations that contained microvesicles. Our observations demonstrate the utility of CD45 immunoaffinity-based approaches for producing highly purified retrovirus preparations for applications that would benefit from the use of virus that is essentially free of microvesicles. C1 NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Res Technol Program, Frederick, MD 21702 USA. RP Ott, DE (reprint author), NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 41 TC 51 Z9 53 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 DEC PY 2003 VL 77 IS 23 BP 12699 EP 12709 DI 10.1128/JVI.77.23.12699-12709.2003 PG 11 WC Virology SC Virology GA 744DM UT WOS:000186612700031 PM 14610192 ER PT J AU Kong, WP Huang, Y Yang, ZY Chakrabarti, BK Moodie, Z Nabel, GJ AF Kong, WP Huang, Y Yang, ZY Chakrabarti, BK Moodie, Z Nabel, GJ TI Immunogenicity of multiple gene and clade human immunodeficiency virus type 1 DNA Vaccines SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; AIDS VACCINE; CELL RESPONSES; RHESUS-MONKEYS; HIV TYPE-1; GAG; IMMUNIZATION; INFECTION; VIREMIA; EXPRESSION AB The ability to elicit an immune response to a spectrum of human immunodeficiency virus type 1 (HIV-1) gene products from divergent strains is a desirable feature of an AIDS vaccine. In this study, we examined combinations of plasmids expressing multiple HIV-1 genes from different clades for their ability to elicit Immoral and cellular immune responses in mice. Immunization with a modified Env, gp145DeltaCFI, in combination with a Gag-Pol-Nef fusion protein plasmid elicited similar CD41(+) ana CD8(+) cellular responses to immunization with either vector alone. Further, when mice were immunized with a mixture of Env from three clades, A, B, and C, together with Gag-Pol-Nef, the overall potency and balance of CD4(+)- and CD8(+)-T-cell responses to all viral antigens were similar, with only minor differences noted. In addition, plasmid mixtures elicited antibody responses comparable to those from individual inoculations. These findings suggest that a multigene and multiclade vaccine, including components from A, B, and C Env and Gag-Pol-Nef, can broaden antiviral immune responses without immune interference. Such combinations of immunogens may help to address concerns about viral genetic diversity for a prospective HIV-1 vaccine. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. NR 41 TC 84 Z9 88 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 DEC PY 2003 VL 77 IS 23 BP 12764 EP 12772 DI 10.1128/JVI.77.23.12764-12772.2003 PG 9 WC Virology SC Virology GA 744DM UT WOS:000186612700037 PM 14610198 ER PT J AU Jung, YT Wu, TY Kozak, CA AF Jung, YT Wu, TY Kozak, CA TI Characterization of recombinant nonecotropic murine leukemia viruses from the wild mouse species Mus spretus SO JOURNAL OF VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; FOCUS-FORMING VIRUSES; HOST-RANGE; HOUSE MICE; SEQUENCES; MUSCULUS; HYBRIDIZATION; LOCUS; RESISTANCE; PROVIRUSES AB The wild mouse species most closely related to the common laboratory strains contain proviral env genes of the xenotropic/polytropic subgroup of mouse leukemia viruses (MLVs). To determine if the polytropic proviruses of Mus spretus contain functional genes, we inoculated neonates with Moloney MLV (MoMLV) or amphotropic MLV (A-MLV) and screened for viral recombinants with altered host ranges. Thymus and spleen cells from MoMLV-inoculated mice were plated on Mus dunni cells and mink cells, since these cells do not support the replication of MoMLV, and cells from A-MLV-inoculated mice were plated on ferret cells. All MoMLV-inoculated mice produced ecotropic viruses that resembled their MoMLV progenitor, although some isolates, unlike MoMLV, grew to high titers in M. dunni cells. All of the MoMLV-inoculated mice also produced nonecotropic virus that was infectious for mink cells. Sequencing of three MoMLV- and two A-MLV-derived nonecotropic recombinants confirmed that these viruses contained substantial substitutions that included the regions of env encoding the surface (SU) protein and the 5' end of the transmembrane (TM) protein. The 5' recombination breakpoint for one of the A-MLV recombinants was identified in RNase H. The M. spretusderived env substitutions were nearly identical to the corresponding regions in prototypical laboratory mouse polytropic proviruses, but the wild mouse infectious viruses had a more restricted host range. The M. spretus proviruses contributing to these recombinants were also sequenced. The seven sequenced proviruses were 99% identical to one another and to the recombinants; only two of the seven had obvious fatal defects. We conclude that the M. spretus proviruses are likely to be recent germ line acquisitions and that they contain functional genes that can contribute to the production of replication-competent virus. C1 NIAID, NIH, LMM, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, NIH, LMM, Bldg 4,Room 329,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. NR 37 TC 11 Z9 11 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 DEC PY 2003 VL 77 IS 23 BP 12773 EP 12781 DI 10.1128/JVI.77.23.12773-12781.2003 PG 9 WC Virology SC Virology GA 744DM UT WOS:000186612700038 PM 14610199 ER PT J AU Igarashi, T Donau, OK Imamichi, H Dumaurier, MJ Sadjadpour, R Plishka, RJ Buckler-White, A Buckler, C Suffredini, AF Lane, HC Moore, JP Martin, MA AF Igarashi, T Donau, OK Imamichi, H Dumaurier, MJ Sadjadpour, R Plishka, RJ Buckler-White, A Buckler, C Suffredini, AF Lane, HC Moore, JP Martin, MA TI Macrophage-tropic simian/human immunodeficiency virus chimeras use CXCR4, not CCR5, for infections of rhesus macaque peripheral blood mononuclear cells and alveolar macrophages SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; MONOCYTE-DERIVED MACROPHAGES; CD4(+) T-CELLS; HIV-1 INFECTION; RECEPTOR-BINDING; SMALL-MOLECULE; TYPE-1 HIV-1; CONFORMATIONAL-CHANGES; FUNCTIONAL CORECEPTOR; ENVELOPE GLYCOPROTEIN AB After the nearly complete and irreversible depletion of CD4(+) T lymphocytes induced by highly pathogenic simian/human immunodeficiency virus chimeric viruses (SHIVs) during infections of rhesus monkeys, tissue macrophages are able to sustain high levels (>10(6) viral RNA copies/ml) of plasma viremia for several months. We recently reported that the virus present in the plasma during the late macrophage phase of infection had acquired changes that specifically targeted the V2 region of gp120 (H. Imamichi et al., Proc. Natl. Acad. Sci. USA 99:13813-13818, 2002); some of these SHIV variants were macrophage-tropic (M-tropic). Those findings have been extended by examining the tropic properties, coreceptor usage, and gp120 structure of five independent SHIVs recovered directly from lymph nodes of late-stage animals. All of these tissue-derived SHIV isolates were able to infect alveolar macrophages. These M-tropic SHIVs used CXCR4, not CCR5, for infections of rhesus monkey PBMC and primary alveolar macrophages. Because the starting highly pathogenic T-tropic SHIV inoculum also utilized CXCR4, these results indicate that the acquisition of M-tropism in the SHIV-macaque system is not accompanied by a change in coreceptor usage. Compared to the initial T-tropic SHIN inoculum, tissue-derived M-tropic SHIVs from individual infected animals carry gp120s containing similar changes (specific amino acid deletions, substitutions, and loss of N-linked glycosylation sites), primarily within the V1 and/or V2 regions of gp120. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA. Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Martin, MA (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Rm 315,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. NR 59 TC 33 Z9 34 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 DEC PY 2003 VL 77 IS 24 BP 13042 EP 13052 DI 10.1128/JVI.77.24.13042-13052.2003 PG 11 WC Virology SC Virology GA 750YF UT WOS:000187025500013 PM 14645561 ER PT J AU Tao, MF Kruhlak, M Xia, SH Androphy, E Zheng, ZM AF Tao, MF Kruhlak, M Xia, SH Androphy, E Zheng, ZM TI Signals that dictate nuclear localization of human papillomavirus type 16 oncoprotein E6 in living cells SO JOURNAL OF VIROLOGY LA English DT Article ID MAMMARY EPITHELIAL-CELLS; PRIMARY HUMAN KERATINOCYTES; GREEN FLUORESCENT PROTEIN; TUMOR-SUPPRESSOR PROTEIN; HIGH-RISK; P53 DEGRADATION; MUTATIONAL ANALYSIS; LOCATION SIGNALS; CERVICAL-CANCER; MESSENGER-RNA AB Human papillomavirus (HPV) type 16 E6 (16E6) is an oncogenic, multifunctional nuclear protein that induces p53 degradation and perturbs normal cell cycle control, leading to immortalization and transformation of infected keratinocytes and epithelial cells. Although it is unclear how 16E6 disrupts the epigenetic profile of host genes, its presence in the nucleus is a key feature. The present report describes intrinsic properties of 16E6 that influence its nuclear import in living cells. When the coding region of full-length 16E6 was inserted in frame into the C terminus of green fluorescent protein (GFP), it effectively prevented the 16E6 pre-mRNA from being spliced and led to the expression of a GFP-E6 fusion which localized predominantly to the nucleus. Further studies identified three novel nuclear localization signals (NLSs) in 16E6 that drive the protein to accumulate in the nucleus. We found that all three NLS sequences are rich in positively charged basic residues and that point mutations in these key residues could abolish the retention of 16E6 in the nucleus as well as the p53 degradation and cell immortalization activities of the protein. When inserted into corresponding regions of low-risk HPV type 6 E6, the three NLS sequences described for 16E6 functioned actively in converting the normally cytoplasmic HPV type 6 E6 into a nuclear protein. The separate NLS sequences, however, appear to play different roles in nuclear import and retention of HPV E6. The discovery of three unique NLS sequences in 16E6 provides new insights into the nuclear association of 16E6 which may reveal other novel activities of this important oncogenic protein. C1 NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Rm 10 S255,MSC-1868, Bethesda, MD 20892 USA. OI Androphy, Elliot/0000-0002-8104-0703 NR 79 TC 37 Z9 38 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 DEC PY 2003 VL 77 IS 24 BP 13232 EP 13247 DI 10.1128/JVI.77.24.13232-13247.2003 PG 16 WC Virology SC Virology GA 750YF UT WOS:000187025500032 PM 14645580 ER PT J AU Hanton, L Axelrod, L Bakalov, V Bondy, CA AF Hanton, L Axelrod, L Bakalov, V Bondy, CA TI The importance of estrogen replacement in young women with Turner syndrome SO JOURNAL OF WOMENS HEALTH LA English DT Article ID HORMONE-THERAPY; MANAGEMENT; DENSITY; RISK AB Background: Most girls with Turner syndrome (TS) need estrogen replacement treatment (ERT) to induce and maintain feminization and prevent osteoporosis. There is abundant information on ERT use in postmenopausal women, but there is little information on this issue in women with TS. We aimed to determine the level of ERT use in women with TS living in the United States and assess the effects of ERT adherence vs. nonadherence on bone mineral density (BMD). Methods: Fifty women with TS aged 30-59 years had ERT history obtained by structured interviews and BMD assessed at the lumbar spine by dual x-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Results: Thirty-four of the 50 women with TS had received ERT according to current recommendations, and the rest did not either because of physician failure to prescribe (5 of 50) or because of nonadherence to prescribed ERT (11 of 50). The mean duration of ERT was 25 +/- 2 years for the standard of care group vs. 8 +/- 2 years for the others (p < 0.0001). The major factor promoting adherence to ERT was education on the importance of ERT for bone health (p < 0.001). As expected, lumbar spine BMD was significantly reduced in women not taking ERT according to current guidelines (e.g., a reduction of 20% by QCT, p < 0.001) with 6 of 16 of these women having osteoporosis and 3 of 16 having vertebral compression fractures compared with 0 of 34 in the ERT adherent group. Conclusions: Approximately 70% of women with TS in this sample of highly educated women in the United States are taking ERT as currently recommended and appear to be protected from osteoporosis of the spine, whereas those women using ERT less than 75% of the time are at grave risk for osteoporosis. In a time of new reservations about postmenopausal ERT, it is important to emphasize to young women with TS and their caregivers that ERT is critical for bone health. C1 Natl Inst Child Hlth, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), Natl Inst Child Hlth, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov NR 15 TC 33 Z9 35 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD DEC PY 2003 VL 12 IS 10 BP 971 EP 977 DI 10.1089/154099903322643893 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 768FL UT WOS:000188532900004 PM 14709185 ER PT J AU Roth, SM Schrager, MA Lee, MR Metter, EJ Hurley, BF Ferrell, RE AF Roth, SM Schrager, MA Lee, MR Metter, EJ Hurley, BF Ferrell, RE TI Interleukin-6 (IL6) genotype is associated with fat-free mass in men but not women SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT FASEB Experimental Biology Annual Meeting CY 2002 CL NEW ORLEANS, LOUISIANA SP FASEB ID RAY ABSORPTIOMETRY METHODS; MUSCLE PROTEIN BREAKDOWN; BONE-MINERAL DENSITY; SKELETAL-MUSCLE; GENE POLYMORPHISM; AGE; SARCOPENIA; GENDER; IL-6; STRENGTH AB We studied the association of the G-174C promoter polymorphism in the interleukin-6 gene (IL6) with total body fat and fat-free mass (FFM) in 242 men and women (IL6 genotypes: G/G, n = 87; G/C, n = 100; C/C, n = 55) across the adult age span (21-92 years). In men, but not women (significant genotype by sex interactions; p = .023-.048), the C/C group exhibited significantly lower total FFM than the G/G group (54.7 +/- 0.8 kg vs 57.2 +/- 0.7 kg, respectively, p = .020), as well as significantly lower FFM of the lower limbs compared with the G/G group (18.4 +/- 0.3 kg vs 19.8 +/- 0.3 kg, respectively, p = .004). No significant genotype differences were observed in total body fat mass in either men or women. The results indicate that the IL6 G-174C polymorphism is significantly associated with FFM in men but not women. C1 Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. NIA, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Roth, SM (reprint author), Univ Maryland, Dept Kinesiol, Coll Hlth & Human Performance, College Pk, MD 20742 USA. NR 29 TC 25 Z9 25 U1 0 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD DEC PY 2003 VL 58 IS 12 BP 1085 EP 1088 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 757RE UT WOS:000187574600004 ER PT J AU Brody, H Miller, FG AF Brody, H Miller, FG TI The clinician-investigator: Unavoidable but manageable tension SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID THERAPEUTIC MISCONCEPTION; INTERNAL MORALITY; TRIALS; ETHICS; EQUIPOISE; MEDICINE AB The "difference position" holds that clinical research and therapeutic medical practice are sufficiently distinct activities to require different ethical rules and principles. The "similarity position" holds instead that clinical investigators ought to be bound by the same fundamental principles that govern therapeutic medicine-specifically, a duty to provide the optimal therapeutic benefit to each patient or subject. Some defenders of the similarity position defend it because of the overlap between the role of attending physician and the role of investigator in a research trial. This overlap is maximal when the same physician occupies both roles with respect to a particular patient-subject. We address the ethical tensions inherent in that role conflict and argue that the tensions are real but manageable. The difference position provides a sound ethical framework within which to manage those tensions, while the similarity position is unsatisfactory because it seeks to deny the existence of the tensions. C1 Michigan State Univ, Ctr Eth & Humanities Life Sci, E Lansing, MI 48824 USA. Michigan State Univ, Dept Family Practice, E Lansing, MI 48824 USA. NIH, Dept Clin Bioeth, Bethesda, MD USA. RP Brody, H (reprint author), Michigan State Univ, Ctr Eth & Humanities Life Sci, E Lansing, MI 48824 USA. NR 17 TC 70 Z9 72 U1 0 U2 4 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD DEC PY 2003 VL 13 IS 4 BP 329 EP 346 DI 10.1353/ken.2004.0003 PG 18 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 765RK UT WOS:000188297100002 PM 15049297 ER PT J AU Miller, PB Weijer, C AF Miller, PB Weijer, C TI Will the real Charles Fried please stand up? SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID EQUIPOISE AB In response to the preceding commentary by Jerry Menikoff in this issue of the journal, the authors argue that Fried's central concern is not that randomized clinical trials (RCTs) are conducted without consent, but rather that various aspects of the design and conduct of RCTs are in tension with physicians' duties of personal care to their patients. Although Fried does argue that the existence of equipoise cannot justify failure to obtain consent from research subjects, informed consent by itself does not supplant ill subjects' rights to personalized judgment and care embodied in Fried's equipoise. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Dalhousie Univ, Dept Bioeth, Halifax, NS, Canada. RP Miller, PB (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4319 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD DEC PY 2003 VL 13 IS 4 BP 353 EP 357 DI 10.1353/ken.2004.0008 PG 5 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 765RK UT WOS:000188297100004 PM 15049299 ER PT J AU Velasquez, MT Bhathena, SJ Ranich, T Schwartz, AM Kardon, DE Ali, AA Haudenschild, CC Hansen, CT AF Velasquez, MT Bhathena, SJ Ranich, T Schwartz, AM Kardon, DE Ali, AA Haudenschild, CC Hansen, CT TI Dietary flaxseed meal reduces proteinuria and ameliorates nephropathy in an animal model of type II diabetes mellitus SO KIDNEY INTERNATIONAL LA English DT Article DE type II diabetes mellitus; hyperglycemia; hyperinsulinemia; flaxseed meal; soy protein; proteinuria; diabetic nephropathy; glomerular disease; tubulointerstitium ID ALPHA-LINOLENIC ACID; POLYCYSTIC KIDNEY-DISEASE; PLATELET-ACTIVATING-FACTOR; EXPERIMENTAL RENAL-DISEASE; VEGETARIAN SOY DIET; SHR/N-CORPULENT RAT; LUPUS NEPHRITIS; MESANGIAL CELLS; FISH-OIL; CP RATS AB Background. Evidence is emerging that varying the type or source of dietary protein intake can have beneficial effects on chronic renal disease. Consumption of soybean and soy-based food products, as the source of plant protein, can retard the development and progression of chronic renal disease. We studied the obese spontaneously hypertensive/NIH-corpulent (SHR/Ncp) rat, a model of obesity and type II diabetes mellitus that consistently develops nephropathy resembling diabetic nephropathy. We specifically sought to determine whether changing the source of protein intake from animal protein, casein, to plant protein in the form of either soy protein concentrate or flaxseed protein in the diet has a different impact on renal function and nephropathy in this model. Methods. Male obese SHR/N-cp rats were randomly assigned to one of three diets containing either 20% casein, 20% soy protein concentrate, or 20% flaxseed meal. Except for the protein source, all three diets were identical and contained similar amounts of protein, fat, carbohydrates, minerals, and vitamins. All animals were maintained on these diets for 6 months. At the end of the study, blood sampling and 24-hour urine collections were performed for renal functional measurements, and the kidneys were harvested and examined for histologic evaluation. Results. All three groups had similar amounts of food intake and body weight gain and exhibited fasting hyperglycemia and hyperinsulinemia. Plasma glucose levels did not differ among the three groups, but plasma insulin concentration was significantly lower in rats fed flaxseed meal than those fed either casein or soy protein concentrate. Mean plasma creatinine, creatinine clearance, and urinary urea excretion also did not differ significantly between the three groups. By contrast, urinary protein excretion was significantly lower (P<0.01) in rats fed flaxseed than in rats fed either casein or soy protein concentrate. Morphologic analysis of renal structural lesions showed that the percentage of abnormal glomeruli with mesangial expansion and the tubulointerstitial score (an index of severity of tubulointerstitial damage) were significantly reduced in rats fed flaxmeal compared to those fed casein or soy protein concentrate. Conclusion. We conclude that dietary protein substitution with flaxseed meal reduces proteinuria and glomerular and tubulointerstitial lesions in obese SHR/N-cp rats and that flaxseed meal is more effective than soy protein in reducing proteinuria and renal histologic abnormalities in this model. The reduction in proteinuria and renal injury was independent of the amount of protein intake and glycemic control. Which dietary component(s) present in flaxseed meal is (are) responsible for the renal protective effect remains to be determined. C1 George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. ARS, Phytonutrients Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. Amer Red Cross, Jerome Holland Labs, Rockville, MD USA. NIH, Bethesda, MD 20892 USA. RP George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, 2150 Penn Ave NW, Washington, DC 20037 USA. EM mvelasquez@mfa.gwu.edu NR 53 TC 21 Z9 22 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 EI 1523-1755 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2003 VL 64 IS 6 BP 2100 EP 2107 DI 10.1046/j.1523-1755.2003.00329.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 740YV UT WOS:000186431600016 PM 14633132 ER PT J AU King, BF Torres, VE Brummer, ME Chapman, AB Bae, KT Glockner, JF Arya, K Felmlee, JP Grantham, JJ Guay-Woodford, LM Bennett, WM Klahr, S Hirschman, GH Kimmel, PL Thompson, PA Miller, JP AF King, BF Torres, VE Brummer, ME Chapman, AB Bae, KT Glockner, JF Arya, K Felmlee, JP Grantham, JJ Guay-Woodford, LM Bennett, WM Klahr, S Hirschman, GH Kimmel, PL Thompson, PA Miller, JP CA CRISP TI Magnetic resonance measurements of renal blood flow as a marker of disease severity in autosomal-dominant polycystic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE autosomal-dominant polycystic kidney disease; kidney volume; cyst volume; renal blood flow; renal vascular resistance; glomerular filtration rate; magnetic resonance; Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease ID RESISTIVE INDEX; CAPILLARY ELECTROPHORESIS; VASCULAR-RESISTANCE; DOPPLER SONOGRAPHY; CONVERTING ENZYME; PRESSURE; RENIN; MR; HEMODYNAMICS; DYSFUNCTION AB Background. Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disorder characterized by renal cyst growth, early development of hypertension, and late occurrence of renal insufficiency. Despite evidence for the importance of nephroangiosclerosis in the progression of renal insufficiency in ADPKD, evaluation of renal blood flow (RBF) as a surrogate marker of disease severity has received little attention. Methods. Flow phantoms and repeat RBF measurements assessed accuracy and reproducibility. One hundred twenty-seven ADPKD subjects with creatinine clearances >70 mL/min underwent measurements of RBF, total, and cyst renal volumes, and % cyst volumes by magnetic resonance (MR) and of glomerular filtration rate (GFR). Renal vascular resistance (RVR) was calculated. MR blood flow sequences utilized a two-dimensional cine phase-contrast breath-hold pulse sequence perpendicular to the renal arteries. Flow rates were calculated utilizing FLOW software. Volumetric analysis was performed using stereology and region-based thresholding. Results. Excellent accuracy and intraobserver and interobserver reproducibility were demonstrated. Anatomic (total kidney volume, total cyst volume, and % cyst volume), hemodynamic (RBF and RVR), and functional (GFR) parameters were strongly correlated. Left polycystic kidneys were larger and had more severe disease. Regression analysis showed that age, diagnosis of hypertension, anatomic parameters and hemodynamic parameters were significant predictors of GFR. Multiple linear regression analysis identified age and hemodynamic parameters only as separate predictors of GFR. Anatomic, hemodynamic, and functional parameters discriminated between normotensive and hypertensive subjects despite antihypertensive treatments. Conclusion. Renal hemodynamic parameters measured by MR correlate with anatomic and functional indices of disease severity, are the strongest predictors of renal function, and deserve further consideration as an outcome measure in clinical trials to guide therapy in ADPKD. C1 Univ Alabama, Dept Med, Div Renal, Birmingham, AL 35294 USA. Univ Alabama, Dept Radiol, Birmingham, AL USA. Emory Univ, Sch Med, Atlanta, GA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. Mayo Fdn, Rochester, MN USA. NIDDK, NIH, KUH, Bethesda, MD USA. NW Renal Clin, Portland, OR USA. Washington Univ, St Louis, MO USA. RP Torres, VE (reprint author), Mayo Clin, Div Nephrol, 200 1st St SW, Rochester, MN 55905 USA. OI Miller, J Philip/0000-0003-4568-6846 FU NCRR NIH HHS [M01-RR00039, M01-RR00585]; NIDDK NIH HHS [DK56957] NR 42 TC 55 Z9 56 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD DEC PY 2003 VL 64 IS 6 BP 2214 EP 2221 DI 10.1046/j.1523-1755.2003.00326.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 740YV UT WOS:000186431600029 PM 14633145 ER PT J AU Chang, JH Oh, KS Moon, YS Kim, GC Park, HJ Um, KI AF Chang, JH Oh, KS Moon, YS Kim, GC Park, HJ Um, KI TI Apoptosis induced by ultraviolet radiation or actinomycin D in HeLaS3 cells SO KOREAN JOURNAL OF GENETICS LA English DT Article DE Bcl-2; caspase-2; caspase-3; apoptosis; HeLaS3 cells; DNA ladder pattern ID DNA FRAGMENTATION; POLY(ADP-RIBOSE) POLYMERASE; ADAPTIVE RESPONSE; ANTICANCER DRUGS; TRANSGENIC MICE; DEATH GENE; EXPRESSION; INDUCTION; PROTEINS; CLEAVAGE AB Ultraviolet radiation (UV) or actinomycin D (AMD) can induce apoptosis in many cancer cells. Understanding the mechanism involved in UV or AMD-induced apoptosis may improve its therapeutic efficacy. The present study has been performed to elucidate apoptosis induced by UV or AMD in HeLa S-3 cells. Three assays were employed in this study: Morphological assessments of apoptotic cells, analysis of DNA electrophoresis and western blot analysis. The number of apoptotic cells or quantitative assay of fragmented DNA in this cell line treated with UV or AMD was increased at 3 or 12 hours, respectively. DNA ladder patterns in the cells treated with UV or AMD also appeared at 3 or 12 hours, respectively. The expression of Bcl-2 and Caspase-2 decreased, and then disappeared in the cells. Precursor of Caspase-3 was degraded, and 20 kDa cleavage products were detected These results suggest that UV or AMID induce apoptosis of HeLa S3 cells via Caspase-3-dependent fashion, and this apoptosis is related to disappearance of Bcl-2 and Caspase-2. C1 Dong A Univ, Dept Biol, Pusan 604714, South Korea. NCI, DNA Repair Sect, BRL, Bethesda, MD 20892 USA. Kei Myung Univ, Coll Med, Daeku 700712, South Korea. Pusan Natl Univ, Coll Dent, Dept Oral Anat, Pusan 602739, South Korea. RP Um, KI (reprint author), Dong A Univ, Dept Biol, Pusan 604714, South Korea. NR 36 TC 2 Z9 2 U1 1 U2 1 PU GENETICS SOC KOREA PI SEOUL PA SEOUL NATL UNIV, DEPT BIOLOGY, COLL EDUCATION, SINLIMDONG SAN 56-1, KWANAKGU, SEOUL 151-742, SOUTH KOREA SN 0254-5934 J9 KOREAN J GENETIC JI Korean J. Genet. PD DEC PY 2003 VL 25 IS 4 BP 301 EP 307 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 759TZ UT WOS:000187754100003 ER PT J AU Guterman, E AF Guterman, E TI Integrating written metacognitive awareness guidance as a 'psychological tool' to improve student performance SO LEARNING AND INSTRUCTION LA English DT Article ID DISCOURSE; RECALL AB A study was designed to test the effect of using MetaCognitive Awareness Guidance (MCAG) as a vehicle for activating and engaging learners' existing prior knowledge before they begin a reading assessment task. A total of 300 pupils (aged 9-10) studying in ten 4th grade classes in four different schools in Israel participated in the research. The major assumption of the study was confirmed: increasing learners' metacognitive awareness by means of well-planned guidance, built on prior knowledge, facilitates their learning and improves outcomes on a reading assessment task. This paper focuses on the linkage between three components of learner performance, what we refer to as the 'Assessment Triangle': (1) achievement on reading assessment tasks; (2) performance on metacognitive awareness guidance; and (3) awareness of metacognitive reading strategies. The implications and the function of this revealed linkage will be discussed. Published by Elsevier Ltd. C1 Natl Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Guterman, E (reprint author), Natl Inst Child Hlth & Human Dev, 1 Rockledge Ctr,Suite 8048,6705 Rockledge Dr, Bethesda, MD 20892 USA. NR 34 TC 7 Z9 12 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-4752 J9 LEARN INSTR JI Learn Instr. PD DEC PY 2003 VL 13 IS 6 BP 633 EP 651 DI 10.1016/S0959-4752(02)00070-1 PG 19 WC Education & Educational Research; Psychology, Educational SC Education & Educational Research; Psychology GA 740EP UT WOS:000186390200004 ER PT J AU Bazinet, RP Douglas, H McMillan, EG Wilkie, BN Cunnane, SC AF Bazinet, RP Douglas, H McMillan, EG Wilkie, BN Cunnane, SC TI Intramuscular injection of antigens and adjuvant preferentially decreases 18 : 2n-6 and 18 : 3n-3 in pig neck muscle SO LIPIDS LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; HORMONE-SENSITIVE LIPASE; ADIPOSE-TISSUE; HYPERSENSITIVITY REACTIONS; ENERGY-EXPENDITURE; IMMUNE-RESPONSE; LYMPHOCYTES; METABOLISM; INFLAMMATION; ALPHA AB Linoleic (18:2n-6) and alpha-linolenic acids (18:3n-3) have many important physiological functions including immunomodulation. We tested how immunization influences the metabolism of 18:2n-6 and 18:3n-3 in the neck muscle of pigs. At 35 d old, pigs received either an intramuscular neck injection containing hen egg white lysozyme (HEWL), killed Mycobacterium tuberculosis, and Freund's complete adjuvant (immunized) or PBS (control). At 49 d old, immunized pigs received a booster injection of HEWL and Freund's incomplete adjuvant, and the control pigs received PBS into the neck. At 56 d old, all pigs received an intradermal injection of Mycobacterium bovis into the hind leg to induce a delayed-type hypersensitivity (DTH) reaction. At 57 d old, immunized pigs had a twofold increase in serum haptoglobin, a 10-fold increase in antibodies to HEWL, and the skinfold at the DTH reaction site was 10 times thicker than the controls. Both 18:2n-6 and 18:3n-3 (% composition) were approximately 25% lower in muscle TG, 40% lower in FFA, 50% lower in phospholipids, but not different in cholesteryl esters of the neck muscle of immunized pigs. The antigens in this model induce an increased response in the innate (haptoglobin), humoral (antibodies), and cellular (DTH) immune systems as well as a preferential decrease of 18:2n-6 and 18:3n-3 in the inflamed neck muscle. It appears that 18:2n-6 and 18:3n-3 are preferentially metabolized (possibly beta-oxidized) in response to antigens. C1 Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. Maple Leaf Foods Agresearch, Guelph, ON, Canada. Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. RP Bazinet, RP (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Rm 6N 202,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rbazinet@mail.nih.gov NR 40 TC 1 Z9 1 U1 0 U2 2 PU AMER OIL CHEMISTS SOC A O C S PRESS PI CHAMPAIGN PA 1608 BROADMOOR DRIVE, CHAMPAIGN, IL 61821-0489 USA SN 0024-4201 J9 LIPIDS JI Lipids PD DEC PY 2003 VL 38 IS 12 BP 1221 EP 1226 DI 10.1007/s11745-003-1182-x PG 6 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 766AM UT WOS:000188323300002 PM 14870924 ER PT J AU Thompson, RB McVeigh, ER AF Thompson, RB McVeigh, ER TI Real-time volumetric flow measurements with complex-difference MRI SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; phase-contrast; complex-difference; real-time flow ID SKELETAL-MUSCLE PERFUSION; MAGNETIC-RESONANCE; ANGIOGRAPHY AB Blood flow in large vessels can be noninvasively evaluated with phase-contrast (PC) MRI by encoding the spin velocity to the image phase. Conventional phase-difference processing of the flow-encoded image data yields velocity images. Complex-difference processing is an alternative to phase-difference methods, and has the advantage of eliminating signal from stationary spins. In this study, two acquisitions with differential flow encoding are subtracted to yield a single projection that contains signal from only those spins moving in the direction of the flow-encoding gradients. The increase in acquisition efficiency allows real-time flow imaging with a temporal window as short as two acquisition lengths (60 ms). Validation of the complex-difference method by comparison with conventional gated-segmented PC-MRI in a flow phantom yielded a correlation of r > 0.99. Peak arterial flow rates in the popliteal artery and desending aorta measured in vivo with the complex-difference method were 0.92 +/- 0.06 of the values measured with conventional PC imaging. Real-time in vivo volumetric flow imaging of transient flow events is also presented. Published 2003 Wiley-Liss, Inc.