FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kim, BS Jang, HS Jwa, SW Jang, BS Kim, MB Oh, CK Kwon, YW Kwon, KS AF Kim, Byung-Soo Jang, Ho-Sun Jwa, Seung-Wook Jang, Bong-Seok Kim, Moon-Bum Oh, Chang-Keun Kwon, Yoo-Wook Kwon, Kyung-Sool TI Generalized pustular psoriasis and hepatic dysfunction associated with oral terbinafine therapy SO JOURNAL OF KOREAN MEDICAL SCIENCE LA English DT Article DE psoriasis; generalized pustular psoriasis; liver diseases; terbinafine ID EXANTHEMATOUS PUSTULOSIS; DRUG ERUPTION AB We report a case of 61-yr-old man with stable psoriasis who progressively developed generalized pustular eruption, erythroderma, fever, and hepatic dysfunction following oral terbinafine. Skin biopsy was compatible with pustular psoriasis. After discontinuation of terbinafine and initiating topical corticosteroid and calcipotriol combination with narrow band ultraviolet B therapy, patient's condition slowly improved until complete remission was reached 2 weeks later. The diagnosis of generalized pustular psoriasis (GPP) induced by oral terbinafine was made. To our knowledge, this is the first report of GPP accompanied by hepatic dysfunction associated with oral terbinafine therapy. C1 Pusan Natl Univ, Coll Med, Dept Dermatol, Pusan 602739, South Korea. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Jang, HS (reprint author), Pusan Natl Univ, Coll Med, Dept Dermatol, 1-10 Ami Dong, Pusan 602739, South Korea. EM hsjang@pusan.ac.kr NR 12 TC 7 Z9 9 U1 1 U2 2 PU KOREAN ACAD MEDICAL SCIENCES PI SEOUL PA 302 75 DONG DU ICHON, DONG YONGSAN KU, SEOUL 140 031, SOUTH KOREA SN 1011-8934 J9 J KOREAN MED SCI JI J. Korean Med. Sci. PD FEB PY 2007 VL 22 IS 1 BP 167 EP 169 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 143NC UT WOS:000244728100034 PM 17297275 ER PT J AU Rosenberg, HF McSorley, SJ Srinivasan, A AF Rosenberg, Helene F. McSorley, Stephen J. Srinivasan, Aparna TI Interview with Dr. Stephen J. McSorley and Ms. Aparna Srinivasan regarding pivotal advance: Secondary exposure to LPS suppresses CD4+T cells and exacerbates murine typhoid SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material ID T-CELLS; SALMONELLA; ANTIGEN C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 9 TC 1 Z9 1 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 FEB PY 2007 VL 81 IS 2 BP 401 EP 402 DI 10.1189/jlb.1306194 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 132TI UT WOS:000243964700005 ER PT J AU Liang, Y Huang, ZF Chen, HW Zhang, TY Ito, Y AF Liang, Yong Huang, Zhaofeng Chen, Hongwei Zhang, Tianyou Ito, Yoichiro TI Preparative isolation and purification of two closely related glycosidic flavonoids from Exocarpium citri grandis by high-speed countercurrent chromatography SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE Exocarpium citri Grandis; countercurrent chromatography; naringin; rhoifolin ID SEPARATION; ALKALOIDS; ISOFLAVONES AB High-speed countercurrent chromatography (HSCCC) was successfully used for the isolation and purification of two closely related glycosidic flavonoids from Exocarpium Citri Grandis. n-Hexane-1-butanol-methanol-0.5% acetic acid (1:3:1:4, v/v) was used as the two-phase solvent system. From 50 mg of crude extracts of Exocarpium citri Grandis, 28.8 mg of naringin, 1.4 mg of rhoifolin, and 5.7 mg of an unknown compound were obtained with the purity of 97.1%, 95.5%, and 97.5%, respectively, in a single run. Two flavonoids fractions were characterized by ESI-MS confirming that the data was identical to the literature values. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. S China Normal Univ, Sch Chem & Environm, Inst Analyt Chem, Guangzhou, Peoples R China. Beijing Inst New Technol Applicat, Beijing, Peoples R China. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334,50 S Dr MSC 8014, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 16 TC 7 Z9 10 U1 0 U2 12 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1082-6076 J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD FEB PY 2007 VL 30 IS 3 BP 419 EP 430 DI 10.1080/10826070601084886 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 120YE UT WOS:000243121900008 ER PT J AU Liang, Y Hu, JY Chen, HW Zhang, TY Ito, Y AF Liang, Yong Hu, Jiangyong Chen, Hongwei Zhang, Tianyou Ito, Yoichiro TI Preparative isolation and purification of four compounds from chinese medicinal herb Gentiana scabra Bunge by high-speed countercurrent chromatography SO JOURNAL OF LIQUID CHROMATOGRAPHY & RELATED TECHNOLOGIES LA English DT Article DE Gentiana scabra Bunge; high speed countercurrent chromatography (HSCCC); 8-hydroxy-10-hydrosweroside; swertiamarin; trifloroside ID SECOIRIDOIDS AB High-speed countercurrent chromatography (HSCCC) was applied to the separation and purification of 8-hydroxy-10-hydrosweroside, swertiamarin, and trifloroside from the Chinese medicinal herb Gentiana scabra Bunge. Fifty milligrams of crude extracts were separated using n-hexane-1-butanol-methanol-0.4% acetic acid in water (1.4:8:3:15.5, v/v) as the two-phase solvent system yielding 8 mg of 8-hydroxy-10-hydrosweroside, 18 mg of swertiamarin, 11 mg of trifloroside, and 4 mg of an unknown compound with the purity of 96.7, 98.4, 97.1, and 96.2%, respectively, in a one step separation. The chemical structures of these components were identified by ESI-MS. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. S China Normal Univ, Sch Chem & Environm, Inst Analyt Chem, Guangzhou, Peoples R China. Beijing Inst New Technol Applicat, Beijing, Peoples R China. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334,50 South Dr MSC 8014, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 11 TC 8 Z9 8 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1082-6076 J9 J LIQ CHROMATOGR R T JI J. Liq. Chromatogr. Relat. Technol. PD FEB PY 2007 VL 30 IS 4 BP 509 EP 520 DI 10.1080/10826070601093812 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 142VQ UT WOS:000244679100006 ER PT J AU Iwahara, J Tang, C Clore, GM AF Iwahara, Junji Tang, Chun Clore, G. Marius TI Practical aspects of H-1 transverse paramagnetic relaxation enhancement measurements on macromolecules SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE H-1-T-2; paramagnetic relaxation enhancement; EDTA-Mn2+; spin-label ID GLOBAL FOLD DETERMINATION; SITE-DIRECTED SPIN; PROTON RELAXATION; NUCLEAR-RELAXATION; NMR STRUCTURE; STAPHYLOCOCCAL NUCLEASE; STRUCTURE REFINEMENT; STRUCTURAL BASIS; PROTEIN; BINDING AB The use of H-1 transverse paramagnetic relaxation enhancement (PRE) has seen a resurgence in recent years as method for providing long-range distance information for structural studies and as a probe of large amplitude motions and lowly populated transient intermediates in macromolecular association. In this paper we discuss various practical aspects pertaining to accurate measurement of PRE 1H transverse relaxation rates (Gamma(2)). We first show that accurate Gamma(2) rates can be obtained from a two time-point measurement without requiring any fitting procedures or complicated error estimations, and no additional accuracy is achieved from multiple time-point measurements recorded in the same experiment time. Optimal setting of the two time-points that minimize experimental errors is also discussed. Next we show that the simplistic single time-point measurement that has been commonly used in the literature, can substantially underestimate the true value of Gamma(2), unless a relatively long repetition delay is employed. We then examine the field dependence of Gamma(2), and show that Gamma(2) exhibits only a very weak field dependence at high magnetic fields typically employed in macromolecular studies. The theoretical basis for this observation is discussed. Finally, we investigate the impact of contamination of the paramagnetic sample by trace amounts (<= 5%) of the corresponding diamagnetic species on the accuracy of Gamma(2) measurements. Errors in Gamma(2) introduced by such diamagnetic contamination are potentially sizeable, but can be significantly reduced by using a relatively short time interval for the two time-point Gamma(2) measurement. Published by Elsevier Inc. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK029023-15] NR 52 TC 116 Z9 118 U1 2 U2 36 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 EI 1096-0856 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2007 VL 184 IS 2 BP 185 EP 195 DI 10.1016/j.jmr.2006.10.003 PG 11 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 136PQ UT WOS:000244237000001 PM 17084097 ER PT J AU Yang, J Shen, J AF Yang, Jehoon Shen, Jun TI Relayed C-13 magnetization transfer: Detection of malate dehydrogenase reaction in vivo SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE in vivo MRS; magnetization transfer; malate dehydrogenase; carbon-13; enzymology ID CITRIC-ACID CYCLE; RAT-BRAIN; 11.7 TESLA; ASPARTATE-AMINOTRANSFERASE; PYRUVATE-CARBOXYLASE; SATURATION-TRANSFER; LIVER; OXALOACETATE; PURIFICATION; NEURONS AB Malate dehydrogenase catalyzes rapid interconversion between dilute metabolites oxaloacetate and malate. Both oxaloacetate and malate are below the detection threshold of in vivo MRS. Oxaloacetate is also in rapid exchange with aspartate catalyzed by aspartate aminotransferase, the latter metabolite is observable in vivo using C-13 MRS. We hypothesized that the rapid turnover of oxaloacetate can effectively relay perturbation of magnetization between malate and aspartate. Here, we report indirect observation of the malate dehydrogenase reaction by saturating malate C2 resonance at 71.2 ppm and detecting a reduced aspartate C2 signal at 53.2 ppm due to relayed magnetization transfer via oxaloacetate C2 at 201.3 ppm. Using this strategy the rate of the cerebral malate clehydrogenase reaction was determined to be 9 +/- 2 mu mol/g wet weight/min (means +/- SD, n = 5) at 11.7 Tesla in anesthetized adult rats infused with [1,6- C-13(2)]glucose. Published by Elsevier Inc. C1 NIMH, Mol Imaging Branch, Hlth Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Hlth Intramural Res Program, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU Intramural NIH HHS [Z01 MH002803-06] NR 28 TC 6 Z9 7 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 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD FEB PY 2007 VL 184 IS 2 BP 344 EP 349 DI 10.1016/j.jmr.2006.11.002 PG 6 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 136PQ UT WOS:000244237000017 PM 17126047 ER PT J AU Gomez, R Romero, R Nien, JK Medina, L Carstens, M Kim, YM Espinoza, J Chaiworapongsa, T Gonzalez, R Iams, JD Rojas, I AF Gomez, Ricardo Romero, Roberto Nien, Jyh Kae Medina, Luis Carstens, Mario Kim, Yeon Mee Espinoza, Jimmy Chaiworapongsa, Tinnakorn Gonzalez, Rogelio Iams, Jay D. Rojas, Ivan TI Antibiotic administration to patients with preterm premature rupture of membranes does not eradicate intra-amniotic infection SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 14-19, 2002 CL NEW ORLEANS, LA SP Soc Maternal Fetal Med DE chorioamnionitis; antibiotic therapy; rupture of membranes; amniocentesis ID FETAL INFLAMMATORY RESPONSE; POLYMERASE-CHAIN-REACTION; UREAPLASMA-UREALYTICUM; AMNIOTIC CAVITY; MACROLIDE ANTIBIOTICS; EXPECTANT MANAGEMENT; MICROBIAL INVASION; INFANT MORBIDITY; RANDOMIZED TRIAL; LABOR AB Objective. Antibiotic administration has become part of the standard of care for patients with preterm premature rupture of membranes (PROM). Yet, the natural history of intrauterine infection/inflammation during antibiotic therapy remains largely unknown. This study was conducted to determine if antibiotic administration to the mother eradicates intra-amniotic infection and/or reduces the frequency of intra-amniotic inflammation, a risk factor for impending preterm labor/delivery and adverse neonatal outcome. Methods. A subset of patients with preterm PROM admitted to our institution underwent amniocenteses before and after antibiotic administration in order to guide clinical management. Amniotic fluid analysis consisted of a Gram stain, culture for aerobic and anaerobic bacteria as well as genital mycoplasmas, and amniotic fluid white blood cell (WBC) count. Microbial invasion of the amniotic cavity (MIAC) was defined as a positive amniotic fluid culture. Intra-amniotic inflammation was defined as an amniotic fluid WBC count >= 100/mm(3). Patients were given antibiotics and steroids after the 24th week of gestation. Antibiotic treatment consisted of ampicillin and erythromycin for 7 days for patients without evidence of intra-amniotic inflammation or MIAC, and ceftriaxone, clindamycin and erythromycin for 10-14 days for those with intra-amniotic inflammation or MIAC. Results. Forty-six patients with preterm PROM whose first amniocentesis was performed between 18 and 32 weeks (median 27.4 weeks) were included in the study. The overall prevalence of intra-amniotic inflammation in the first amniocentesis was 39% (18/46). Seven had a positive amniotic fluid culture for microorganisms. At the time of the second amniocentesis, six of the seven patients with a positive amniotic fluid culture had microorganisms. Of 18 patients with intra-amniotic inflammation at admission, only three showed no evidence of inflammation after antibiotic treatment. Among patients with no evidence of intra-amniotic inflammation at admission, 32% (9/28) developed inflammation despite therapy. Five of these nine patients had positive amniotic fluid cultures. Conclusions. (1) Antibiotic administration (ceftriaxone, clindamycin, and erythromycin) rarely eradicates intra-amniotic infection in patients with preterm PROM; (2) intra-amniotic inflammation developed in one-third of patients who did not have inflammation at admission, despite antibiotic administration; (3) a sub-group of patients with documented inflammation of the amniotic cavity demonstrated a decrease in the intensity of the inflammatory process after antibiotic administration. C1 NICHD, Perinatal Res Branch, NIH, US Dept HHS, Detroit, MI 48201 USA. P Univ Catolica Chile, Hosp Dr Sotero Rio, Ctr Perinatal Diag & Res CEDIP, Puente Alto, Chile. Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. RP Romero, R (reprint author), NICHD, Perinatal Res Branch, NIH, US Dept HHS, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS NR 43 TC 52 Z9 59 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD FEB PY 2007 VL 20 IS 2 BP 167 EP 173 DI 10.1080/14767050601135485 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 145LK UT WOS:000244866400010 PM 17437216 ER PT J AU Goldstein, AM Chan, M Harland, M Hayward, NK Demenais, F Bishop, DT Azizi, E Bergman, W Bianchi-Scarra, G Bruno, W Calista, D Albright, LAC Chaudru, V Chompret, A Cuellar, F Elder, DE Ghiorzo, P Gillanders, EM Gruis, NA Hansson, J Hogg, D Holland, EA Kanetsky, PA Kefford, RF Landi, MT Lang, J Leachman, SA MacKie, RM Magnusson, V Mann, GJ Bishop, JN Palmer, JM Puig, S Puig-Butille, JA Stark, M Tsao, H Tucker, MA Whitaker, L Yakobson, E AF Goldstein, Alisa M. Chan, May Harland, Mark Hayward, Nicholas K. Demenais, Florence Bishop, D. Timothy Azizi, Esther Bergman, Wilma Bianchi-Scarra, Giovanna Bruno, William Calista, Donato Albright, Lisa A. Cannon Chaudru, Valerie Chompret, Agnes Cuellar, Francisco Elder, David E. Ghiorzo, Paola Gillanders, Elizabeth M. Gruis, Nelleke A. Hansson, Johan Hogg, David Holland, Elizabeth A. Kanetsky, Peter A. Kefford, Richard F. Landi, Maria Teresa Lang, Julie Leachman, Sancy A. MacKie, Rona M. Magnusson, Veronica Mann, Graham J. Bishop, Julia Newton Palmer, Jane M. Puig, Susana Puig-Butille, Joan A. Stark, Mitchell Tsao, Hensin Tucker, Margaret A. Whitaker, Linda Yakobson, Emanuel CA Lund Melanoma Study Grp Melaoma Genet Consortium TI Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID MULTIPLE PRIMARY MELANOMAS; DYSPLASTIC NEVUS SYNDROME; POPULATION-BASED SAMPLE; CUTANEOUS MELANOMA; MALIGNANT-MELANOMA; PANCREATIC-CANCER; P16; KINDREDS; RISK; CDK4 AB Background: The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Methods: These four features were examined in 385 families with >= 3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents. Results: Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p=0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, >= 2 patients with MPM, median age at melanoma diagnosis <= 40 years and >= 6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only >= 1 patient with MPM and age at diagnosis <= 40 years simultaneously predicted the mutation risk. Conclusions: The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer-CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed. C1 DHHS, NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Canc Res UK Clin Ctr, Genet Epidemiol Div, Leeds, W Yorkshire, England. Queensland Inst Med Res, Brisbane, Qld, Australia. Univ Evry, U794, INSERM, Evry, France. Tel Aviv Univ, Chaim Sheba Med Ctr, Dept Dermatol, Tel Aviv, Israel. Leiden Univ, Ctr Med, Dept Dermatol, Leiden, Netherlands. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. Maurizio Bufalini Hosp, Dermatol Unit, Cesena, Italy. Univ Utah, Sch Med, Dept Med Informat, Salt Lake City, UT USA. Inst Gustave Roussy, Serv Genet, Villejuif, France. IDIBAPS, Hosp Clin Barcelona, Melanoma Unit, Dermatol Dept, Barcelona, Spain. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. DHHS, Natl Human Genome Res Inst, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. Karolinska Univ Hosp Solna, Stockholm, Sweden. Univ Toronto, Dept Med, Toronto, ON, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Goldstein, AM (reprint author), DHHS, NCI, Genet Epidemiol Branch, NIH, Execut Plaza S,Room 7004,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. EM goldstea@exchange.nih.gov RI Stark, Mitchell/E-3542-2010; Mann, Graham/G-4758-2014; Hoiom, Veronica/F-4153-2012; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; Whiteman, David/P-2728-2014; Bruno, William/N-7477-2013 OI Bishop, Tim/0000-0002-8752-8785; Brunet, Joan/0000-0003-1945-3512; albright, lisa/0000-0003-2602-3668; Puig, Susana/0000-0003-1337-9745; Martin, Nicholas/0000-0003-4069-8020; Stark, Mitchell/0000-0002-4510-2161; Mann, Graham/0000-0003-1301-405X; Gruis, Nelleke/0000-0002-5210-9150; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; hayward, nicholas/0000-0003-4760-1033; Whiteman, David/0000-0003-2563-9559; Bruno, William/0000-0002-0337-0168 FU Intramural NIH HHS; NCI NIH HHS [1 R01 CA83115-01A2, K07 CA080700, K07 CA80700, N01-PC-35141, R01 CA083115, R01 CA088363, R01 CA102422, R01 CA88363] NR 48 TC 88 Z9 93 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 EI 1468-6244 J9 J MED GENET JI J. Med. Genet. PD FEB PY 2007 VL 44 IS 2 BP 99 EP 106 DI 10.1136/jmg.2006.043802 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 134QG UT WOS:000244098100003 PM 16905682 ER PT J AU Sachdeva, G D'Costa, J Cho, JE Kachapati, K Choudhry, V Arya, SK AF Sachdeva, Geetanjali D'Costa, Jenice Cho, Jang E. Kachapati, Kritika Choudhry, Vidita Arya, Suresh K. TI Chimeric HIV-1 and HIV-2 lentiviral vectors with added safety insurance SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE hybrid vectors; cross-packaging; cis elements; trans factors; non-reciprocal interaction ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNA INTERFERENCE; GENE-TRANSFER; REGULATORY ELEMENT; PACKAGING SIGNAL; HUMAN GENOME; EXPRESSION; ENCAPSIDATION; TRANSDUCTION; HEPATITIS AB Lentiviruses are unique in their ability to infect both dividing and non-dividing cells. This makes the vectors derived from them particularly useful for gene transfer into non-dividing cells, including stem cells. Lentiviral vectors are becoming the vectors of choice for si/shRNA delivery. The utility of the lentiviral vectors will be enhanced if additional elements of safety are built into their design. One safety concern is the generation of replication competent virus by recombination. We reasoned that HIV-1 and HIV-2 hybrid or chimeric lentiviral vectors will have added safety insurance in this regard. This is based on the premise that HIV-1 and HIV-2 are dissimilar enough in sequence to curtail recombination, yet similar enough to complement functionally. For hybrid vectors, we found that both HIV-1 and HIV-2 transfer vector RNAs could be packaged to equivalent titer by the HIV-1 packaging machinery. However, HIV-2 packaging machinery was unable to package HIV-1 transfer vector as well as it did HIV-2 transfer vector. This non-reciprocacity suggested that the requirement for HIV-2 vectors was more stringent and that for HIV-1 vectors more promiscuous. When the HIV-1 transfer vector was packaged with the chimeric packaging construct where the leader-gag region of HIV-2 was replaced with that of HIV-1 packaging construct, the titer of the vector went up. This suggests that at least some of the determinants of specificity for vector assembly reside in the leader-gag region. Incorporation of central polypurine tract (cPPT) and woodchuck post-transcriptional enhance element (WPRE) into the HIV-2 vectors had only modest effect on vector titer. Thus, chimeric lentiviral vectors with added safety features can be designed without compromising transduction efficiency. (c) 2006 Wiley-Liss, Inc. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Arya, SK (reprint author), NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20892 USA. EM aryas@mail.nih.gov FU Intramural NIH HHS NR 32 TC 7 Z9 9 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD FEB PY 2007 VL 79 IS 2 BP 118 EP 126 DI 10.1002/jmv.20767 PG 9 WC Virology SC Virology GA 121RV UT WOS:000243175600003 PM 17177309 ER PT J AU Maltsev, VA Lakatta, EG AF Maltsev, Victor A. Lakatta, Edward G. TI Cardiac pacemaker cell failure with preserved I-f, I-CaL, and I-Kr: A lesson about pacemaker function learned from ischemia-induced bradycardia SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Editorial Material ID RABBIT SINOATRIAL NODE; SARCOPLASMIC-RETICULUM; GUINEA-PIG; DIASTOLIC DEPOLARIZATION; INTRACELLULAR CA2+; RYANODINE RECEPTOR; NA+-CA2+ EXCHANGER; CALCIUM CURRENTS; RELEASE; HEART C1 NIA, Lab Cardiovasc Sci, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Lab Cardiovasc Sci, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 41 TC 10 Z9 12 U1 0 U2 1 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 FEB PY 2007 VL 42 IS 2 BP 289 EP 294 DI 10.1016/j.yjmcc.2006.11.009 PG 6 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 139OS UT WOS:000244442200005 PM 17188292 ER PT J AU Chen, QR Vansant, G Oades, K Pickering, M Wei, JS Song, YK Monforte, J Khan, J AF Chen, Qing-Rong Vansant, Gordon Oades, Kahuku Pickering, Maria Wei, Jun S. Song, Young K. Monforte, Joseph Khan, Javed TI Diagnosis of the small round blue cell tumors using multiplex polymerase chain reaction SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Article ID ARTIFICIAL NEURAL-NETWORKS; GENE; CLASSIFICATION; PREDICTION AB The small round blue cell tumors of childhood, which include neuroblastoma, rhabdomyosarcoma, non Hodgkin's lymphoma, and the Ewing's family of tumors, are so called because of their similar appearance on routine histology. Using cDNA microarray gene expression profiles and artificial neural networks (ANNs), we previously identified 93 genes capable of diagnosing these cancers. Using a subset of these, together with some additional genes (total 39), we developed a multiplex polymerase chain reaction (PCR) assay to diagnose these cancer types. Blinded testing of 96 new samples (26 Ewing's family of tumors, 29 rhabdomyosarcomas, 24 neuroblastomas, and 17 lymphomas) using ANNs in a complete leave-one-out analysis demonstrated that all except one sample were accurately diagnosed as their respective category. Moreover, using an ANN-based gene minimization strategy in a separate analysis, we found that the top 31 genes could correctly diagnose an 96 tumors. Our results suggest that this molecular test based on a multiplex PCR reaction may assist the physician in the rapid confirmation of the diagnosis of these cancers. C1 NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, Gaithersburg, MD 20877 USA. NCI, SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. Althea Technol, San Diego, CA USA. RP Khan, J (reprint author), NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM jmonforte@altheatech.com; khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 11 TC 34 Z9 39 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD FEB PY 2007 VL 9 IS 1 BP 80 EP 88 DI 10.2353/jmoldx.2007.060111 PG 9 WC Pathology SC Pathology GA 131VF UT WOS:000243898200011 PM 17251339 ER PT J AU Jones, TH Voegtle, HL Miras, HM Weatherford, RG Spande, TF Garraffo, HM Daly, JW Davidson, DW Snelling, RR AF Jones, Tappey H. Voegtle, Heather L. Miras, Heather M. Weatherford, Robert G. Spande, Thomas F. Garraffo, H. Martin Daly, John W. Davidson, Diane W. Snelling, Roy R. TI Venom chemistry of the ant Myrmicaria melanogaster from Brunei SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID POISON GLAND SECRETION; THIEF ANTS; ALKALOIDS; SOLENOPSIS; INDOLIZIDINES; DECAHYDROQUINOLINES; PYRROLIDINES; QUINOLIZIDINES; PYRROLIZIDINES; HYMENOPTERA AB Analysis of the extracts of the ant Myrmicaria melanogaster from Brunei in the Indonesian archipelago by GC-MS and GC-IR revealed the presence of five new alkaloids, identified as (9Z)-3-propylindolizidine (1), cis- and trans-2-butyl-5-propylpyrrolidine (2 and 3, respectively), (10E)-3-butyllehmizidine (7), and (5Z,8Z,9Z)-3-butyl-5-propyl-8-hydroxyindolizidine (10a), whose structures were established by comparison with synthetic samples. In addition the monoterpene hydrocarbons beta-pinene, myrcene, and limonene were detected along with all four isomers of 3-butyl-5-methylindolizidine (4a-d), cis- and trans-2-butyl-5-(4-pentenyl)pyrrolidine (5a and 5b), trans-2-butyl-5-pentylpyrrolidine (6), (5Z,9Z)-3-butyl-5-propylindolizidine (8), and (5Z,9E)-3-butyl-5-propylindolizidine (9), alkaloids well known from ants and frogs, whose structures were established on the basis of published spectra or comparison with authentic samples. This study utilized vapor-phase infrared analysis for the assignment of stereochemistry using Bohlmann bands for the bicyclic alkaloids and, in the case of 10a, the detection of an intramolecular hydrogen bond. A biogenetic relationship between the mono- and bicyclic ring systems is proposed. C1 Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. NIDDK, Bioorgan Chem Lab, NIH, HHS, Bethesda, MD 20892 USA. Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. Los Angeles Cty Museum Nat Hist, Los Angeles, CA 90007 USA. RP Jones, TH (reprint author), Virginia Mil Inst, Dept Chem, Lexington, VA 24450 USA. EM jonesth@vmi.edu FU Intramural NIH HHS NR 39 TC 37 Z9 38 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2007 VL 70 IS 2 BP 160 EP 168 DI 10.1021/np068034t PG 9 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 138VH UT WOS:000244390900004 PM 17243727 ER PT J AU Turner, A Chen, SN Nikolic, D van Breemen, R Farnsworth, NR Pauli, GF AF Turner, Allison Chen, Shao-Nong Nikolic, Dejan van Breemen, Richard Farnsworth, Norman R. Pauli, Guido F. TI Coumaroyl iridoids and a depside from cranberry (Vaccinium macrocarpon) SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID FIMBRIATED ESCHERICHIA-COLI; B2 EPICATECHIN-(4-BETA-8)-EPICATECHIN; INHIBIT ADHERENCE; CONDENSED TANNINS; JUICE; URINARY; PROCYANIDINS; RATS; METABOLISM; ABSORPTION AB Cranberry (Vaccinium macrocarpon) juice has been used for urinary tract infections for approximately 50 years. Recent research suggests that this botanical blocks adherence of pathogenic E. coli to urinary tract cells, thus preventing infection. While current evidence indicates that proanthocyanidins are responsible for this activity, these compounds may not reach the urinary tract; thus further investigation is warranted. Fractionation of cranberry juice concentrate was guided by a recently published antiadherence assay, and the resulting fractions were phytochemically characterized. Two new coumaroyl iridoid glycosides, 10-p-trans- (1) and 10-p-cis-coumaroyl-1S-dihydromonotropein (2), and a depside, 2-O-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxyphenylmethylacetate (3), were isolated, and although these compounds did not have antiadherent activity in isolation, they might constitute a new group of marker compounds for this active fraction of cranberry. C1 Univ Illinois, Coll Pharm, UIC,NIH,Ctr Bot Dietary Supplements Res, Dept Med Chem & Pharmacognosy MC 781, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, PCRPS, Chicago, IL 60612 USA. RP