(dagger). C1 NIH, Lab Cardiac Energet, Bethesda, MD 20892 USA. RP Thompson, RB (reprint author), NIH, Lab Cardiac Energet, 10 Ctr Dr,Bldg 10,Room B1D 416, Bethesda, MD 20892 USA. RI Thompson, Richard/E-9821-2011 FU Intramural NIH HHS [Z01 HL004608-08] NR 12 TC 21 Z9 21 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD DEC PY 2003 VL 50 IS 6 BP 1248 EP 1255 DI 10.1002/mrm.10637 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 750LE UT WOS:000186991500016 PM 14648573 ER PT J AU Ward, K Schussheim, AE Balaban, RS AF Ward, K Schussheim, AE Balaban, RS TI Contribution of mitochondria to cardiac muscle water macromolecule proton magnetization transfer SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE T-2; T-1; mitochondria matrix; ischemia; MTC ID TRANSFER CONTRAST; RELAXATION; HEART; MYOCARDIUM; TISSUE; DOGS; MRI AB The contribution of mitochondria to water-macromolecule proton magnetization transfer (MT) was evaluated in porcine heart tissue. An examination of isolated mitochondria in suspension, at the same concentration as found in heart tissue, revealed MT effects very similar in magnitude and bandwidth to those in intact heart tissue. Disruption of the gross structure of the mitochondria by freeze-thawing or with detergent resulted in only similar to25% decreases in MT, which suggests that the structure of the mitochondria is not critical for these effects. The current data indicate that mitochondria macromolecules contribute significantly to MT in the intact heart. Published 2003 Wiley-Liss, Inc.(dagger). C1 NHLBI, Cardiac Energet Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20817 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, Dept Hlth & Human Serv, NIH, Bldg 10,Rm B1D161, Bethesda, MD 20817 USA. RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 20 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD DEC PY 2003 VL 50 IS 6 BP 1312 EP 1316 DI 10.1002/mrm.10625 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 750LE UT WOS:000186991500024 PM 14648581 ER PT J AU Steinbach, WJ Mitchell, TG Schell, WA Espinel-Ingroff, A Coico, RF Walsh, TJ Perfect, JR AF Steinbach, WJ Mitchell, TG Schell, WA Espinel-Ingroff, A Coico, RF Walsh, TJ Perfect, JR TI Status of medical mycology education SO MEDICAL MYCOLOGY LA English DT Review DE mycology education; mycology teaching ID FUNGAL-INFECTIONS; UNITED-STATES; EPIDEMIOLOGY; COUNTRIES; DISEASES; TRENDS AB The number of immunocompromised patients and subsequent invasive fungal infections continues to rise. However, the education of future medical mycologists to engage this growing problem is diminishing. While there are an increasing number of publications and grants awarded in mycology, the time and detail devoted to teaching medical mycology in United States medical schools are inadequate. Here we review the history in medical mycology education and the current educational opportunities. To accurately gauge contemporary teaching we also conducted a prospective survey of microbiology and immunology departmental chairpersons in United States medical schools to determine the amount and content of contemporary education in medical mycology. C1 Duke Univ, Med Ctr, Div Pediat Infect Dis, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Div Infect Dis & Int Hlth, Durham, NC 27710 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Med, Div Infect Dis, Richmond, VA 23284 USA. CUNY, Sch Med, Dept Microbiol & Immunol, New York, NY USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Steinbach, WJ (reprint author), Duke Univ, Med Ctr, Div Pediat Infect Dis, Dept Pediat, Box 3499, Durham, NC 27710 USA. EM stein022@mc.duke.edu RI Mitchell, Thomas/A-2356-2008 NR 20 TC 7 Z9 7 U1 2 U2 3 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD DEC PY 2003 VL 41 IS 6 BP 457 EP 467 DI 10.1080/13693780310001631322 PG 11 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 762ZU UT WOS:000188043500001 PM 14725319 ER PT J AU Fraass, BA Smathers, J Deye, J AF Fraass, BA Smathers, J Deye, J TI Summary and recommendations of a National Cancer Institute workshop on issues limiting the clinical use of Monte Carlo dose calculation algorithms for megavoltage external beam radiation therapy SO MEDICAL PHYSICS LA English DT Article; Proceedings Paper CT Workshop on Issues Limiting the Clinical Use of Monte Carlo Dose Calculation Algorithms CY OCT, 2001 CL GATLINBURG, TN DE Monte Carlo; clinical use; verification; recommendations ID PHOTON-BEAM; ELECTRON-TRANSPORT; QUALITY ASSURANCE; SOURCE MODEL; LUNG-CANCER; PHASE-SPACE; RADIOTHERAPY; CODE; DISTRIBUTIONS; VERIFICATION AB Due to the significant interest in Monte Carlo dose calculations for external beam megavoltage radiation therapy from both the research and commercial communities, a workshop was held in October 2001 to assess the status of this computational method with regard to use for clinical treatment planning.,The Radiation Research Program of the National Cancer Institute, in conjunction with the Nuclear Data and Analysis Group at the Oak Ridge National Laboratory, gathered a group of experts in clinical radiation therapy treatment planning and Monte Carlo dose calculations, and examined issues involved in clinical implementation of Monte Carlo dose calculation methods in clinical radiotherapy. The workshop examined the current status of Monte Carlo algorithms, the rationale for using Monte Carlo, algorithmic concerns, clinical issues, and verification methodologies. Based on these discussions, the workshop developed recommendations for future NCI-funded research and development efforts. This paper briefly summarizes the issues presented at the workshop and the recommendations developed by the group. (C) 2003 American Association of Physicists in Medicine. C1 Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Univ Calif Los Angeles, Dept Radiat Oncol, Los Angeles, CA 90024 USA. NCI, Radiat Res Program, Bethesda, MD 20892 USA. RP Fraass, BA (reprint author), Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. EM deyej@mail.nih.gov NR 70 TC 32 Z9 36 U1 1 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD DEC PY 2003 VL 30 IS 12 BP 3206 EP 3216 DI 10.1118/1.1626990 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 756GE UT WOS:000187456800018 PM 14713087 ER PT J AU Saito, S Matoba, R Kato, K AF Saito, S Matoba, R Kato, K TI Adapter-tagged competitive PCR (ATAC-PCR) - a high-throughput quantitative PCR method for microarray validation SO METHODS LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Neuroscience CY NOV 02-07, 2002 CL ORLANDO, FLORIDA SP Soc Neurosci DE adapter-tagged competitive PCR; gene expression profiling; laser capture microdissection ID GENE-EXPRESSION; MOUSE CEREBELLUM; PATTERNS AB Adapter-tagged competitive PCR (ATAC-PCR) is an advanced version of competitive quantitative PCR that is characterized by the addition of unique adapters to cDNA derived from each sample RNA. Using multiple adapters, we can accurately measure the relative expression ratios of many samples, with a calibration curve obtained from internal standards included in the same reaction. ATAC-PCR can identify differences in gene expression as small as twofold, even from very small amounts of sample RNA. This technique is suitable for confirming results obtained with cDNA microarrays or differential display, and it can process more than a thousand of genes per day when used in conjunction with a capillary DNA sequencer. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Nara Inst Sci & Technol, Taisho Lab Funct Genom, Nara 6300101, Japan. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Kato, K (reprint author), Nara Inst Sci & Technol, Taisho Lab Funct Genom, 8916-5 Takayama, Nara 6300101, Japan. NR 13 TC 6 Z9 6 U1 1 U2 2 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 DEC PY 2003 VL 31 IS 4 BP 326 EP 331 DI 10.1016/S1046-2023(03)00160-9 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 742ZK UT WOS:000186547800009 PM 14597317 ER PT J AU Inoue, K Sobhany, M Transue, TR Oguma, K Pedersen, LC Negishi, M AF Inoue, K Sobhany, M Transue, TR Oguma, K Pedersen, LC Negishi, M TI Structural analysis by X-ray crystallography and calorimetry of a haemagglutinin component (HA1) of the progenitor toxin from Clostridium botulinum SO MICROBIOLOGY-SGM LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; TRYPSIN-INHIBITOR KUNITZ; RICIN B-CHAIN; CRYSTAL-STRUCTURE; ONE SUBCOMPONENT; RESOLUTION; BINDING; INTERLEUKIN-1-BETA; NEUROTOXINS; SEQUENCE AB Botulism food poisoning is caused primarily by ingestion of the Clostridium botulinum neurotoxin (BoNT). The 1300 amino acid BoNT forms a progenitor toxin (PTX) that, when associated with a number of other proteins, increases its oral toxicity by protecting it from the low pH of the stomach and from intestinal proteases. One of these associated proteins, HA1, has also been suggested to be involved with internalization of the toxin into the bloodstream by binding to oligosaccharides lining the intestine. Here is reported the crystal structure of HA1 from type C Clostridium botulinum at a resolution of 1-7 Angstrom. The protein consists of two beta-trefoil domains and bears structural similarities to the lectin B-chain from the deadly plant toxin ricin. Based on structural comparison to the ricin B-chain lactose-binding sites, residues of type A HA1 were selected and mutated. The D263A and N285A mutants lost the ability to bind carbohydrates containing galactose moieties, implicating these residues in carbohydrate binding. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Okayama Univ, Sch Med, Dept Bacteriol, Okayama 7008558, Japan. RP Pedersen, LC (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 50 Z9 53 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 DEC PY 2003 VL 149 BP 3361 EP 3370 DI 10.1099/mic.0.26586-0 PN 12 PG 10 WC Microbiology SC Microbiology GA 754KY UT WOS:000187317000005 PM 14663070 ER PT J AU Abati, A Yarchoan, R Sorbara, L Filie, AC Little, R Wilson, W Raffeld, M Bryant-Greenwood, P AF Abati, A Yarchoan, R Sorbara, L Filie, AC Little, R Wilson, W Raffeld, M Bryant-Greenwood, P TI Correspondence re: Bryant-Greenwood P, Sorbara L, Filie AC, Little R, Yarchoan R, Wilson W, Raffeld M, Abati A infection of mesothelial cells with human herpes virus 8 in human immunodeficiency virus-infected patients with kaposi's sarcoma, Castleman's disease, and recurrent pleural effusions - In reply SO MODERN PATHOLOGY LA English DT Letter ID MALIGNANT MESOTHELIOMA C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD DEC PY 2003 VL 16 IS 12 BP 1300 EP 1302 PG 3 WC Pathology SC Pathology GA 758VR UT WOS:000187672300016 ER PT J AU Yan, QS Cho, E Lockett, S Muegge, K AF Yan, QS Cho, E Lockett, S Muegge, K TI Association of Lsh, a regulator of DNA methylation, with pericentromeric heterochromatin is dependent on intact heterochromatin SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HISTONE H3 METHYLTRANSFERASE; DE-NOVO METHYLATION; SNF2 FAMILY-MEMBER; NUCLEAR-MATRIX; LYSINE-9 METHYLATION; CHROMATIN; GENE; PROTEIN; COMPLEX; REPLICATION AB The eukaryotic genome is packaged into distinct domains of transcriptionally active euchromatin and silent heterochromatin. A hallmark of mammalian heterochromatin is CpG methylation. Lsh, a member of the SNF2 family, is a major regulator of DNA methylation in mice and thus crucial for normal heterochromatin formation. In order to define the molecular function of Lsh, we examined its cellular localization and its association with chromatin. Our studies demonstrate that Lsh is an exclusively nuclear protein, and we define a nuclear localization domain within the N-terminal portion of Lsh. Lsh strongly associates with chromatin and requires the internal and C-terminal regions for this interaction. Lsh accumulates at pericentromeric heterochromatin, suggesting a direct role for Lsh in the methylation of centromeric DNA sequences and the formation of heterochromatin. In search of a signal that is responsible for Lsh recruitment to pericentromeric heterochromatin, we found that histone tail modifications were critical. Prolonged treatment with histone deacetylase inhibitors has been reported to disrupt higher-order heterochromatin organization, and this was accompanied by dissociation of Lsh from pericentromeric heterochromatin. These results are consistent with a model in which Lsh is recruited by intact heterochromatin structure and then assists in maintaining heterochromatin organization by establishing CpG methylation patterns. C1 NCI, SAIC, Mol Immunoregulat Lab, Basic Res Program, Frederick, MD 21702 USA. NCI, SAIC, Image Anal Lab, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, SAIC, Mol Immunoregulat Lab, Basic Res Program, Bldg 469,Rm 243, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 46 TC 44 Z9 46 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 23 BP 8416 EP 8428 DI 10.1128/MCB.23.23.8416-8428.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 744FY UT WOS:000186618300002 PM 14612388 ER PT J AU Kwon, SY Badenhorst, P Martin-Romero, FJ Carlson, BA Paterson, BM Gladyshev, VN Lee, BJ Hatfield, DL AF Kwon, SY Badenhorst, P Martin-Romero, FJ Carlson, BA Paterson, BM Gladyshev, VN Lee, BJ Hatfield, DL TI The Drosophila selenoprotein BthD is required for survival and has a role in salivary gland development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DOUBLE-STRANDED-RNA; SELENOPHOSPHATE SYNTHETASE; INTERFERENCE; GENE; EXPRESSION; IDENTIFICATION; MELANOGASTER; EUKARYOTES; PHENOTYPES; METABOLISM AB Selenium is implicated in many diseases, including cancer, but its function at the molecular level is poorly understood. BthD is one of three selenoproteins recently identified in Drosophila. To elucidate the function of BthD and the role of selenoproteins in cellular metabolism and health, we analyzed the developmental expression profile of this protein and used inducible RNA interference (RNAi) to ablate function. We find that BthD is dynamically expressed during Drosophila development. bthD mRNA and protein are abundant in the ovaries of female flies and are deposited into the developing oocyte. Maternally contributed protein and RNA persist during early embryonic development but decay by the onset of gastrulation. At later stages of embryogenesis, BthD is expressed highly in the developing salivary gland. We generated transgenic fly lines carrying an inducible gene-silencing construct, in which an inverted bthD genomic-cDNA hybrid is under the control of the Drosophila Gal4 upstream activation sequence system. Duplex RNAi induced from this construct targeted BthD mRNA for destruction and reduced BthD protein levels. We found that loss of BthD compromised salivary gland morphogenesis and reduced animal viability. C1 Seoul Natl Univ, Sch Biol Sci, Mol Genet Lab, Seoul 151742, South Korea. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Sch Biol Sci, Mol Genet Lab, Seoul 151742, South Korea. RI Gladyshev, Vadim/A-9894-2013; Kwon, So Yeon/M-5625-2014; OI Kwon, So Yeon/0000-0002-8490-9101; Badenhorst, Paul/0000-0002-2542-0250; Martin-Romero, Francisco Javier/0000-0001-6796-7396 FU NIGMS NIH HHS [R01 GM061603, GM061603] NR 39 TC 10 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 23 BP 8495 EP 8504 DI 10.1128/MCB.23.23.8495-8504.2003 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 744FY UT WOS:000186618300009 PM 14612395 ER PT J AU von Kobbe, C Harrigan, JA May, A Opresko, PL Dawut, L Cheng, WH Bohr, VA AF von Kobbe, C Harrigan, JA May, A Opresko, PL Dawut, L Cheng, WH Bohr, VA TI Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LYMPHOBLASTOID CELL-LINES; PREMATURE AGING SYNDROMES; BASE EXCISION-REPAIR; SYNDROME PROTEIN; S-PHASE; FUNCTIONAL INTERACTION; INDUCED APOPTOSIS; HUMAN-LYMPHOCYTES; MAMMALIAN-CELLS; SYNDROME GENE AB A defect in the Werner syndrome protein (WRN) leads to the premature aging disease Werner syndrome (WS). Hallmark features of cells derived from WS patients include genomic instability and hypersensitivity to certain DNA-damaging agents. WRN contains a highly conserved region, the RecQ conserved domain, that plays a central role in protein interactions. We searched for proteins that bound to this region, and the most prominent direct interaction was with poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme that protects the genome by responding to DNA damage and facilitating DNA repair. In pursuit of a functional interaction between WRN and PARP-1, we found that WS cells are deficient in the poly(ADP-ribosyl)ation pathway after they are treated with the DNA-damaging agents H2O2 and methyll methanesulfonate. After cellular stress, PARP-1 itself becomes activated, but the poly (ADP-ribosyl) ation of other cellular proteins is severely impaired in WS cells. Overexpression of the PARP-1 binding domain of WRN strongly inhibits the poly(ADP-ribosyl)ation activity in H2O2-treated control cell lines. These results indicate that the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Opresko, Patricia/0000-0002-6470-2189 NR 52 TC 104 Z9 110 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 23 BP 8601 EP 8613 DI 10.1128/MCB.23.23.8601-8613.2003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 744FY UT WOS:000186618300018 PM 14612404 ER PT J AU Yoon, S Qiu, HF Swanson, MJ Hinnebusch, AG AF Yoon, S Qiu, HF Swanson, MJ Hinnebusch, AG TI Recruitment of SWI/SNF by Gcn4p does not require Snf2p or Gcn5p but depends strongly on SWI/SNF integrity, SRB mediator, and SAGA SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMATIN-REMODELING COMPLEX; POLYMERASE-II HOLOENZYME; SACCHAROMYCES-CEREVISIAE; IN-VIVO; HISTONE ACETYLTRANSFERASE; TRANSCRIPTIONAL ACTIVATION; MULTISUBUNIT COMPLEX; PROMOTER NUCLEOSOMES; COACTIVATOR COMPLEX; ESCHERICHIA-COLI AB The nucleosome remodeling complex SWI/SNF is a coactivator for yeast transcriptional activator Gcn4p. We provide strong evidence that Gcn4p recruits the entire SWI/SNF complex to its target genes ARG1 and SNZ1 but that SWI/SNF is dispensable for Gcn4p binding to these promoters. It was shown previously that Snf2p/Swi2p, Snf5p, and Swi1p interact directly with Gcn4p in vitro. However, we found that Snf2p is not required for recruitment of SWI/SNF by Gcn4p nor can Snf2p be recruited independently of other SWI/SNF subunits in vivo. Snf5p was not recruited as an isolated subunit but was required with Snf6p and Swi3p for optimal recruitment of other SWI/SNF subunits. The results suggest that Snf2p, Snf5p, and Swi1p are recruited only as subunits of intact SWI/SNF, a model consistent with the idea that Gcn4p makes multiple contacts with SWI/SNF in vivo. Interestingly, Swp73p is necessary for efficient SWI/SNF recruitment at SNZ1 but not at ARG1, indicating distinct subunit requirements for SWI/SNF recruitment at different genes. Optimal recruitment of SWI/SNF by Gcn4p also requires specific subunits of SRB mediator (Gal11p, Med2p, and Rox3p) and SAGA (Ada1p and Ada5p) but is independent of the histone acetyltransferase in SAGA, Gcn5p. We suggest that SWI/SNF recruitment is enhanced by cooperative interactions with subunits of SRB mediator and SAGA recruited by Gcn4p to the same promoter but is insensitive to histone H3 acetylation by Gcn5p. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6A,Room B1A-13, Bethesda, MD 20892 USA. NR 58 TC 39 Z9 41 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 23 BP 8829 EP 8845 DI 10.1128/MCB.23.23.8829-8845.2003 PG 17 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 744FY UT WOS:000186618300036 PM 14612422 ER PT J AU Tanimoto, K Sugiura, A Omori, A Felsenfeld, G Engel, JD Fukamizu, A AF Tanimoto, K Sugiura, A Omori, A Felsenfeld, G Engel, JD Fukamizu, A TI Human beta-globin locus control region HS5 contains CTCF- and developmental stage-dependent enhancer-blocking activity in erythroid cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSGENIC MICE; INTERGENIC TRANSCRIPTION; HYPERSENSITIVE SITES; GENE-EXPRESSION; RECEPTOR GENES; INSULATOR; MOUSE; POSITION; ELEMENTS; ORIENTATION AB The human beta-globin locus contains five developmentally regulated beta-type globin genes. All five genes depend on the locus control region (LCR), located at the 5' end of the locus, for abundant globin gene transcription. The LCR is composed of five DNase I-hypersensitive sites (HSs), at least a subset of which appear to cooperate to form a holocomplex in activating genes within the locus. We previously tested the requirement for proper LCR polarity by inverting it in human beta-globin yeast artificial chromosome transgenic mice and observed reduced expression of all the beta-type globin genes regardless of developmental stage. This phenotype clearly demonstrated an orientation-dependent activity of the LCR, although the mechanistic basis for the observed activity was obscure. Here, we describe genetic evidence demonstrating that human HS5 includes enhancer-blocking (insulator) activity that is both CTCF and developmental stage dependent. Curiously, we also observed an attenuating activity in HS5 that was specific to the epsilon-globin gene at the primitive stage and was independent of the HS5 CTCF binding site. These observations demonstrate that the phenotype observed in the LCR-inverted locus was in part attributable to placing the HS5 insulator between the LCR HS enhancers (HS1 to HS4) and the promoter of the beta-globin gene. C1 Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Inst Appl Biochem, Tsukuba, Ibaraki 3058577, Japan. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. RP Tanimoto, K (reprint author), Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Inst Appl Biochem, Tennoudai 1-1-1, Tsukuba, Ibaraki 3058577, Japan. RI Fukamizu, Akiyoshi/J-5350-2012; Tanimoto, Keiji/B-2600-2014 OI Fukamizu, Akiyoshi/0000-0002-8786-6020; FU NHLBI NIH HHS [HL 24415, R01 HL024415] NR 38 TC 42 Z9 43 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 24 BP 8946 EP 8952 DI 10.1128/MCB.23.24.8946-8952.2003 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 751ET UT WOS:000187040400003 PM 14645507 ER PT J AU Zhao, M Gold, L Dorward, H Liang, LF Hoodbhoy, T Boja, ES Fales, HM Dean, J AF Zhao, M Gold, L Dorward, H Liang, LF Hoodbhoy, T Boja, ES Fales, HM Dean, J TI Mutation of a conserved hydrophobic patch prevents incorporation of ZP3 into the zona pellucida surrounding mouse eggs SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SPERM RECEPTOR ACTIVITY; FURIN CLEAVAGE-SITE; STRUCTURAL-CHARACTERIZATION; CELL-SURFACE; FEMALE MICE; GLYCOPROTEINS; PROTEINS; SECRETION; OOCYTES; FERTILITY AB Three glycoproteins (ZP1, ZP2, and ZP3) are synthesized in growing mouse oocytes and secreted to form an extracellular zona pellucida that mediates sperm binding and fertilization. Each has a signal peptide to direct it into a secretory pathway, a "zona" domain implicated in matrix polymerization and a transmembrane domain from which the ectodomain must be released. Using confocal microscopy and enhanced green fluorescent protein (EGFP), the intracellular trafficking of ZP3 was observed in growing mouse oocytes. Replacement of the zona domain with EGFP did not prevent secretion of ZP3, suggesting the presence of trafficking signals and a cleavage site in the carboxyl terminus. Analysis of linker-scanning mutations of a ZP3-EGFP fusion protein in transient assays and in transgenic mice identified an eight-amino-acid hydrophobic region required for secretion and incorporation into the zona pellucida. The hydrophobic patch is conserved among mouse zona proteins and lies between a potential proprotein convertase (furin) cleavage site and the transmembrane domain. The cleavage site that releases the ectodomain from the transmembrane domain was defined by mass spectrometry of native zonae pellucidae and lies N-terminal to a proprotein convertase site that is distinct from the hydrophobic patch. C1 NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bldg 50,Rm 3134, Bethesda, MD 20892 USA. NR 42 TC 19 Z9 21 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 24 BP 8982 EP 8991 DI 10.1128/MCB.23.23.8982-8991.2003 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 751ET UT WOS:000187040400007 PM 14645511 ER PT J AU McConnell, MJ Chevallier, N Berkofsky-Fessler, W Giltnane, JM Malani, RB Staudt, LM Licht, JD AF McConnell, MJ Chevallier, N Berkofsky-Fessler, W Giltnane, JM Malani, RB Staudt, LM Licht, JD TI Growth suppression by acute promyelocytic leukemia-associated protein PLZF is mediated by repression of c-myc expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ZINC-FINGER PROTEIN; NUCLEASE-HYPERSENSITIVE ELEMENT; ONCOGENIC TRANSCRIPTION FACTOR; ACID-INDUCED DIFFERENTIATION; HUMAN EMBRYONAL CARCINOMA; ACUTE MYELOID-LEUKEMIA; RETINOIC ACID; GENE-EXPRESSION; CELL-GROWTH; TARGET GENES AB The transcriptional repressor PLZF was identified by its translocation with retinoic acid receptor alpha in t(11;17) acute promyelocytic leukemia (APL). Ectopic expression of PLZF leads to cell cycle arrest and growth suppression, while disruption of normal PLZF function is implicated in the development of APL. To clarify the function of PLZF in cell growth and survival, we used an inducible PLZF cell line in a microarray analysis to identify the target genes repressed by PLZF. One prominent gene identified was c-myc. The array analysis demonstrated that repression of c-myc by PLZF led to a reduction in c-myc-activated transcripts and an increase in c-myc-repressed transcripts. Regulation of c-myc by PLZF was shown to be both direct and reversible. An interaction between PLZF and the c-myc promoter could be detected both in vitro and in vivo. PLZF repressed the wild-type c-myc promoter in a reporter assay, dependent on the integrity of the binding site identified in vitro. PLZF binding in vivo was coincident with a decrease in RNA polymerase occupation of the c-myc promoter, indicating that repression occurred via a reduction in the initiation of transcription. Finally, expression of c-myc reversed the cell cycle arrest induced by PLZF. These data suggest that PLZF expression maintains a cell in a quiescent state by repressing c-myc expression and preventing cell cycle progression. Loss of this repression through the translocation that occurs in t(11;17) would have serious consequences for cell growth control. C1 Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, New York, NY 10029 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Licht, JD (reprint author), Mt Sinai Sch Med, Dept Med, Div Hematol Oncol, Box 1130,1 Gustave L Levy Pl, New York, NY 10029 USA. RI Giltnane, Jennifer/D-2584-2013 FU NCI NIH HHS [CA 59936, R01 CA059936] NR 80 TC 90 Z9 91 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC PY 2003 VL 23 IS 24 BP 9375 EP 9388 DI 10.1128/MCB.23.24.9375-9388.2003 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 751ET UT WOS:000187040400041 PM 14645547 ER PT J AU Hongpaisan, J Winters, CA Andrews, SB AF Hongpaisan, J Winters, CA Andrews, SB TI Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID GENE-EXPRESSION; SYMPATHETIC NEURONS; TRANSCRIPTION FACTORS; PROTEIN PHOSPHATASES; SYNAPTIC PLASTICITY; SIGNALING PATHWAYS; CA ACCUMULATION; KINASE-IV; CALMODULIN; DEPHOSPHORYLATION AB We report evidence that mitochondrially produced superoxide (O-2(-)) is involved in signaling in hippocampal neurons by examining the relationship between strong but physiological increases in cytosolic free Ca2+, mitochondrial calcium accumulation, O-2(-) production, and CREB phosphorylation. Strong depolarization-induced Ca2+ entry through NMDA or L-type Ca2+ channels evoked large Ca2+ transients, a sustained increase in O-2(-), and a large rise in nuclear CaM and pCREB. Under these conditions, inhibition of mitochondrial Ca2+ uptake and consequent O-2(-) production suppressed Ca2+ entry-induced pCREB elevation, indicating that O-2(-) produced by mitochondria supports CREB phosphorylation. Similarly, inhibiting mitochondrial respiration blocked O-2 production and also depressed the elevation of pCREB. Blocking calcineurin reversed this depression. We conclude that strong Ca2+ entry promotes mitochondrial calcium accumulation and the subsequent enhancement of mitochondrial O-2(-) production, which in turn prolongs the lifetime of pCREB by suppressing calcineurin-dependent pCREB dephosphorylation. (C) 2003 Elsevier Inc. All rights reserved. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Andrews, SB (reprint author), NINDS, Neurobiol Lab, NIH, 36-2A-21,36 Convent Dr, Bethesda, MD 20892 USA. NR 53 TC 33 Z9 34 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD DEC PY 2003 VL 24 IS 4 BP 1103 EP 1115 DI 10.1016/j.mcn.2003.09.003 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 756GY UT WOS:000187458500020 PM 14697672 ER PT J AU Neuhuber, B Daniels, MP AF Neuhuber, B Daniels, MP TI Targeting of recombinant agrin to axonal growth cones SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCAN; CULTURED HIPPOCAMPAL-NEURONS; EXTRACELLULAR-MATRIX; IN-VITRO; SYNAPSE FORMATION; BASAL LAMINA; NEUROMUSCULAR-JUNCTION; MEMBRANE-PROTEINS; CORTICAL-NEURONS; TERMINAL DOMAIN AB Targeting of proteins to specific subcellular locations within pre- and postsynaptic neurons is essential for synapse formation. The heparan sulfate proteoglycan agrin orchestrates postsynaptic differentiation of the neuromuscular junction and may be involved in synaptic development and signaling in the central nervous system (CNS). Agrin is expressed as transmembrane and secretory isoforms with distinct N-termini. We examined the distribution of recombinant agrin in cultured motor and hippocampal neurons by transfection with agrin-GFP constructs. Immunostaining revealed a vesicular transport compartment within all neurites. Plasma membrane insertion and secretion of recombinant agrin were targeted to axonal growth cones of motor neurons; transmembrane agrin-GFP was targeted predominantly to axons and axonal growth cones in hippocampal neurons. We used agrin deletion mutants to show that axonal targeting of agrin depends on multiple domains that function in an additive fashion, including the very N-terminal portions and the C-terminal half of the molecule. (C) 2003 Elsevier Inc. All rights reserved. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Daniels, MP (reprint author), NHLBI, Cell Biol Lab, NIH, 50 S Dr MSC 8017, Bethesda, MD 20892 USA. FU NICHD NIH HHS [N01-HD-7-3263] NR 64 TC 10 Z9 10 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD DEC PY 2003 VL 24 IS 4 BP 1180 EP 1196 DI 10.1016/j.mcn.2003.08.008 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 756GY UT WOS:000187458500025 PM 14697677 ER PT J AU Hose, CD Hollingshead, M Sausville, EA Monks, A AF Hose, CD Hollingshead, M Sausville, EA Monks, A TI Induction of CYP1A1 in tumor cells by the antitumor agent 2-[4-amino-3-methylphenyl]-5-fluoro-benzothiazole: A potential surrogate marker for patient sensitivity SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID FINE-NEEDLE-ASPIRATION; BREAST-CANCER CELLS; IN-VITRO; 2-(4-AMINOPHENYL)BENZOTHIAZOLES; QUANTIFICATION; INHIBITION; CARCINOMA; COMPARE; GROWTH; LINES AB A candidate antitumor agent, 2-(4-amino-3-methylphenyl)5-fluoro-benzothiazole (5F-203), like its non-fluorinated parent compound (DF-203), has a unique cytotoxicity pattern in the National Cancer Institute in vitro anticancer drug screen. These compounds show selective toxicity for a subset of cell types including estrogen receptor positive breast cancer and certain renal and ovarian cancer cell lines. Metabolic activation of these benzothiazoles seems to be mediated through the CYP1 family of cytochrome P450s. In an effort to characterize the involvement of CYP1A1 and CYP1B1 in the unique toxicity response of 5F-203, constitutive and 5F-203-induced gene expression patterns were measured in 60 cell lines of the National Cancer Institute drug screen using TaqMan real-time PCR. The patterns of CYP1A1 and CYP1B1 gene expression in the 60 cell lines were correlated with the toxicity pattern of 5F-203 and DF-203. There was significant correlation between drug sensitivity and induced CYP1A1 (R = 0.752, P < 0.001), but not constitutive CYP1A1 mRNA expression. CYP1A1 protein expression was found to mirror the corresponding gene expression, indicating that gene expression changes were concordant with function. Treatment of sensitive cell lines with 10 muM resveratrol, an inhibitor of CYP1A1 induction, in combination with either 1 or 10 muM 5F-203 showed an ablation of the observed CYP1A1, but not CYP1B1 mRNA induction in parallel with a decreased sensitivity to 5F-203. Fine needle aspirates were obtained from a variety of human tumor xenografts, and treated ex vivo with 1 muM 5F-203 for 24 h. In these samples, induction of CYP1A1 by 5F-203 correlated with in vitro sensitivity (R = 0.711, P < 0.05), and corresponded to in vivo sensitivity in human tumor xenografts. These data are concordant with the idea that toxicity of 5F203 requires activation by CYP1A1, and therefore induction of CYP1A1 mRNA in response to 5F-203 treatments ex vivo may provide a possible surrogate marker for determination of drug-sensitive tumors in patients. C1 SAIC Frederick Inc, STB Lab Funct Genom, Natl Canc Inst, Dev Therapeut Program, Frederick, MD 21702 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Monks, A (reprint author), SAIC Frederick Inc, STB Lab Funct Genom, Natl Canc Inst, Dev Therapeut Program, Bldg 432-230,POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 21 TC 34 Z9 35 U1 2 U2 6 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 DEC PY 2003 VL 2 IS 12 BP 1265 EP 1272 PG 8 WC Oncology SC Oncology GA 759PW UT WOS:000187746900002 PM 14707267 ER PT J AU Dhar, A Brindley, JM Stark, C Citro, ML Keefer, LK Colburn, NH AF Dhar, A Brindley, JM Stark, C Citro, ML Keefer, LK Colburn, NH TI Nitric oxide does not mediate but inhibits transformation and tumor phenotype SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MOUSE EPIDERMAL-CELLS; NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; NEOPLASTIC TRANSFORMATION; SKIN CARCINOGENESIS; SYNTHASE GENE; JB6 CELLS; ANCHORAGE INDEPENDENCE; AP-1 TRANSACTIVATION AB Although inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are implicated in tumor pathology, their role in the early stages of carcinogenesis is not well defined. Tumor necrosis factor alpha (TNFot) induces NOS and NO production in transformation-sensitive 1136 P+, but not in transformation-resistant JB6 P-, mouse epidermal cells. We tested the hypothesis that NOS, by generating NO and reactive nitrogen species, mediates tumor promoter-induced transformation. Specific [N-[3(aminomethyl)benzyllacetamidine (1400W)] and non-specific (N-omega-methyl-L-arginine) NOS inhibitors significantly reduced TNFalpha-induced NO production in P+ cells but both NOS inhibitors enhanced TNFalpha-induced anchorage-independent transformation, thus ruling out a mediator role and suggesting an inhibitor role for NO. Independent support for an inhibitor role came from the observation that the NO donor [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NO)] inhibited TNFalpha- and 12-0-tetradecanoylphorbol-13-acetate-induced transformation. DETA/NO treatment also suppressed tumor phenotype in tumorigenic JB6 RT101 (Tx) cells. Higher concentrations of DETA/NO induced apoptosis. The transformation inhibitory effect of lower DETA/NO concentrations may be attributable in part to inhibition by NO of NF-kappaB-dependent but not of AP-1-dependent transcription. In conclusion: (a) induction of NOS and NO production does not mediate but actually prevents tumor promotion; (b) NOS inhibitors enhance the transformation response, and therefore appear not to be appropriate as chemoprevention agents; and (c) NO has both chemopreventive and tumoricidal effects, suggesting promise in cancer chemoprevention and therapy. C1 NCI, Gene Regulat Sect, Basic Res Lab, Frederick, MD 21702 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAID Frederick, Basic Res Program, Frederick, MD USA. RP Dhar, A (reprint author), NCI, Gene Regulat Sect, Basic Res Lab, Bldg 567,Room 180, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 58 TC 38 Z9 38 U1 0 U2 0 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 DEC PY 2003 VL 2 IS 12 BP 1285 EP 1293 PG 9 WC Oncology SC Oncology GA 759PW UT WOS:000187746900004 PM 14707269 ER PT J AU Hu, JJ Liu, J Ghirlando, R Saltiel, AR Hubbard, SR AF Hu, JJ Liu, J Ghirlando, R Saltiel, AR Hubbard, SR TI Structural basis for recruitment of the adaptor protein APS to the activated insulin receptor SO MOLECULAR CELL LA English DT Article ID SRC HOMOLOGY-2 DOMAIN; AFFINITY PHOSPHOTYROSYL PEPTIDE; SH2 DOMAIN; TYROSINE KINASE; C-CBL; PLECKSTRIN HOMOLOGY; GLUT4 TRANSLOCATION; SUBSTRATE; PH; BINDING AB The adaptor protein APS is a substrate of the insulin receptor and couples receptor activation with phosphorylation of Cbl to facilitate glucose uptake. The interaction with the activated insulin receptor is mediated by the Src homology 2 (SH2) domain of APS. Here, we present the crystal structure of the APS SH2 domain in complex with the phosphorylated tyrosine kinase domain of the insulin receptor. The structure reveals a novel dimeric configuration of the APS SH2 domain, wherein the C-terminal half of each protomer is structurally divergent from conventional, monomeric SH2 domains. The APS SH2 dimer engages two kinase molecules, with pTyr-1 158 of the kinase activation loop bound in the canonical phosphotyrosine binding pocket of the SH2 domain and a second phosphotyrosine, pTyr-1162, coordinated by two lysine residues in beta strand D. This structure provides a molecular visualization of one of the initial downstream recruitment events following insulin activation of its dimeric receptor. C1 NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. Univ Michigan, Ctr Med, Inst Life Sci, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Med, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Med, Dept Physiol, Ann Arbor, MI 48109 USA. NIDDKD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hubbard, SR (reprint author), NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. RI Ghirlando, Rodolfo/A-8880-2009; Hu, Junjie/F-9713-2013; OI Saltiel, Alan/0000-0002-9726-9828 FU NIDDK NIH HHS [DK060591] NR 38 TC 76 Z9 82 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD DEC PY 2003 VL 12 IS 6 BP 1379 EP 1389 DI 10.1016/S1097-2765(03)00487-8 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 756XT UT WOS:000187511600008 PM 14690593 ER PT J AU Kasuga, T White, TJ Koenig, G Mcewen, J Restrepo, A Castaneda, E Lacaz, CD Heins-Vaccari, EM De Freitas, RS Zancope-Oliveira, RM Qin, ZY Negroni, R Carter, DA Mikami, Y Tamura, M Taylor, ML Miller, GF Poonwan, N Taylor, JW AF Kasuga, T White, TJ Koenig, G Mcewen, J Restrepo, A Castaneda, E Lacaz, CD Heins-Vaccari, EM De Freitas, RS Zancope-Oliveira, RM Qin, ZY Negroni, R Carter, DA Mikami, Y Tamura, M Taylor, ML Miller, GF Poonwan, N Taylor, JW TI Phylogeography of the fungal pathogen Histoplasma capsulatum SO MOLECULAR ECOLOGY LA English DT Article DE allopatric speciation; glacial refugia; last glacial maxima; phylogenetic species; population diversity; star phylogeny ID AMPLIFIED POLYMORPHIC DNA; CLINICAL SPECIMENS; SEQUENCES; PROGRAM; GENE; POPULATIONS; HAPLOTYPES; CONFIDENCE; INFECTION; DUBOISII AB Until recently, Histoplasma capsulatum was believed to harbour three varieties, var. capsulatum (chiefly a New World human pathogen), var. duboisii (an African human pathogen) and var. farciminosum (an Old World horse pathogen), which varied in clinical manifestations and geographical distribution. We analysed the phylogenetic relationships of 137 individuals representing the three varieties from six continents using DNA sequence variation in four independent protein-coding genes. At least eight clades were idengified: (i) North American class 1 clade; (ii) North American class 2 clade; (iii) Latin American group A clade; (iv) Latin American group B clade; (v) Australian clade; (vi) Netherlands (Indonesian?) clade; (vii) Eurasian clade and (viii) African clade. Seven of eight clades represented genetically isolated groups that may be recognized as phylogenetic species. The sole exception was the Eurasian clade which originated from within the Latin American group A clade. The phylogenetic relationships among the clades made a star phylogeny. Histoplasma capsulatum var. capsulatum individuals were found in all eight clades. The African clade included all of the H. capsulatum var. duboisii individuals as well as individuals of the other two varieties. The 13 individuals of var. farciminosum were distributed among three phylogenetic species. These findings suggest that the three varieties of Histoplasma are phylogenetically meaningless. Instead we have to recognize the existence of genetically distinct geographical populations or phylogenetic species. Combining DNA substitution rates of protein-coding genes with the phylogeny suggests that the radiation of Histoplasma started between 3 and 13 million years ago in Latin America. C1 Univ Calif Berkeley, Dept Plant & Microbial Biol, Berkeley, CA 94720 USA. Celera Diagnost, Alameda, CA USA. Roche Mol Syst, Alameda, CA USA. Corp Invest Biol, Medellin, Colombia. Inst Nacl Salud Santafe Bogota, Bogota, Colombia. Inst Med Trop Sao Paulo, Sao Paulo, Brazil. Univ Fed Rio de Janeiro, Inst Microbiol, BR-21941 Rio De Janeiro, Brazil. Chinese Acad Med Sci, Inst Dermatol, Ctr Med Mycol, Nanjing, Peoples R China. Hosp Enfermedades Infecciosas, Buenos Aires, DF, Argentina. Univ Sydney, Dept Microbiol, Sydney, NSW 2006, Australia. Chiba Univ, Pathogen Fungi & Microbial Toxicoses Res Ctr, Chiba 280, Japan. Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo, Japan. Univ Nacl Autonoma Mexico, Fac Med, Dept Microbiol & Parasitol, Mexico City 04510, DF, Mexico. NIH, Vet Resources Program, Bethesda, MD 20892 USA. Natl Inst Hlth, Dept Med Sci, Nonthaburi, Thailand. RP Kasuga, T (reprint author), Univ Calif Berkeley, Dept Plant & Microbial Biol, 321 Koshland Hall, Berkeley, CA 94720 USA. EM kasugat@uclink.berkeley.edu; jtaylor@socraks.berkeley.edu RI Carter, Dee/C-1331-2010; Freitas, Roseli /F-5952-2013; Zancope-Oliveira, Rosely /I-1955-2013; OI Freitas, Roseli/0000-0001-5811-5255 FU NHLBI NIH HHS [HL55953]; NIAID NIH HHS [AI37232] NR 59 TC 153 Z9 160 U1 1 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1083 EI 1365-294X J9 MOL ECOL JI Mol. Ecol. PD DEC PY 2003 VL 12 IS 12 BP 3383 EP 3401 DI 10.1046/j.1365-294X.2003.01995.x PG 19 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 744TF UT WOS:000186648400017 PM 14629354 ER PT J AU Froicu, M Weaver, V Wynn, TA McDowell, MA Welsh, JE Cantorna, MT AF Froicu, M Weaver, V Wynn, TA McDowell, MA Welsh, JE Cantorna, MT TI A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BONE-MINERAL DENSITY; REGULATORY T-CELLS; 1,25-DIHYDROXYVITAMIN D-3; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; SCID MICE; CD4(+); COLITIS; INDUCE; HOMEOSTASIS AB The active form of vitamin D (1,25D(3)) suppressed the development of animal models of human autoimmune diseases including experimental inflammatory bowel disease (IBD). The vitamin D receptor (VDR) is required for all known biologic effects of vitamin D. Here we show that VDR deficiency (knockout, KO) resulted in severe inflammation of the gastrointestinal tract in two different experimental models of IBD. In the CD45RB transfer model of IBD, CD4(+)/CD45RB(high) T cells from VDR KO mice induced more severe colitis than wild-type CD4(+)/CD45RB(high) T cells. The second model of IBD used was the spontaneous colitis that develops in IL-10 KO mice. VDR/IL-10 double KO mice developed accelerated IBD and 100% mortality by 8 wk of age. At 8 wk of age, all of the VDR and IL-10 single KO mice were healthy. Rectal bleeding was observed in every VDR/IL-10 KO mouse. Splenocytes from the VDR/IL-10 double KO mice cells transferred IBD symptoms. The severe IBD in VDR/IL-10 double KO mice is a result of the immune system and not a result of altered calcium homeostasis, or gastrointestinal tract function. The data establishes an essential role for VDR signaling in the regulation of inflammation in the gastrointestinal tract. C1 Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. NIAID, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. Univ Notre Dame, Dept Biol, Notre Dame, IN 46556 USA. RP Cantorna, MT (reprint author), Penn State Univ, Dept Nutr, 126 S Henderson Bldg, University Pk, PA 16802 USA. RI Wynn, Thomas/C-2797-2011 FU NINDS NIH HHS [1R01 NS38888-01A2] NR 30 TC 237 Z9 245 U1 0 U2 7 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD DEC 1 PY 2003 VL 17 IS 12 BP 2386 EP 2392 DI 10.1210/me.2003-0281 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 751NF UT WOS:000187072900001 PM 14500760 ER PT J AU Davison, EA Lee, CSL Naylor, MJ Oakes, SR Sutherland, RL Hennighausen, L Ormandy, CJ Musgrove, EA AF Davison, EA Lee, CSL Naylor, MJ Oakes, SR Sutherland, RL Hennighausen, L Ormandy, CJ Musgrove, EA TI The cyclin-dependent kinase inhibitor p27 (Kip1) regulates both DNA synthesis and apoptosis in mammary epithelium but is not required for its functional development during pregnancy SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BREAST-CANCER CELLS; GLAND DEVELOPMENT; TUMOR SUPPRESSION; CDK INHIBITORS; MICE LACKING; P27(KIP1); D1; GROWTH; MORPHOGENESIS; ONCOGENE AB Decreased expression of the cyclin-dependent kinase (CDK) inhibitor p27(Kip1) is common in breast cancer and is associated with poor prognosis. p27 is also an important mediator of steroidal regulation of cell cycle progression. We have therefore investigated the role of p27 in mammary epithelial cell proliferation. Examination of the two major functions of p27, assembly of cyclin D1-Cdk4 complexes and inhibition of Cdk2 activity, revealed that cyclin D1-Cdk4 complex formation was not impaired in p27(-/-) mammary epithelial cells in primary culture. However, cyclin E-Cdk2 activity was increased approximately 3-fold, indicating that the CDK inhibitory function of p27 is important in mammary epithelial cells. Increased epithelial DNA synthesis was observed during pregnancy in p27(-/-) mammary gland transplants, but this was paralleled by increased apoptosis. During pregnancy and at parturition, development and differentiation of p27(+/+) and p27(-/-) mammary tissue were indistinguishable. These results demonstrate a role for p27 in both the proliferation and survival of mammary epithelial cells. However, the absence of morphological and cellular defects in p27(-/-) mammary tissue during pregnancy raises the possibility that loss of p27 in breast cancer may not confer an overall growth advantage unless apoptosis is also impaired. C1 St Vincents Hosp, Garvan Inst Med Res, Canc Res Program, Sydney, NSW 2010, Australia. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Musgrove, EA (reprint author), Garvan Inst Med Res, Canc Res Program, 384 Victoria St, Darlinghurst, NSW 2010, Australia. RI Ormandy, Chris/G-4165-2014; OI Oakes, Samantha/0000-0003-1838-2310 NR 46 TC 17 Z9 17 U1 0 U2 1 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD DEC 1 PY 2003 VL 17 IS 12 BP 2436 EP 2447 DI 10.1210/me.2003-0199 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 751NF UT WOS:000187072900005 PM 12933906 ER PT J AU Parle-McDermott, A McManus, EJ Mills, JL O'Leary, VB Pangilinan, F Cox, C Weiler, A Molloy, AM Conley, M Watson, D Scott, JM Brody, LC Kirke, PN AF Parle-McDermott, A McManus, EJ Mills, JL O'Leary, VB Pangilinan, F Cox, C Weiler, A Molloy, AM Conley, M Watson, D Scott, JM Brody, LC Kirke, PN CA Birth Defects Res Grp TI Polymorphisms within the vitamin B-12 dependent methylmalonyl-coA mutase are not risk factors for neural tube defects SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE neural tube defects; methylmalonyl-CoA; B-12; MUT; MMA; Spina bifida; MTHFR; folate; homocysteine ID METHYLENETETRAHYDROFOLATE REDUCTASE GENE; METHIONINE SYNTHASE; AMNIOTIC-FLUID; SPINA-BIFIDA; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; HOMOCYSTEINE REMETHYLATION; COBALAMIN VITAMIN-B-12; LINKAGE-DISEQUILIBRIUM; FOLATE; ACIDEMIA AB Methionine synthase and methylmalonyl-CoA mutase (mutase) are the only two known vitamin B-12 (B-12)dependent enzymes in humans. A lower level of B-12 has been shown to be an independent maternal risk factor for neural tube defects (NTDs) prompting an investigation of common genetic variants within B-12 dependent enzymes. To investigate the role of methylmalonyl-CoA mutase variants we studied 279 complete NTD triads (NTD affected case and both parents) and 256 controls. Based on case-control and family based (transmission disequilibrium test) analyses we did not find an association between the mutase single nucleotide polymorphisms (SNPs) K212K (636A-->G), H532R (1595A-->G) and V671I (2011G-->A) and NTDs. However, there was a significant difference in the frequencies of these polymorphisms between a group of African Americans and American Caucasians (K212K, P = 0.002; H532R, P less than or equal to 0.001; V671I, P = 0.006). In conclusion, common variants in the mutase gene do not appear to be risk factors for NTDs but their allele frequencies are significantly different between ethnic groups. Published by Elsevier Inc. C1 NHGRI, Genome Technol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Dublin Trinity Coll, Dept Biochem, Dublin 2, Ireland. NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Dublin Trinity Coll, Dept Clin Med, Dublin 2, Ireland. Hlth Res Board, Child Hlth Epidemiol Div, Dublin, Ireland. RP Brody, LC (reprint author), NHGRI, Genome Technol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. OI Molloy, Anne/0000-0002-1688-9049; O'Leary, Valerie/0000-0003-1171-9830 NR 52 TC 5 Z9 6 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD DEC PY 2003 VL 80 IS 4 BP 463 EP 468 DI 10.1016/j.ymgme.2003.09.009 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 754WW UT WOS:000187356700012 PM 14654360 ER PT J AU Cristillo, AD Bierer, BE AF Cristillo, AD Bierer, BE TI Regulation of CXCR4 expression in human T lymphocytes by calcium and calcineurin SO MOLECULAR IMMUNOLOGY LA English DT Article DE CXCR4; cyclosporine; chemokine receptors; HIV; FK506 ID CHEMOKINE RECEPTOR CXCR4; IMMUNODEFICIENCY-VIRUS TYPE-1; HEMATOPOIETIC PROGENITOR CELLS; HIV-1 ENTRY; SIGNAL-TRANSDUCTION; PROTEIN PHOSPHATASE; TYROSINE PHOSPHORYLATION; TRANSCRIPTIONAL ACTIVITY; PERIPHERAL-BLOOD; FUSION COFACTOR AB Principally expressed on the surface of T lymphocytes, the chemokine and HIV receptor CXCR4 has been shown to serve key roles in both chemotaxis and HIV-1-entry into T cells. Understanding the regulation of CXCR4 expression is therefore of paramount importance to further elucidating its endogenous role and contributions to HIV-1 pathogenesis. Using an RNase protection assay (RPA), we have demonstrated that mitogenic stimulation of purified human peripheral blood T lymphocytes (PBL) decreased CXCR4 mRNA relative to unstimulated controls in a calcineurin-dependent manner; an expression pattern mimicked by the chemokine receptor CCR7. A change in transcriptional activity, not in mRNA stability, was required for control of CXCR4 and CCR7 expression. Changes in CXCR4 mRNA expression translated into a stimulation- and calcineurin-dependent decrease in cell surface CXCR4 expression. We have previously demonstrated that CXCR4 mRNA and protein is regulated by cAMP; here we show that calcium and calcineurin signaling pathways modify cAMP-driven changes. Moreover, we provide data supporting a role for the transcription factor YY1 in calcineurin-dependent regulation of CXCR4 expression. (C) 2003 Elsevier Ltd. All rights reserved. C1 NHLBI, Lab Lymphocyte Biol, NIH, Bethesda, MD 20892 USA. RP Bierer, BE (reprint author), Res Brigham & Womens Hosp, 75 Francis St,PB-4, Boston, MA 02115 USA. NR 71 TC 12 Z9 12 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD DEC PY 2003 VL 40 IS 8 BP 539 EP 553 DI 10.1016/S0161-5890(03)00169-X PG 15 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 739NP UT WOS:000186353600007 PM 14563373 ER PT J AU Cabrera, JE Jin, DJ AF Cabrera, JE Jin, DJ TI The distribution of RNA polymerase in Escherichia coli is dynamic and sensitive to environmental cues SO MOLECULAR MICROBIOLOGY LA English DT Article ID GREEN FLUORESCENT PROTEIN; ONE-DIMENSIONAL DIFFUSION; BACILLUS-SUBTILIS; TEXTURE ANALYSIS; LIFETIME IMAGES; RPOB MUTANTS; TRANSCRIPTION; DNA; CHROMOSOME; SEGREGATION AB Despite extensive genetic, biochemical and structural studies on Escherichia coli RNA polymerase (RNAP), little is known about its location and distribution in response to environmental changes. To visualize the RNAP by fluorescence microscopy in E. coli under different physiological conditions, we constructed a functional rpoC-gfp gene fusion on the chromosome. We show that, although RNAP is located in the nucleoid and at its periphery, the distribution of RNAP is dynamic and dramatically influenced by cell growth conditions, nutrient starvation and overall transcription activity inside the cell. Moreover, mutational analysis suggests that the stable RNA synthesis plays an important role in nucleoid condensation. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Jin, DJ (reprint author), NCI Federick, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. NR 56 TC 104 Z9 108 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD DEC PY 2003 VL 50 IS 5 BP 1493 EP 1505 DI 10.1046/j.1365-2958.2003.03805.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 745QD UT WOS:000186698600004 PM 14651633 ER PT J AU Werbovetz, KA Sackett, DL Delfin, D Bhattacharya, G Salem, M Obrzut, T Rattendi, D Bacchi, C AF Werbovetz, KA Sackett, DL Delfin, D Bhattacharya, G Salem, M Obrzut, T Rattendi, D Bacchi, C TI Selective antimicrotubule activity of N1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) against kinetoplastid parasites SO MOLECULAR PHARMACOLOGY LA English DT Article ID MICROTUBULE POLYMERIZATION INVITRO; ANTITUBULIN HERBICIDE TRIFLURALIN; TRYPANOSOME CELL-CYCLE; LEISHMANIA-DONOVANI; AMIPROPHOS-METHYL; ASSEMBLY INVITRO; PLANT TUBULIN; IN-VITRO; INHIBITION; ORYZALIN AB Analogs of the antimitotic herbicide oryzalin (3,5-dinitro-N4, N4-di-n-propylsulfanilamide) were recently prepared that were more potent in vitro than the parent compound against the kinetoplastid parasite Leishmania donovani (Bioorg Med Chem Lett 12: 2395-2398, 2002). In the present work, we show that the most active molecule in the group, N1-phenyl-3,5-dinitro-N4, N4-di-n-propylsulfanilamide (GB-II-5), is a potent, selective antimitotic agent against kinetoplastid parasites. GB-II-5 possesses IC50 values of 0.41 and 0.73 muM in vitro against two strains of the related parasite Trypanosoma brucei but is much less toxic to J774 murine macrophages and PC3 prostate cancer cells, exhibiting IC50 values of 29 and 35 muM against these lines, respectively. Selectivity is also observed for GB-II-5 with purified leishmanial and mammalian tubulin. The assembly of 15 muM leishmanial tubulin is completely inhibited by 10 muM GB-II-5, whereas 40 muM GB-II-5 inhibits the assembly of 15 muM porcine brain tubulin by only 17%. In cultured L. donovani and T. brucei, treatment with 5 and 0.5 muM GB-II-5, respectively, causes a striking increase in the fraction of G(2)M cells compared with control. Given the potency and selectivity of this agent against kinetoplastid tubulin, GB-II-5 emerges as an exciting new antitrypanosomal and antileishmanial lead compound. C1 Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Pace Univ, Dept Biol, New York, NY 10038 USA. Pace Univ, Haskins Labs, New York, NY 10038 USA. RP Werbovetz, KA (reprint author), Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, 500 W 12th Ave, Columbus, OH 43210 USA. RI Werbovetz, Karl/E-4290-2011 NR 31 TC 56 Z9 56 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2003 VL 64 IS 6 BP 1325 EP 1333 DI 10.1124/mol.64.6.1325 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748DM UT WOS:000186846900008 PM 14645662 ER PT J AU Wang, QMJ Fang, TW Yang, DZ Lewin, NE Van Lint, J Marquez, VE Blumberg, PM AF Wang, QMJ Fang, TW Yang, DZ Lewin, NE Van Lint, J Marquez, VE Blumberg, PM TI Ligand structure-activity requirements and phospholipid dependence for the binding of phorbol esters to protein kinase D SO MOLECULAR PHARMACOLOGY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; PLECKSTRIN HOMOLOGY DOMAIN; CYSTEINE-RICH REGION; HIGH-AFFINITY; D PKD; C-DELTA; MOLECULAR-CLONING; DIACYLGLYCEROL; MEMBRANE; RECEPTOR AB Although protein kinase D (PKD), like protein kinase C (PKC), possesses a C1 domain that binds phorbol esters and diacylglycerol, the structural differences from PKC within this and other domains of PKD imply differential regulation by lipids and ligands. We characterized the phorbol ester and phospholipid binding properties of a glutathione S-transferase-tagged full-length PKD and compared them with those of PKC-alpha and -delta. We found that PKD is a high-affinity phorbol ester receptor for a range of structurally and functionally divergent phorbol esters and analogs and showed both similarities and differences in structure-activity relations compared with the PKCs examined. In particular, PKD had lower affinity than PKC for certain diacylglycerol analogs, which might be caused by a lysine residue at the 22 position of the PKD-C1b domain in place of the tryptophan residue at this position conserved in the PKCs. The membrane-targeting domains in PKD are largely different from those in PKC; among these differences, PKD contains a pleckstrin homology (PH) domain that is absent in PKC. However, phosphatidylinositol-4,5-bisphosphate PIP2, a lipid ligand for some PH domains, reconstitutes phorbol 12,13-dibutyrate (PDBu) binding to PKD similarly as it does to PKC-alpha and -delta, implying that the PH domain in PKD may not preferentially interact with PIP2. Overall, the requirement of anionic phospholipids for the reconstitution of [H-3] PDBu binding to PKD was intermediate between those of PKC-alpha and -delta. We conclude that PKD is a high-affinity phorbol ester receptor; its lipid requirements for ligand binding are approximately comparable with those of PKC but may be differentially regulated in cells through the binding of diacylglycerol to the C1 domain. C1 Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA. NCI, Mol Mech Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Bethesda, MD 20892 USA. Katholieke Univ Leuven, Fac Med, Div Biochem, Louvain, Belgium. RP Wang, QMJ (reprint author), Univ Pittsburgh, Dept Pharmacol, E1354 Biomed Sci Tower, Pittsburgh, PA 15261 USA. RI Wang, Qiming/B-6064-2012 NR 36 TC 17 Z9 18 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2003 VL 64 IS 6 BP 1342 EP 1348 DI 10.1124/mol.64.6.1342 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748DM UT WOS:000186846900010 PM 14645664 ER PT J AU Struckmann, N Schwering, S Wiegand, S Gschnell, A Yamada, M Kummer, W Wess, U Haberberger, RV AF Struckmann, N Schwering, S Wiegand, S Gschnell, A Yamada, M Kummer, W Wess, U Haberberger, RV TI Role of muscarinic receptor subtypes in the constriction of peripheral airways: Studies on receptor-deficient mice SO MOLECULAR PHARMACOLOGY LA English DT Article ID ACETYLCHOLINE-RECEPTOR; SMOOTH-MUSCLE; KNOCKOUT MICE; LUNG; IDENTIFICATION; RELEASE; LACKING; TRACHEA; M-2; CONTRACTIONS AB In the airways, increases in cholinergic nerve activity and cholinergic hypersensitivity are associated with chronic obstructive pulmonary disease and asthma. However, the contribution of individual muscarinic acetylcholine receptor subtypes to the constriction of smaller intrapulmonary airways that are primarily responsible for airway resistance has not been analyzed. To address this issue, we used videomicroscopy and digital imaging of precision-cut lung slices derived from wild-type mice and mice deficient in either the M-1 (mAChR1(-/-) mice), M-2 (mAChR2(-/-) mice), or M-3 receptor subtype (mAChR3(-/-) mice) or lacking both the M-2 and M-3 receptor subtypes (mAChR2/3(-/-) double-knockout mice). In peripheral airways from wildtype mice (mAChR(-/-) mice), muscarine induced a triphasic concentration-dependent response, characterized by an initial constriction, a transient relaxation, and a sustained constriction. The bronchoconstriction was diminished by up to 60% in mAChR3(-/-) lungs and was completely abolished in mAChR2/3(-/-) lungs. The sustained bronchoconstriction was reduced in mAChR2(-/-) bronchi, and, interestingly, the transient relaxation was absent; the bronchoconstriction in response to 10(-8) M muscarine was increased by 158% in mAChR1(-/-) mice. Quantitative reverse transcriptase-polymerase chain reaction analysis revealed that the disruption of specific mAChR genes had no significant effect on the expression levels of the remaining mAChR subtypes. These results demonstrate that cholinergic constriction of murine peripheral airways is mediated by the concerted action of the M-2 and M-3 receptor subtypes and suggest the existence of pulmonary M-1 receptor activation, which counteracts cholinergic bronchoconstriction. Given the important role of muscarinic cholinergic mechanisms in pulmonary disease, these findings should be of considerable therapeutic relevance. C1 Univ Giessen, Inst Anat & Cell Biol, D-35385 Giessen, Germany. NIDDKD, Bioorgan Chem Lab, US Dept HHS, Bethesda, MD 20892 USA. RP Haberberger, RV (reprint author), Univ Giessen, Inst Anat & Cell Biol, Autweg 123, D-35385 Giessen, Germany. OI Haberberger, Rainer Viktor/0000-0001-8043-3786 NR 36 TC 67 Z9 71 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2003 VL 64 IS 6 BP 1444 EP 1451 DI 10.1124/mol.64.6.1444 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748DM UT WOS:000186846900021 PM 14645675 ER PT J AU Hahm, SH Chen, Y Vinson, C Eiden, LE AF Hahm, SH Chen, Y Vinson, C Eiden, LE TI A calcium-initiated signaling pathway propagated through calcineurin and cAMP response element-binding protein activates proenkephalin gene transcription after depolarization SO MOLECULAR PHARMACOLOGY LA English DT Article ID BOVINE CHROMAFFIN CELLS; CYCLOSPORINE-A; AP-1 PROTEINS; CYCLIC-AMP; EXPRESSION; ENKEPHALIN; CREB; FK506; FOS; IDENTIFICATION AB Essential components of a signal-transduction pathway regulating activity-dependent neuropeptide gene transcription have been identified. Proenkephalin (PEnk) gene activation after depolarization of chromaffin cells with 40 mM KCl was blocked by the voltage-sensitive calcium-channel blocker methoxyverapamil (D600) (30 muM) and by calcineurin inhibition with 100 nM cyclosporin A or ascomycin but not by inhibiting new protein synthesis with 0.5 mug/ml cycloheximide. KCl-induced elevation of PEnk mRNA was distinct from activation of the PEnk gene by either cAMP or protein kinase C. Twenty-five micromolar forskolin- and 100 nM phorbol 12-myristate 13-acetate-induced elevations of PEnk mRNA were cycloheximide-sensitive and were not blocked by cyclosporin A or ascomycin. KCl stimulated Ser-133 phosphorylation of cAMP response element-binding protein ( CREB) in chromaffin cells, and CREB phosphorylation was blocked by both ascomycin and D600. A reporter gene containing 193 bases of the PEnk gene 5' flank driving luciferase gene expression (pENK12-Luc) transfected into chromaffin cells was transcriptionally activated by KCl depolarization. Activation was blocked by both ascomycin and D600 and required an intact CREB binding site (ENKCRE2). An oligonucleotide containing the PEnk cAMP response element-2 was gel-shifted by both unstimulated and potassium-stimulated chromaffin cell nuclear extracts into a prominent complex supershifted by CREB antibodies. Finally, stimulation of transcription of the pENK12-Luc reporter by KCl in chromaffin cells was blocked by coexpression of the CREB antagonist A-CREB but not by the AP-1 antagonist A-Fos. Stimulus-transcription coupling after depolarization in chromaffin cells occurs via calcineurin-dependent activation of CREB, a pathway distinct from cAMP- or protein kinase C-initiated signaling and independent of immediate early gene regulation. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Recognit, NIH, Bethesda, MD 20892 USA. NCI, Div Biol Sci, NIH, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Recognit, NIH, Bldg 36,Room 2A-11, Bethesda, MD 20892 USA. OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21, Z01 MH002386-22, Z99 MH999999] NR 40 TC 10 Z9 11 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD DEC PY 2003 VL 64 IS 6 BP 1503 EP 1511 DI 10.1124/mol.64.6.1503 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 748DM UT WOS:000186846900027 PM 14645681 ER PT J AU Gao, CJ Kang, EM Kuramoto, K Agricola, BA Metzger, M von Kalle, C Donahue, RE Tisdale, JF AF Gao, CJ Kang, EM Kuramoto, K Agricola, BA Metzger, M von Kalle, C Donahue, RE Tisdale, JF TI Retrovirally transduced muscle-derived cells contribute to hematopoiesis at very low levels in the nonhuman primate model SO MOLECULAR THERAPY LA English DT Article ID BONE-MARROW-CELLS; MURINE SKELETAL-MUSCLE; NEURAL STEM-CELLS; IN-VIVO; PERIPHERAL-BLOOD; TRANSPLANTATION; DIFFERENTIATE; ENGRAFTMENT; HEPATOCYTES; EXPRESSION AB Recent studies have suggested a remarkable potential of adult stem cells from a variety of organs to give rise to cells of disparate organs, but evidence of such potential at a clonal level is lacking in most if not all studies to date. To assess directly the hematopoietic potential of muscle-derived cells in a relevant large animal, we initiated retroviral-tagging studies in the rhesus macaque to allow tracking at the clonal level by integration site analysis. Four rhesus macaques underwent transplantation with transduced muscle-derived cells after lethal irradiation followed by delayed infusion of an autologous hematopoietic graft. The first animal showed no evidence of hematopoietic recovery and, despite infusion of the backup hematopoietic graft, succumbed due to complications of prolonged cytopenias. In the remaining three animals, the overall contribution of retrovirally tagged muscle-derived cells toward hematopoiesis was exceedingly low. Retroviral integration site analysis among clonally derived muscle cells and bone marrow cells in vivo in one animal suggests a common source. These results demonstrate that harvesting disparate organs for cellular therapy is currently highly inefficient at best. C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. RP Tisdale, JF (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bldg 10,Room 9N116, Bethesda, MD 20892 USA. NR 33 TC 5 Z9 5 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 1525-0016 J9 MOL THER JI Mol. Ther. PD DEC PY 2003 VL 8 IS 6 BP 974 EP 980 DI 10.1016/j.ymthe.2003.08.017 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 752QG UT WOS:000187178200019 PM 14664800 ER PT J AU Kung, SKP An, DS Bonifacino, A Metzger, ME Ringpis, GE Mao, SH Chen, ISY Donahue, RE AF Kung, SKP An, DS Bonifacino, A Metzger, ME Ringpis, GE Mao, SH Chen, ISY Donahue, RE TI Induction of transgene-specific immunological tolerance in myeloablated nonhuman primates using lentivirally transduced CD34(+) progenitor cells SO MOLECULAR THERAPY LA English DT Article DE gene therapy; transplantation; lentiviral vectors ID GREEN FLUORESCENT PROTEIN; HEMATOPOIETIC STEM-CELLS; BONE-MARROW-CELLS; HUMAN ADENOSINE-DEAMINASE; LONG-TERM EXPRESSION; GENE-THERAPY; IMMUNE-RESPONSES; CPG MOTIFS; IMMUNOSTIMULATORY DNA; PERIPHERAL-BLOOD AB Modeling human hematopoietic progenitor cell gene therapy in nonhuman primates allows long-term evaluation of safety, maintenance of gene expression, and potential immune response against transgene products. We transplanted autologous G-CSF/SCF-mobilized CD34(+) cells transduced with lentiviral vectors expressing EGFP into myeloablated rhesus macaques. To date, more than 4 years posttransplantation, 0.5-8% EGFP expression is maintained in multiple cell lineages. The animals remain healthy with no evidence of hematopoietic abnormalities or malignancies. To assess immune functions, we actively immunized two of our transplanted animals with purified rEGFP proteins and CpG adjuvant and demonstrated stable levels of EGFP(+) cell populations maintained for over 29 months despite four active immunizations. We did not detect a persistent anti-EGFP antibody response or anti-EGFP T cell response in these immunized animals. Immune response to an irrelevant antigen was normal. Taken together, our data provide formal support that transplantation of lentivirally transcluced CD34(+) progenitor cells in myeloablated rhesus macaques induces specific immunological tolerance toward a foreign transgene. C1 Univ Calif Los Angeles, UCLA AIDS Inst, Dept Microbiol Mol Genet & Immunol, David Geffen Sch Med, Los Angeles, CA 90095 USA. NHLBI, Hematol Branch, NIH, Rockville, MD 20850 USA. RP Chen, ISY (reprint author), Univ Calif Los Angeles, UCLA AIDS Inst, Dept Microbiol Mol Genet & Immunol, David Geffen Sch Med, 10833 LeConte Ave,11-934 Factor Bldg, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [AI39975] NR 45 TC 25 Z9 28 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD DEC PY 2003 VL 8 IS 6 BP 981 EP 991 DI 10.1016/j.ymthe.2003.08.020 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 752QG UT WOS:000187178200020 PM 14664801 ER PT J AU Schiffmann, R Floeter, MK Dambrosia, JM Gupta, S Moore, DF Sharabi, Y Khurana, RK Brady, RO AF Schiffmann, R Floeter, MK Dambrosia, JM Gupta, S Moore, DF Sharabi, Y Khurana, RK Brady, RO TI Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease SO MUSCLE & NERVE LA English DT Article DE Fabry disease; quantitative sensory testing; small-fiber neuropathy; sweat; thermal sensation ID SMALL FIBER DYSFUNCTION; GROWTH-FACTOR; DIABETIC POLYNEUROPATHY; SENSORY NEUROPATHY; SENSATION; TRIAL; PAIN; CANCER AB Fabry disease is an X-I inked disorder caused by a deficiency of lysosomal alpha-galactosidase A resulting in accumulation of alpha-D-galatosyl conjugated glycosphingolipids. Clinical manifestations include a small-fiber neuropathy associated with debilitating pain and hypohidrosis. We report the effect of a 3-year open-label extension of a previously reported 6-month placebo-controlled enzyme replacement therapy (ERT) trial in which 26 hemizygous patients with Fabry disease received 0.2 mg/kg of alpha-galactosidase A every 2 weeks. The effect of ERT on neuropathic pain scores while off pain medications, quantitative sensory testing, quantitative sudomotor axon reflex test (QSART), and thermoregulatory sweat test (TST) is reported. In the patients who crossed-over from placebo to ERT (n = 10), mean pain-at-its-worst scores on a 0-10 scale decreased (from 6.9 to 4.5). There was a significant reduction in the threshold for cold and warm sensation in the foot. At the 3-year time-point, pre-ERT sweat excretion in 17 Fabry patients was 0.24 +/- 0.33 mul/mm(2) VS. 1.05 +/- 0.81 in concurrent controls (n = 38). Sweat function improved 24-72 h post-enzyme infusion (0.57 +/- 0.71 mul/mm(2)) and normalized in four anhidrotic patients. TST confirmed the QSART results. We conclude that prolonged ERT in Fabry disease leads to a modest but significant improvement in the clinical manifestations of the small-fiber neuropathy associated with this disorder. QSART may be useful to further optimize the dose and frequency of ERT. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Union Mem Hosp, Baltimore, MD USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 138 Z9 145 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD DEC PY 2003 VL 28 IS 6 BP 703 EP 710 DI 10.1002/mus.10497 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 749GT UT WOS:000186912000006 PM 14639584 ER PT J AU Mattei, D Mordini, N Lo Nigro, C Gallamini, A Osenda, M Pugno, F Viscoli, C AF Mattei, D Mordini, N Lo Nigro, C Gallamini, A Osenda, M Pugno, F Viscoli, C TI Successful treatment of Acremonium fungemia with voriconazole SO MYCOSES LA English DT Article DE Acremonium; fungemia; antimycotic chemotherapy; voriconazole ID INFECTION; PATIENT; FUSARIUM AB We report two cases of Acremonium fungemia with proven involvement of the skin and probably of the lung in patients who were both undergoing chemotherapy, one for mantle cell lymphoma and the other for acute lymphoblastic leukemia. Both patients failed amphotericin B deoxycholate treatment and were successfully treated with voriconazole with very mild toxicity. C1 Osped S Croce, Div Ematol, Dept Hematol, I-12100 Cuneo, Italy. Osped S Croce, Dept Lab, I-12100 Cuneo, Italy. Osped S Croce, Dept Pathol, I-12100 Cuneo, Italy. Univ Genoa, Natl Canc Inst, Genoa, Italy. RP Mattei, D (reprint author), Osped S Croce, Div Ematol, Dept Hematol, Via Michele Coppino 26, I-12100 Cuneo, Italy. OI Mattei, Daniele /0000-0003-3152-4416 NR 11 TC 36 Z9 40 U1 0 U2 1 PU BLACKWELL VERLAG GMBH PI BERLIN PA KURFURSTENDAMM 57, D-10707 BERLIN, GERMANY SN 0933-7407 J9 MYCOSES JI Mycoses PD DEC PY 2003 VL 46 IS 11-12 BP 511 EP 514 DI 10.1046/j.0933-7407.2003.00924.x PG 4 WC Dermatology; Mycology SC Dermatology; Mycology GA 748RZ UT WOS:000186876000012 PM 14641626 ER PT J AU Mattson, MP Chan, SL AF Mattson, MP Chan, SL TI Calcium orchestrates apoptosis SO NATURE CELL BIOLOGY LA English DT Editorial Material ID ENDOPLASMIC-RETICULUM; DEATH; CA2+ AB Apoptosis is a feature of many diseases and is critical for the sculpting and maintenance of tissues. New work demonstrates that calcium released from the endoplasmic reticulum synchronizes the mass exodus of cytochrome c from the mitochondria, a phenomenon that coordinates apoptosis. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 12 TC 241 Z9 248 U1 4 U2 27 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD DEC PY 2003 VL 5 IS 12 BP 1041 EP 1043 DI 10.1038/ncb1203-1041 PG 3 WC Cell Biology SC Cell Biology GA 748ZK UT WOS:000186892900004 PM 14647298 ER PT J AU Johnson, EN Seasholtz, TM Waheed, AA Kreutz, B Suzuki, N Kozasa, T Jones, TLZ Brown, JH Druey, KM AF Johnson, EN Seasholtz, TM Waheed, AA Kreutz, B Suzuki, N Kozasa, T Jones, TLZ Brown, JH Druey, KM TI RGS16 inhibits signalling through the G alpha 13-Rho axis SO NATURE CELL BIOLOGY LA English DT Letter ID GTPASE-ACTIVATING PROTEIN; TERMINAL CYSTEINE RESIDUES; G-ALPHA-Q; FUNCTIONAL-CHARACTERIZATION; KINASE ACTIVATION; LIPID RAFTS; P115 RHOGEF; G-ALPHA(13); REGULATORS; PALMITOYLATION AB Galpha13 stimulates the guanine nucleotide exchange factors (GEFs) for Rho, such as p115Rho-GEF(1). Activated Rho induces numerous cellular responses, including actin polymerization, serum response element (SRE)-dependent gene transcription and transformation(2). p115Rho-GEF contains a Regulator of G protein Signalling domain (RGS box) that confers GTPase activating protein (GAP) activity towards Galpha12 and Galpha13 (ref. 3). In contrast, classical RGS proteins (such as RGS16 and RGS4) exhibit RGS domain-dependent GAP activity on Galphai and Galphaq, but not Galpha12 or Galpha13 (ref 4). Here, we show that RGS16 inhibits Galpha13-mediated, RhoA-dependent reversal of stellation and SRE activation. The RGS16 amino terminus binds Galpha13 directly, resulting in translocation of Galpha13 to detergent-resistant membranes (DRMs) and reduced p115Rho-GEF binding. RGS4 does not bind Galpha13 or attenuate Galpha13-dependent responses, and neither RGS16 nor RGS4 affects Galpha12-mediated signalling. These results elucidate a new mechanism whereby a classical RGS protein regulates Galpha13-mediated signal transduction independently of the RGS box. C1 NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. FU NIGMS NIH HHS [GM36927] NR 30 TC 20 Z9 20 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD DEC PY 2003 VL 5 IS 12 BP 1095 EP 1103 DI 10.1038/ncb1065 PG 9 WC Cell Biology SC Cell Biology GA 748ZK UT WOS:000186892900016 PM 14634662 ER PT J AU Dam, J Guan, RJ Natarajan, K Dimasi, N Chlewicki, LK Kranz, DM Schuck, P Margulies, DH Mariuzza, RA AF Dam, J Guan, RJ Natarajan, K Dimasi, N Chlewicki, LK Kranz, DM Schuck, P Margulies, DH Mariuzza, RA TI Variable MHC class I engagement by Ly49 natural killer cell receptors demonstrated by the crystal structure of Ly49C bound to H-2K(b) SO NATURE IMMUNOLOGY LA English DT Article ID LIGAND-SPECIFIC OLIGOMERIZATION; YEAST SURFACE-DISPLAY; NK CELLS; HUMAN CD4; COMPLEX; BINDING; RECOGNITION; ACTIVATION; NKG2D; MOLECULES AB The Ly49 family of natural killer (NK) receptors regulates NK cell function by sensing major histocompatibility complex (MHC) class I. Ly49 receptors show complex patterns of MHC class I cross-reactivity and, in certain cases, peptide selectivity. To investigate whether specificity differences result from topological differences in MHC class I engagement, we determined the structure of the peptide-selective receptor Ly49C in complex with H-2K(b). The Ly49C homodimer binds two MHC class I molecules in symmetrical way, a mode distinct from that of Ly49A, which binds MHC class I asymmetrically. Ly49C does not directly contact the MHC-bound peptide. In addition, MHC crosslinking by Ly49C was demonstrated in solution. We propose a dynamic model for Ly49-MHC class I interactions involving conformational changes in the receptor, whereby variations in Ly49 dimerization mediate different MHC-binding modes. C1 NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. Univ Illinois, Dept Biochem, Urbana, IL 61801 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM dhm@nih.gov; mariuzza@carb.nist.gov RI Margulies, David/H-7089-2013; OI Dam, Julie/0000-0001-6871-2678; Margulies, David/0000-0001-8530-7375; Schuck, Peter/0000-0002-8859-6966 NR 50 TC 87 Z9 89 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 DEC PY 2003 VL 4 IS 12 BP 1213 EP 1222 DI 10.1038/ni1006 PG 10 WC Immunology SC Immunology GA 746VZ UT WOS:000186769500015 PM 14595439 ER PT J AU Wink, DA AF Wink, DA TI Ion implicated in blood pact SO NATURE MEDICINE LA English DT Editorial Material ID NITRIC-OXIDE SYNTHASE; PATHWAY AB Nitric oxide has achieved fame as a regulator of numerous physiological processes, far outshining its humbler cousins, nitrate and nitrite. Now, nitrite steps into the spotlight. It appears that this ion may provide a source of NO during the regulation of blood flow under stressful conditions (pages 1498- 1505). C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Wink, DA (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NR 12 TC 6 Z9 6 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2003 VL 9 IS 12 BP 1460 EP 1461 DI 10.1038/nm1203-1460 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 748CV UT WOS:000186845400018 PM 14647519 ER PT J AU Cosby, K Partovi, KS Crawford, JH Patel, RP Reiter, CD Martyr, S Yang, BK Waclawiw, MA Zalos, G Xu, XL Huang, KT Shields, H Kim-Shapiro, DB Schechter, AN Cannon, RO Gladwin, MT AF Cosby, K Partovi, KS Crawford, JH Patel, RP Reiter, CD Martyr, S Yang, BK Waclawiw, MA Zalos, G Xu, XL Huang, KT Shields, H Kim-Shapiro, DB Schechter, AN Cannon, RO Gladwin, MT TI Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation SO NATURE MEDICINE LA English DT Article ID SMOOTH-MUSCLE RELAXATION; REGIONAL BLOOD-FLOW; S-NITROSOHEMOGLOBIN; SODIUM-NITRITE; XANTHINE-OXIDASE; AUTOCATALYTIC OXIDATION; GLYCERYL TRINITRATE; BIOLOGICAL-SYSTEMS; SYNTHASE ACTIVITY; HUMAN-HEMOGLOBIN AB Nitrite anions comprise the largest vascular storage pool of nitric oxide (NO), provided that physiological mechanisms exist to reduce nitrite to NO. We evaluated the vasodilator properties and mechanisms for bioactivation of nitrite in the human forearm. Nitrite infusions of 36 and 0.36 mumol/ min into the forearm brachial artery resulted in supra- and near- physiologic intravascular nitrite concentrations, respectively, and increased forearm blood flow before and during exercise, with or without NO synthase inhibition. Nitrite infusions were associated with rapid formation of erythrocyte iron- nitrosylated hemoglobin and, to a lesser extent, S- nitroso- hemoglobin. NO- modified hemoglobin formation was inversely proportional to oxyhemoglobin saturation. Vasodilation of rat aortic rings and formation of both NO gas and NO- modified hemoglobin resulted from the nitrite reductase activity of deoxyhemoglobin and deoxygenated erythrocytes. This finding links tissue hypoxia, hemoglobin allostery and nitrite bioactivation. These results suggest that nitrite represents a major bioavailable pool of NO, and describe a new physiological function for hemoglobin as a nitrite reductase, potentially contributing to hypoxic vasodilation. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Pathol, Ctr Free Rad Biol, Birmingham, AL 35294 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Off Biostat Res, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Sch Med, Dept Biomed Engn, Winston Salem, NC 27157 USA. RP Gladwin, MT (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bldg 10,10 Ctr Dr,Room 7D43, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408; Patel, Rakesh/0000-0002-1526-4303 FU NHLBI NIH HHS [HL58091, R01 HL058091, R01HL70146]; NIGMS NIH HHS [T32GM08361] NR 46 TC 990 Z9 1013 U1 6 U2 92 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD DEC PY 2003 VL 9 IS 12 BP 1498 EP 1505 DI 10.1038/nm954 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 748CV UT WOS:000186845400033 PM 14595407 ER PT J AU Yewdell, JW Reits, E Neefjes, J AF Yewdell, JW Reits, E Neefjes, J TI Making sense of mass destruction: Quantitating MHC class I antigen presentation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID T-CELL RECEPTOR; PROTEIN DISULFIDE-ISOMERASE; NEWLY SYNTHESIZED PROTEINS; TAP-TRANSLOCATED PEPTIDES; CYTOTOXIC LYMPHOCYTES-T; ENDOPLASMIC-RETICULUM; PROTEASOMAL DEGRADATION; TRIPEPTIDYL PEPTIDASE; THIMET OLIGOPEPTIDASE; CROSS-PRESENTATION AB MHC class I molecules bind short peptides and present them to CD8(+) T cells. Contrary to textbook descriptions, the generation of MHC class-I-associated peptides from endogenous proteins is a highly dynamic and remarkably inefficient process. Here, we describe recent experiments that show how nascent and mature proteins are degraded into peptides that are trimmed, transported and trimmed again to enable presentation of a small portion of the generated peptides. By linking the failure rate of protein synthesis with antigen presentation, a rapid T-cell response is ensured, which is crucial in combating viral infections. Presentation on MHC class I molecules is achieved by less than 0.1% of the specific peptides that have survived intracellular destruction. The other peptides are converted into free amino acids that are used for recycling into new proteins. C1 Netherlands Canc Inst, Div Tumor Biol, NL-1066 CX Amsterdam, Netherlands. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Neefjes, J (reprint author), Netherlands Canc Inst, Div Tumor Biol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 91 TC 241 Z9 246 U1 2 U2 16 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 DEC PY 2003 VL 3 IS 12 BP 952 EP 961 DI 10.1038/nri1250 PG 10 WC Immunology SC Immunology GA 748ZJ UT WOS:000186892700013 PM 14647477 ER PT J AU Berg, JM AF Berg, JM TI Fingering nucleic acids: the RNA did it SO NATURE STRUCTURAL BIOLOGY LA English DT Editorial Material ID TRANSCRIPTION FACTOR IIIA; ZINC FINGERS; 5S RNA; DNA RECOGNITION; BINDING; TFIIIA; COMPLEX; GENE; DETERMINANTS; PROTEINS AB Although zinc fingers are best known to interact with DNA, they can, as in the case of the TFIIIA protein, also interact with RNA. A recent crystal structure reveals that zinc fingers can take advantage of the variability of RNA structure to recognize a particular RNA fragment. C1 NIGMS, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), NIGMS, Bethesda, MD 20892 USA. OI Berg, Jeremy/0000-0003-3022-0963 NR 20 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD DEC PY 2003 VL 10 IS 12 BP 986 EP 987 DI 10.1038/nsb1203-986 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 746BF UT WOS:000186725900006 PM 14634631 ER PT J AU Zheng, WP Zhang, ZS Ganguly, S Weller, JL Klein, DC Cole, PA AF Zheng, WP Zhang, ZS Ganguly, S Weller, JL Klein, DC Cole, PA TI Cellular stabilization of the melatonin rhythm enzyme induced by nonhydrolyzable phosphonate incorporation SO NATURE STRUCTURAL BIOLOGY LA English DT Article ID SEROTONIN N-ACETYLTRANSFERASE; NATIVE CHEMICAL LIGATION; TYROSINE PHOSPHORYLATION; CATALYTIC MECHANISM; 14-3-3 PROTEINS; EC-2.3.1.87; COMPLEX; SHP-2 AB Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) controls daily changes in the production and circulating levels of melatonin. Here, the significance of the phosphorylation of AANAT was studied using a semisynthetic enzyme in which a nonhydrolyzable phosphoserine/threonine mimetic, phosphonomethylenealanine (Pma), was incorporated at position 31 (AANAT-Pma31). The results of studies in which AANAT-Pma31 and related analogs were injected into cells provide the first direct evidence that Thr31 phosphorylation controls AANAT stability in the context of the intact cells by binding to 14-3-3 protein. These findings establish Thr31 phosphorylation as an essential element in the intracellular regulation of melatonin production. The application of Pma in protein semisynthesis is likely to be broadly useful in the analysis of protein serine/threonine phosphorylation. C1 Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Cole, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, 725 N Wolfe St, Baltimore, MD 21205 USA. NR 19 TC 41 Z9 45 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD DEC PY 2003 VL 10 IS 12 BP 1054 EP 1057 DI 10.1038/nsb1005 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 746BF UT WOS:000186725900016 PM 14578935 ER PT J AU Coleman, PD Yao, PJ AF Coleman, PD Yao, PJ TI Synaptic slaughter in Alzheimer's disease SO NEUROBIOLOGY OF AGING LA English DT Article; Proceedings Paper CT Meeting on Molecular and Cellular Basis of Synaptic Loss and Dysfunction in Alzheimers Disease CY 2002 CL ORLANDO, FLORIDA DE Alzheimer's disease; synapses; neurofibrillary tangles; synaptic vesicle trafficking; gene expression profiling ID SENILE DEMENTIA; NEUROFIBRILLARY TANGLES; SYNAPTOPHYSIN MESSAGE; FRONTAL-CORTEX; NEURONS; EXPRESSION; DENSITY AB Synaptic loss is currently established as the best neurobiological correlate of the cognitive deficits of Alzheimer's disease (AD) [Ann. Neurol. 27 (1990) 457; Ann. Neurol. 30 (1991) 572]. We provide evidence that still living neurons lose synapses in AD, in addition to the synapse loss due to death of neurons. We also provide evidence indicating that in addition to loss of synapses, synaptic function is also affected in AD by decrements in transcript species related to synaptic vesicle trafficking. (C) 2003 Elsevier Inc. All rights reserved. C1 Univ Rochester, Ctr Aging & Dev Biol, Rochester, NY 14642 USA. NIA, Gerontol Res Ctr, NIH, Neurosci Lab, Baltimore, MD 21224 USA. RP Coleman, PD (reprint author), Univ Rochester, Ctr Aging & Dev Biol, 601 Elmwood Ave, Rochester, NY 14642 USA. FU NIA NIH HHS [AG14441] NR 20 TC 203 Z9 223 U1 2 U2 9 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 DEC PY 2003 VL 24 IS 8 BP 1023 EP 1027 DI 10.1016/j.neurobiolaging.2003.09.001 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 754XT UT WOS:000187359300002 PM 14643374 ER PT J AU Schueler, UH Kolter, T Kaneski, CR Blusztajn, JK Herkenham, M Sandhoff, K Brady, RO AF Schueler, UH Kolter, T Kaneski, CR Blusztajn, JK Herkenham, M Sandhoff, K Brady, RO TI Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3 SO NEUROBIOLOGY OF DISEASE LA English DT Article DE neuronopathic Gaucher disease; glucosylsphingosine; glucopsychosine; acetylcholine; cholinergic LA-N-2 cells ID MACROPHAGE-TARGETED GLUCOCEREBROSIDASE; MANNOSE-TERMINAL GLUCOCEREBROSIDASE; BETA-GLUCOSIDASE; ACETYLCHOLINE SYNTHESIS; REPLACEMENT THERAPY; PHOSPHOLIPASE-D; RAT-BRAIN; ACCUMULATION; TISSUES; PSYCHOSINE AB Patients with Gaucher disease have been classified as type 1 nonneuronopathic, type 2 acute neuronopathic, and type 3 chronic neuronopathic phenotypes. Increased quantities of glucocerebroside and glucosylsphingosine (glucopsychosine) are present in the brain of type 2 and type 3 Gaucher patients. Galactosylsphingosine has previously been shown to be neurotoxic in globoid cell leukodystrophy (Krabbe disease). To determine whether glucosylsphingosine is also neurotoxic, we examined its effect on cultured cholinergic neuron-like LA-N-2 cells. When these cells were exposed to 1, 5, or 10 muM glucosylsphingosine for a period of 18 h, they became shriveled, neurite outgrowth was suppressed, and the activities of the lysosomal enzymes glucocerebrosidase, sphingomyelinase, and beta-galactosidase were reduced in a dose-dependent manner. Acetylcholine in cells exposed to glucosylsphingosine also declined. Cells switched to glucosylsphingosine-free medium partially recovered. The data suggest that accumulation of glucosylsphingosine contributes to neuronal dysfunction and destruction in patients with neuronopathic Gaucher disease. (C) 2003 Elsevier Inc. All rights reserved. C1 DHHS, NINDA, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. Univ Bonn, Kekule Inst Organ Chem & Biochem, Bonn, Germany. DHHS, NIMH, Lab Cellular & Mol Regulat, Sect Funct Neuroanat,NIH, Bethesda, MD USA. Boston Univ, Sch Med, Dept Pathol & Lab Med, Boston, MA USA. RP Schueler, UH (reprint author), NIMH, LCMR, Sect Funct Neuroanat, NIH, Bldg 36,Rm 2D15,36 Convent Dr, Bethesda, MD 20892 USA. OI Kaneski, Christine/0000-0003-1453-2502; Herkenham, Miles/0000-0003-2228-4238 FU NIA NIH HHS [AG09525]; NINDS NIH HHS [NS042793] NR 47 TC 34 Z9 35 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD DEC PY 2003 VL 14 IS 3 BP 595 EP 601 DI 10.1016/j.nbd.2003.08.015 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 754XJ UT WOS:000187358300027 PM 14678774 ER PT J AU Keightley, ML Seminowicz, DA Bagby, RM Costa, PT Fossati, P Mayberg, HS AF Keightley, ML Seminowicz, DA Bagby, RM Costa, PT Fossati, P Mayberg, HS TI Personality influences limbic-cortical interactions during sad mood induction SO NEUROIMAGE LA English DT Article DE personality; neuroticism; extraversion; depression; PET; mood ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; PARTIAL LEAST-SQUARES; MAJOR DEPRESSION; TRYPTOPHAN DEPLETION; ORBITOFRONTAL CORTEX; RECEPTOR-BINDING; HEALTHY-SUBJECTS; BRAIN ACTIVITY; MODEL AB The current study examined limbic-cortical activation under transient emotional stress as a function of personality style. A ventral cingulate (Cg25)-centred limbic-cortical network was identified using positron emission tomography (PET) measures of regional cerebral blood flow (rCBF) during a sad mood challenge that demonstrated differences for individuals selected for specific patterns of Negative and Positive emotional traits, indexed by the NEO Personality Inventory-Revised. Healthy subjects scoring both low on the dispositional Depression facet of Neuroticism (N3) and high on the Positive Emotions facet of Extraversion (E6) were compared to those scoring high on the Depression facet (N3) and low on Positive Emotions (E6), a combination of traits previously linked to normal variations in mood reactivity. Scan analyses were designed to further characterize known variations in Cg25 activity previously reported in studies of negative mood in both healthy subjects and depressed patients. A multivariate technique, partial least squares (PLS) demonstrated a divergent Cg25-mediated network that differentiated temperamentally negative (NAS) from temperamentally positive (PAS) subjects providing a potential neural link between these specific combinations of trait affective styles and vulnerability to depression. (C) 2003 Elsevier Inc. All rights reserved. C1 Baycrest Ctr Geriatr Care, Rotman Res Inst, Toronto, ON M6A 2E1, Canada. Univ Toronto, Dept Psychol, Toronto, ON M5S 1A1, Canada. Univ Toronto, Dept Psychiat, Toronto, ON M5S 1A1, Canada. NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. Ctr Addict & Mental Hlth, Toronto, ON, Canada. RP Mayberg, HS (reprint author), Baycrest Ctr Geriatr Care, Rotman Res Inst, 3560 Bathurst St, Toronto, ON M6A 2E1, Canada. RI Seminowicz, David/F-8732-2015; OI Seminowicz, David/0000-0003-3111-3756; Costa, Paul/0000-0003-4375-1712 NR 59 TC 44 Z9 44 U1 2 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD DEC PY 2003 VL 20 IS 4 BP 2031 EP 2039 DI 10.1016/j.neuroimage.2003.08.022 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 756CM UT WOS:000187448300012 PM 14683707 ER PT J AU Holmes, A Yang, RJ Lesch, KP Crawley, JN Murphy, DL AF Holmes, A Yang, RJ Lesch, KP Crawley, JN Murphy, DL TI Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin; serotonin transporter; gene; mouse; anxiety; 5-HT1A receptor ID ELEVATED PLUS-MAZE; CORTICOTROPIN-RELEASING-FACTOR; IMPAIRED STRESS-RESPONSE; PRIOR TEST EXPERIENCE; DEFENSE TEST BATTERY; KNOCK-OUT MICE; BINDING-SITES; DORSAL RAPHE; ANIMAL-MODEL; IN-VIVO AB The serotonin transporter (5-HTT) regulates serotonergic neurotransmission via clearance of extracellular serotonin. Abnormalities in 5-HTT expression or function are found in mood and anxiety disorders, and the 5-HTT is a major target for antidepressants and anxiolytics. The 5-HTT is further implicated in the pathophysiology of these disorders by evidence that genetic variation in the promoter region of the HTT (SLC6A4) is associated with individual differences in anxiety and neural responses to fear. To further evaluate the role of the 5-HTT in anxiety, we employed a mouse model in which the 5-HTT gene (htt) was constitutively inactivated. 5-HTT -/- mice were characterized for anxiety-related behaviors using a battery of tests ( elevated plus maze, light <----> dark exploration test, emergence test, and open field test). Male and female 5-HTT -/- mice showed robust phenotypic abnormalities as compared to +/+ littermates, suggestive of increased anxiety-like behavior and inhibited exploratory locomotion. The selective 5-HT1A receptor antagonist, WAY 100635 (0.05 - 0.3 mg/kg), produced a significant anxiolytic-like effect in the elevated plus maze in 5-HTT -/- mice, but not +/+ controls. The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT1A receptor in mediating these abnormalities. 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders. C1 NIMH, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97070 Wurzburg, Germany. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Holmes, A (reprint author), NIMH, Lab Behav Neurosci, NIH, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. RI Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 99 TC 178 Z9 183 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2003 VL 28 IS 12 BP 2077 EP 2088 DI 10.1038/sj.npp.1300266 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 748ZD UT WOS:000186892200003 PM 12968128 ER PT J AU Butterweck, V Winterhoff, H Herkenham, M AF Butterweck, V Winterhoff, H Herkenham, M TI Hyperforin-containing extracts of St John's wort fail to alter gene transcription in brain areas involved in HPA axis control in a long-term treatment regimen in rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE St John's wort; hypericum; hyperforin; fluoxetine; HPA axis; in situ hybridization ID CORTICOTROPIN-RELEASING HORMONE; HYPERICUM-PERFORATUM L.; PITUITARY-ADRENOCORTICAL SYSTEM; CENTRAL NORADRENERGIC SYSTEMS; II CORTICOSTEROID RECEPTORS; MESSENGER-RNA EXPRESSION; FORCED SWIMMING TEST; ANTIDEPRESSANT ACTIVITY; MINERALOCORTICOID RECEPTOR; TYROSINE-HYDROXYLASE AB We previously showed that a methanolic extract of St John's wort (SJW) (Hypericum) and hypericin, one of its active constituents, both have delayed regulation of genes that are involved in the control of the hypothalamic - pituitary - adrenal (HPA) axis. Hyperforin, another constituent of SJW, is active in vitro and has been proposed to be the active constituent for therapeutic efficacy in depression. We therefore examined if hyperforin has delayed effects on HPA axis control centers similar to those of Hypericum and hypericin. We used in situ hybridization histochemistry to examine in rats the effects of short-term (2 weeks) and long-term (8 weeks) oral administration of two hyperforin preparations, fluoxetine ( positive control), and haloperidol ( negative control) on the expression of genes involved in the regulation of the HPA axis. Fluoxetine (10 mg/kg) given daily for 8 weeks, but not 2 weeks, significantly decreased levels of corticotropin-releasing hormone (CRH) mRNA by 22% in the paraventricular nucleus (PVN) of the hypothalamus and tyrosine hydroxylase (TH) mRNA by 23% in the locus coeruleus. Fluoxetine increased levels of mineralocorticoid (MR) (17%), glucocorticoid (GR) (18%), and 5-HT1A receptor (21%) mRNAs in the hippocampus at 8, but not 2, weeks. Comparable to haloperidol (1 mg/kg), neither the hyperforinrich CO2 extract (27 mg/kg) nor hyperforin-trimethoxybenzoate (8 mg/kg) altered mRNA levels in brain structures relevant for HPA axis control at either time point. These data suggest that hyperforin and hyperforin derivatives are not involved in the regulation of genes that control HPA axis function. C1 NIMH, Funct Neuroanat Sect, NIH, DHHS, Bethesda, MD 20892 USA. Univ Klinikum Muenster, Inst Pharmacol & Toxicol, Munster, Germany. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, NIH, DHHS, Bldg 36,Rm 2D15, Bethesda, MD 20892 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 76 TC 6 Z9 6 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD DEC PY 2003 VL 28 IS 12 BP 2160 EP 2168 DI 10.1038/sj.npp.1300253 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 748ZD UT WOS:000186892200010 PM 12865894 ER EF