Pauli, GF (reprint author), Univ Illinois, Coll Pharm, UIC,NIH,Ctr Bot Dietary Supplements Res, Dept Med Chem & Pharmacognosy MC 781, 833 S Wood St, Chicago, IL 60612 USA. EM gfp@uic.edu FU NCCIH NIH HHS [F31 AT000623, P50 AT000155, F3 AT00623, P50 AT000155-070001, P50 AT00155] NR 46 TC 27 Z9 29 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD FEB PY 2007 VL 70 IS 2 BP 253 EP 258 DI 10.1021/np060260f PG 6 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 138VH UT WOS:000244390900018 PM 17269823 ER PT J AU Murthy, A Ray, S Shorter, SM Priddy, EG Schall, JD Thompson, KG AF Murthy, Aditya Ray, Supriya Shorter, Stephanie M. Priddy, Elizabeth G. Schall, Jeffrey D. Thompson, Kirk G. TI Frontal eye field contributions to rapid corrective Saccades SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID STIMULUS-RESPONSE COMPATIBILITY; ANTERIOR CINGULATE CORTEX; DOUBLE-STEP STIMULI; VISUAL-SEARCH TASK; SUPERIOR COLLICULUS; TARGET SELECTION; CURVED SACCADES; COUNTERMANDING SACCADES; NEURAL SELECTION; ERROR CORRECTION AB Visually guided movements can be inaccurate, especially if unexpected events occur while the movement is programmed. Often errors of gaze are corrected before external feedback can be processed. Evidence is presented from macaque monkey frontal eye field (FEF), a cortical area that selects visual targets, allocates attention, and programs saccadic eye movements, for a neural mechanism that can correct saccade errors before visual afferent or performance monitoring signals can register the error. Macaques performed visual search for a color singleton that unpredictably changed position in a circular array as in classic double-step experiments. Consequently, some saccades were directed in error to the original target location. These were followed frequently by unrewarded, corrective saccades to the final target location. We previously showed that visually responsive neurons represent the new target location even if gaze shifted errantly to the original target location. Now we show that the latency of corrective saccades is predicted by the timing of movement-related activity in the FEF. Preceding rapid corrective saccades, the movement-related activity of all neurons began before explicit error signals arise in the medial frontal cortex. The movement-related activity of many neurons began before visual feedback of the error was registered and that of a few neurons began before the error saccade was completed. Thus movement-related activity leading to rapid corrective saccades can be guided by an internal representation of the environment updated with a forward model of the error. C1 Natl Brain Res Ctr, Gurgaon 122050, Haryana, India. Vanderbilt Univ, Vanderbilt Vis Res Ctr, Ctr Integrat & Cognit Neurosci, Dept Psychol, Nashville, TN USA. NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Murthy, A (reprint author), Natl Brain Res Ctr, Near NSG Campus,NH-8,Nainwal Mode, Gurgaon 122050, Haryana, India. EM aditya@nbrc.ac.in FU NEI NIH HHS [T32 EY 08126, P30 EY 08126, R01 EY 08890, F32 EY 14502]; NICHD NIH HHS [P30 HD 015052] NR 73 TC 49 Z9 50 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2007 VL 97 IS 2 BP 1457 EP 1469 DI 10.1152/jn.00433.2006 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 134NQ UT WOS:000244090500047 PM 17135479 ER PT J AU Purvis, LK Smith, JC Koizumi, H Butera, RJ AF Purvis, L. K. Smith, J. C. Koizumi, H. Butera, R. J. TI Intrinsic bursters increase the robustness of rhythm generation in an excitatory network SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PRE-BOTZINGER COMPLEX; PERSISTENT SODIUM CURRENT; BRAIN-STEM SLICES; RESPIRATORY RHYTHM; IN-VITRO; PACEMAKER NEURONS; MEDULLARY SLICES; SPINAL-CORD; CURRENTS; MODULATION AB The pre-Botzinger complex (pBC) is a vital subcircuit of the respiratory central pattern generator. Although the existence of neurons with pacemaker-like bursting properties in this network is not questioned, their role in network rhythmogenesis is unresolved. Modeling is ideally suited to address this debate because of the ease with which biophysical parameters of individual cells and network architecture can be manipulated. We modeled the parameter variability of experimental data from pBC bursting pacemaker and nonpacemaker neurons using a modified version of our previously developed pBC neuron and network models. To investigate the role of pacemakers in networkwide rhythmogenesis, we simulated networks of these neurons and varied the fraction of the population made up of pacemakers. For each number of pacemaker neurons, we varied the amount of tonic drive to the network and measured the frequency of synchronous networkwide bursting produced. Both excitatory networks with all-to-all coupling and sparsely connected networks were explored for several levels of synaptic coupling strength. Networks containing only nonpacemakers were able to produce networkwide bursting, but with a low probability of bursting and low input and output ranges. Our results indicate that inclusion of pacemakers in an excitatory network increases robustness of the network by more than tripling the input and output ranges compared with networks containing no pacemakers. The largest increase in dynamic range occurs when the number of pacemakers in the network is greater than 20% of the population. Experimental tests of our model predictions are proposed. C1 Georgia Inst Technol, Lab Neuroengn, Atlanta, GA 30332 USA. Georgia Inst Technol, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. Georgia Inst Technol, Wallace Coulter Dept Biomed Engn, Atlanta, GA 30332 USA. Natl Inst Neurol Disorders & Stroke, Cellular & Syst Neurobiol Sect, Bethesda, MD USA. Osaka Univ, Grad Sch Dent, Osaka, Japan. RP Butera, RJ (reprint author), Georgia Inst Technol, Lab Neuroengn, 313 Ferst Dr, Atlanta, GA 30332 USA. EM rbutera@gatech.edu OI Butera, Robert/0000-0002-1806-0621 FU Intramural NIH HHS; NIMH NIH HHS [R01 MH 62057] NR 44 TC 52 Z9 53 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 EI 1522-1598 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD FEB PY 2007 VL 97 IS 2 BP 1515 EP 1526 DI 10.1152/jn.00908.2006 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 134NQ UT WOS:000244090500052 PM 17167061 ER PT J AU Szerlip, NJ Fox, E Manosca, F Pegram, LD Lonser, RR AF Szerlip, Nicholas J. Fox, Elizabeth Manosca, Frances Pegram, Linda D. Lonser, Russell R. TI Pancreatoblastoma metastases to the brain - Case illustration SO JOURNAL OF NEUROSURGERY LA English DT Editorial Material DE metastasis; pancreatoblastoma; brain; radiation; chemotherapy; pediatric neurosurgery C1 Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Pathol Lab,NCI, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Pediat Oncol Branch, NIH, Pathol Lab,NCI, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Cytopathol Sect, NIH, Pathol Lab,nci, Bethesda, MD 20892 USA. Univ Maryland, Med Ctr, Dept Neurosurg, Baltimore, MD 21201 USA. Childrens Hosp Kings Daughters, Norfolk, VA USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Pathol Lab,NCI, 10 Ctr Dr,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2007 VL 106 IS 2 SU S BP 169 EP 169 DI 10.3171/ped.2007.106.2.169 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 140QH UT WOS:000244520100022 PM 17330549 ER PT J AU Murad, GJA Walbridge, S Morrison, PF Szerlip, N Butman, JA Oldfield, EH Lonser, RR AF Murad, Gregory J. A. Walbridge, Stuart Morrison, Paul F. Szerlip, Nicholas Butman, John A. Oldfield, Edward H. Lonser, Russell R. TI Image-guided convection-enhanced delivery of gemcitabine to the brainstem SO JOURNAL OF NEUROSURGERY LA English DT Article DE glioma; brainstem; gemcitabine; convection-enhanced delivery; magnetic resonance imaging; pediatrics; treatment; Macaca mulatta ID GROUP PHASE-I/II; HYPERFRACTIONATED RADIATION-THERAPY; PRIMATE BRAIN; COMPUTERIZED-TOMOGRAPHY; DRUG-DELIVERY; GLIOMAS; CHILDREN; MACROMOLECULES; INFUSION; CHEMOTHERAPY AB Object. To determine if the potent antiglioma chemotherapeutic agent gemcitabine could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution using a surrogate magnetic resonance (MR) imaging tracer, the authors used convection-enhanced delivery to perfuse the primate brainstem with gemcitabine and Gd-diethylenetnamine pentaacetic acid (DTPA). Methods. Six primates underwent convective brainstem perfusion with gemcitabine (0.4 mg/ml; two animals), GdDTPA (5 mM; two animals), or a coinfusion of gemcitabine (0.4 mg/ml) and Gd-DTPA (5 mM; two animals), and were killed 28 days afterward. These primates were observed over time clinically (six animals), and with MR imaging (five animals), quantitative autoradiography (one animal), and histological analysis (all animals). In an additional primate, H-3-gemcitabine and Gd-DTPA were confused and the animal was killed immediately afterward. In the primates there was no histological evidence of infusate-related tissue toxicity. Magnetic resonance images obtained during infusate delivery demonstrated that the anatomical region infused with Gd-DTPA was clearly distinguishable from surrounding noninfused tissue. Quantitative autoradiography confirmed that Gd-DTPA tracked the distribution of 3H-gemcitabine and closely approximated its volume of distribution (mean volume of distribution difference 13.5%). Conclusions. Gemcitabine can be delivered safely and effectively to the primate brainstern at therapeutic concentrations and at volumes that are higher than those considered clinically relevant. Moreover, MR imaging can be used to track the distribution of gemcitabine by adding Gd-DTPA to the infusate. This delivery paradigm should allow for direct therapeutic application of gemcitabine to brainstern gliomas while monitoring its distribution to ensure effective tumor coverage and to maximize safety. C1 Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Neuroradiol Sect, Bethesda, MD 20892 USA. Univ Florida, J Hillis Miller Hlth Ctr, Dept Neurosurg, Gainesville, FL 32610 USA. Univ Maryland, Dept Neurosurg, Baltimore, MD 21201 USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Warren Grant Magnuson Clin Ctr, 10 Ctr Dr,Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS NR 27 TC 35 Z9 35 U1 0 U2 2 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 FEB PY 2007 VL 106 IS 2 BP 351 EP 356 DI 10.3171/jns.2007.106.2.351 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 140QD UT WOS:000244519700027 PM 17410722 ER PT J AU Dilsizian, V Eckelman, WC Loredo, ML Jagoda, EM Shirani, J AF Dilsizian, Vasken Eckelman, William C. Loredo, Maria L. Jagoda, Elaine M. Shirani, Jamshid TI Evidence for tissue angiotensin-converting enzyme in explanted hearts of ischemic cardiomyopathy using targeted radiotracer technique SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE angiotensin-converting enzyme; angiotensin receptor; heart failure; radionuclide imaging; remodeling; chymase ID LEFT-VENTRICULAR DYSFUNCTION; IN-VIVO MEASUREMENTS; RENIN-ANGIOTENSIN; ACE-INHIBITION; FAILURE; PROGRESSION; FIBROSIS; LISINOPRIL; ACTIVATION; KINETICS AB This study aimed to determine the magnitude and distribution of tissue angiotensin-converting enzyme (ACE), mast-cell chymase, and angiotensin II, type 1, plasma membrane receptor (AT(1)R), in relation to collagen replacement in infarcted and noninfarcted left ventricular myocardial segments. A new radiotracer, F-18-fluorobenzoyl-lisinopril (FBL), was synthesized without compromising its affinity for tissue ACE. Methods: Five- to 10-mu m contiguous short-axis slices of explanted hearts from 3 patients with ischemic cardiomyopathy were incubated in vitro with FBL, with and without 10(-6) M lisinopril. Tissue radioactivity was recorded as a function of position in photostimulating luminescence units (PSL). Immunohistochemistry studies were performed with mouse monoclonal antibody against ACE, anti-mast cell chymase, and polyclonal antibody against the human AT(1)R. Results: There was specific binding of FBL to ACE; mean FBL binding was 6.6 +/- 5.2 PSL/mm(2), compared with 3.4 +/- 2.5 PSL/mm(2) in segments incubated in solution containing cold, 10(-6) M lisinopril (P < 0.0001). Mean FBL binding was 6.3 +/- 4.5 PSL/mm(2) in infarcted, 7.6 +/- 4.7 PSL/mm(2) in periinfarcted, and 5.0 +/- 1.0 PSL/mm(2) in remote, noninfarcted (P < 0.02 vs. periinfarcted) segments. The autoradiographic observations concerning FBL binding were confirmed by ACE and AT(1)R immunoreactivity. Distribution of mast cell chymase differed from ACE, as a higher number of mast cells was present in the remote, noninfarcted myocardium than in the periinfarcted myocardium (5.1 +/- 3.2 vs. 3.2 +/- 2.2 mast cells per field, P < 0.001). The number of mast cells in ischemic hearts exceeded that in normal hearts (4.2 +/- 2.7 vs. 1.5 +/- 2.2 mast cells per field, x200, P < 0.001). Conclusion: FBL binds specifically to ACE. The binding is nonuniform in infarcted, periinfarcted, and remote, noninfarcted segments, and there is apparently increased ACE activity in the juxtaposed areas of replacement fibrosis. On the other hand, the distribution of mast cell chymase appears nonuniform and disparate from ACE. C1 Univ Maryland Hosp, Div Nucl Med, Baltimore, MD 21201 USA. Sch Med, Baltimore, MD USA. Mol Tracer LLC, Bethesda, MD USA. Univ Panamer, Sch Med, Mexico City, DF, Mexico. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. Geisinger Med Ctr, Div Cardiol, Danville, PA 17822 USA. RP Dilsizian, V (reprint author), Univ Maryland, Med Ctr, 22 S Greene St,Room N2W78, Baltimore, MD 21201 USA. EM vdilsizian@umm.edu FU Intramural NIH HHS NR 26 TC 32 Z9 34 U1 0 U2 2 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD FEB PY 2007 VL 48 IS 2 BP 182 EP 187 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 134WR UT WOS:000244115600021 PM 17268012 ER PT J AU Wanke, KL Daston, C Slonim, A Albert, PS Snyder, K Schatzkin, A Lanza, E AF Wanke, Kay L. Daston, Cassandra Slonim, Amy Albert, Paul S. Snyder, Kirk Schatzkin, Arthur Lanza, Elaine TI Adherence to the polyp prevention trial dietary intervention is associated with a behavioral pattern of adherence to nondietary trial requirements and general health recommendations SO JOURNAL OF NUTRITION LA English DT Article ID LOW-FAT; PLASMA CAROTENOIDS; BREAST-CANCER; WEIGHT-LOSS; FUNDAMENTAL PRINCIPLES; ENERGY PHYSIOLOGY; HIGH-FIBER; HIGH-FRUIT; RISK; BIOMARKERS AB This study investigated the factors associated with success in meeting the dietary goals of the Polyp Prevention Trial (PPT), a 4-y low-fat, high-fiber, high-fruit/vegetable dietary intervention. The PPT provided a rare opportunity to assess factors in long-term adherence to a dietary pattern that required changes to multiple aspects rather than a single aspect of diet. Demographics, health indicators, and dietary intake were assessed at baseline and annually for 4 y of follow-up. Participants (n = 833) received dietary and behavioral counseling to support adherence to trial dietary goals. We assessed the association of baseline variables and trial participation with success in meeting dietary goals. Participant adherence to the intervention goals was significantly associated with never smoking, no history of weight gain, and consumption of less fat and more fiber, fruits, and vegetables at trial baseline. Successful participants were also more educated and married, whereas those with the poorest adherence were older. In addition, successful participants demonstrated greater participation throughout the trial, including attendance at counseling sessions, completion of dietary records, and contacts with staff. Of particular interest were the behavioral and demographic characteristics that distinguished the subset of participants who achieved most or all dietary intervention goals across all 4 study years who we termed Super Compliers. These individuals also were more likely to adhere to social norms for healthy lifestyles and demonstrated greater adherence to other aspects of trial participation. C1 NIDA, Epidemiol Res Branch, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. Daston Commun, Chapel Hill, NC 27514 USA. Michigan Publ Hlth Inst, Okemos, MI 48864 USA. Informat Management Serv Inc, Silver Spring, MD 20904 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Lab Canc Prevent, Canc Res Ctr, Bethesda, MD 20892 USA. RP Wanke, KL (reprint author), NIDA, Epidemiol Res Branch, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. EM wankek@mail.nih.gov FU Intramural NIH HHS NR 42 TC 15 Z9 15 U1 0 U2 0 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2007 VL 137 IS 2 BP 391 EP 398 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 130DM UT WOS:000243779600018 PM 17237317 ER PT J AU Seaverson, EL Buell, JS Fleming, DJ Bermudez, OI Potischman, N Wood, RJ Chasan-Taber, L Tucker, KL AF Seaverson, Erin L. Buell, Jennifer S. Fleming, Diana J. Bermudez, Odilia I. Potischman, Nancy Wood, Richard J. Chasan-Taber, Lisa Tucker, Katherine L. TI Poor iron status is more prevalent in Hispanic than in non-Hispanic white older adults in Massachusetts SO JOURNAL OF NUTRITION LA English DT Article ID EASTERN FINNISH MEN; HEART-STUDY COHORT; SERUM FERRITIN; NONHEME-IRON; HEMOGLOBIN CONCENTRATION; MYOCARDIAL-INFARCTION; ELDERLY POPULATION; ASCORBIC-ACID; UNITED-STATES; STORES AB Iron status and dietary correlates of iron status have not been well described in Hispanic older adults of Caribbean origin. The aim of this study was to evaluate iron status and describe dietary components and correlates of iron status in Hispanic older adults and in a neighborhood-based comparison group of non-Hispanic white older adults. Six hundred four Hispanic and non-Hispanic white adults (59-91 y of age) from the Massachusetts Hispanic Elders Study were included in the analysis. We examined physiological markers of iron status as well as dietary factors in relation to iron status. Dietary intake was assessed by FFQ. Our results revealed that Hispanics had significantly lower geometric mean serum ferritin (74.1 mu g/L vs. 100 mu g/L; P < 0.001), lower hemoglobin concentrations (137 +/- 13 vs. 140 +/- 12 mu g/L; P < 0.01), higher prevalence of anemia (11.5 vs. 7.3%; P < 0.05), and suboptimal hemoglobin concentrations (< 125 g/L) for this age group (21.4 vs. 13.3%, P < 0.05). Iron deficiency anemia was higher (7.2% vs. 2.3%; P < 0.05) in Hispanic women. Hispanics had lower mean intakes of total iron, vitamin C, supplemental vitamin C, and total calcium than did non-Hispanic whites. After adjusting for age, sex, BMI, alcohol use, smoking, total energy intake, inflammation, diabetes, and liver disease, intake of heme iron from red meat was positively associated and dietary calcium was negatively associated with serum ferritin. This population of Hispanic older adults was significantly more likely than their non-Hispanic white neighbors to suffer from anemia and poor iron status, particularly among women. Cultural variation in dietary patterns may influence iron availability and body iron stores and contribute to an increased risk for iron deficiency anemia among some Hispanic older adults. C1 Tufts Univ, Jean Mayers USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Tufts Univ, Gearld J & Dorothy R Friedman Sch Nutr Sci & Poli, Boston, MA 02111 USA. NCI, Bethesda, MD 20892 USA. Univ Massachusetts, Dept Biostat & Epidemiol, Amherst, MA 01003 USA. RP Tucker, KL (reprint author), Tufts Univ, Jean Mayers USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM katherine.tucker@tufts.edu RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X FU NIA NIH HHS [AG023394, AG10425, P01 AG023394] NR 49 TC 10 Z9 10 U1 0 U2 4 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD FEB PY 2007 VL 137 IS 2 BP 414 EP 420 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 130DM UT WOS:000243779600021 PM 17237320 ER PT J AU Lekhanont, K Park, CY Smith, JA Combs, JC Preechawat, P Suwan-Apichon, O Rangsin, R Chuck, RS AF Lekhanont, Kaevalin Park, Choul Yong Smith, Janine A. Combs, Juan Castro Preechawat, Pisit Suwan-Apichon, Olan Rangsin, Ram Chuck, Roy S. TI Effects of topical anti-inflammatory agents in a botulinum toxin B-induced mouse model of keratoconjunctivitis Sicca SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID DRY EYE DISEASE; FILAMENTARY KERATITIS; OPHTHALMIC EMULSION; DICLOFENAC SODIUM; DRUGS; CYCLOSPORINE; INHIBITION; THERAPY; SAFETY; HISTOPATHOLOGY AB Purpose: The aim of this study was to compare the effects of topical nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroid, doxycycline, and artificial tears for the treatment of ocular surface damage in the Botulinum toxin B (BTX-B)-induced mouse model of dry eye. Methods: CBA/J mice were randomized into 2 experimental groups of 35 animals each. The control group received a transconjunctival injection of 0.05 mL of saline into the left lacrimal gland, and another group was injected with 0.05 mL of 20 milliunits BTX-B solution (SPSS, Inc., Chicago, W. Three (3) days after intralacrimal gland injections, each group was equally randomized into 7 subgroups (n = 5 each) to receive treatment unilaterally into their left eyes with topical artificial tears (0.5% carboxymethylcellulose sodium), 0.1% fluorometholone, 0.1% nepafenac, 0.4% ketorolac, 0.09% bromfenac, 0.1% diclofenac, or 0.025% doxycycline. Tear volume, ocular surface changes, and spontaneous blink rate were evaluated in each of the 14 experimental subgroups. Results: Topical fluorometholone, nepafenac, and doxycycline significantly improved corneal surface staining in the BTX-B-injected mice within 2 weeks of treatment. Topical ketorolac, diclofenac, and bromfenac, applied twice-daily, partially reduce corneal staining, and did so more slowly by the 4-week time point. In comparison, topical artificial tear-treated mice did not demonstrate significant improvement of the corneal surface at any time point. Aqueous tear production in the BTX-B-injected fluorometholone-treated group started to return to baseline level within 2 weeks, although not significantly. Meanwhile, BTX-B-injected mice treated with artificial tears, topical NSAIDs, and doxycycline still exhibited a reduction in tear production up to 4 weeks. No significant differences in blink rate between the control and study groups undergoing the various treatments were noted at all time points. Conclusions: This study suggests the potential usefulness of topical NSAIDs, corticosteroid, and doxycycline for the clinical treatment of ocular surface epithelial disorders associated with dry eye. C1 Johns Hopkins Univ, Wilmer Ophthalmol Inst, Baltimore, MD 21286 USA. NEI, NIH, Bethesda, MD 20892 USA. Khon Kaen Univ, Fac Med, Dept Ophthalmol, Khon Kaen 40002, Thailand. Phramongkutklao Coll Med, Dept Mil & Community Med, Bangkok, Thailand. RP Chuck, RS (reprint author), Johns Hopkins Univ, Wilmer Ophthalmol Inst, 255 Woods Bldg,600 N Wolfe St, Baltimore, MD 21286 USA. EM rchuck1@jhmi.edu RI Khon Kaen University, Faculty of Medicine/A-3133-2009; 郑, 雪丽/H-3486-2012 NR 31 TC 12 Z9 15 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD FEB PY 2007 VL 23 IS 1 BP 27 EP 34 DI 10.1089/jop.2006.0071 PG 8 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 146DK UT WOS:000244914500004 PM 17341147 ER PT J AU Kador, PF Takahashi, Y Akagi, Y Blessing, K Randazzo, J Wyman, M AF Kador, Peter F. Takahashi, Yukio Akagi, Yoshio Blessing, Karen Randazzo, James Wyman, Milton TI Age-dependent retinal capillary pericyte degeneration in galactose-fed dogs SO JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS LA English DT Article ID ALDOSE REDUCTASE LOCALIZATION; VESSEL CHANGES; DIABETIC-RETINOPATHY; MURAL CELLS; LENS; QUANTITATION; PREVENTION; INHIBITORS; CATARACTS AB The galactose-fed beagle develops diabetes-like microvascular changes that are histologically and clinically similar in appearance to all stages of human diabetic retinopathy. This animal model is extremely useful for evaluating drugs for the treatment of diabetic retinopathy; however, the time required to develop the various retinal lesions (24-72 months for background to the proliferative stage) may be considered prohibitive. Retinal vascular changes begin with an initial degeneration of capillary pericytes, which has been linked to the aldose reductase catalyzed formation of galactitol. Because aldose reductase-linked sugar cataract formation is known to be age dependent, with the onset and severity of cataract higher in younger diabetic and galactose-fed animals, retinal capillary changes in the eyes of initially 2- versus 9-month-old beagles fed a diet containing 30% galactose were compared. Eyes were enucleated after 36 months of galactose feeding, the intact retinal capillaries were isolated by trypsin digestion, and defined retinal regions were evaluated by computer image analysis. Nicotinamide adenine dinucleotide phosphate-dependent reductase activity, using DL-glyceraldehyde and D-xylose as substrates, was also compared in the lenses and whole retinas of eyes from the 2- and 9-month-old beagles. Significantly (P <= 0.05) increased pericyte degeneration, expressed as either the number of pericytes/mm capillary length or the ratio of endothelial cells versus pericytes (E/P ratio) was observed in the retinas of the younger dogs. The number of microaneurysms per eye was also significantly increased in the younger dogs, but no difference in acellular capillary areas was observed. This correlates with a threefold higher level of reductase activity in the retinas of the 2-month-old dogs. Because retinal capillary pericyte destruction,is age dependent similar to the formation of sugar cataracts, the use of younger dogs may shorten the time period required for evaluating the efficacy of drugs for diabetic retinopathy in this animal model. C1 Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA. Univ Nebraska Med Ctr, Coll Med, Dept Ophthalmol, Omaha, NE 68198 USA. Fukui Med Univ, Dept Ophthalmol, Fukui, Japan. NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. RP Kador, PF (reprint author), Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, 986025, Omaha, NE 68198 USA. EM pkador@unmc.edu NR 27 TC 6 Z9 6 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1080-7683 J9 J OCUL PHARMACOL TH JI J. Ocular Pharmacol. Ther. PD FEB PY 2007 VL 23 IS 1 BP 63 EP 69 DI 10.1089/jop.2006.0069 PG 7 WC Ophthalmology; Pharmacology & Pharmacy SC Ophthalmology; Pharmacology & Pharmacy GA 146DK UT WOS:000244914500010 PM 17341153 ER PT J AU Mohan, P Colvin, C Glymph, C Chandra, RR Kleiner, DE Patel, KM Luban, NLC Alter, HJ AF Mohan, Parvathi Colvin, Camilla Glymph, Chevelle Chandra, Roma R. Kleiner, David E. Patel, Kantilal M. Luban, Naomi L. C. Alter, Harvey J. TI Clinical spectrum and histopathologic features of chronic hepatitis C infection in children SO JOURNAL OF PEDIATRICS LA English DT Article ID LIVER FIBROSIS PROGRESSION; VIRUS-INFECTION; NATURAL-HISTORY; POSTTRANSFUSION HEPATITIS; BLOOD-TRANSFUSION; CHILDHOOD-CANCER; PREVALENCE; SURVIVORS; UPDATE; BACK AB Objective: To define the natural history and outcomes of children infected with hepatitis C virus (HCV) at birth or in early childhood. Study design: This retrospective, prospective study identified 60 HCV-infected children through a transfusion look-back program (group 1) and by referrals (group 2). Perinatal/transfusion history, clinical course, and laboratory studies were correlated with findings from 42 liver biopsy specimens. Results: Mean age at infection was 7.1 months, and duration of infection 13.4 years. The sources of infection were blood transfusion (68%), perinatal transmission (13%), and both (7%). Most patients were asymptomatic; three referral patients had advanced liver disease at presentation. Mean alanine aminotransferase level was normal in 25%, 1 to 3 times normal in 62%, and greater than 3 times normal in 13%. Liver biopsy specimens showed minimal to mild inflammation in 71%, absent or minimal fibrosis in 88%, and bridging fibrosis in 12%. Age at infection and serum gamma-glutamyltranspeptidase correlated with fibrosis; serum alanine aminotransferase correlated with inflammation unless complicated by comorbidity. Repeat biopsies within 1 to 4 years in four patients showed no significant progression in three and cirrhosis in one. Two patients died after liver transplantation. Conclusions: Children with chronic HCV infection are generally asymptomatic. By 13 years after infection, 12% of patients had significant fibrosis. Patients enrolled by referral had more severe liver disease than those identified through the look-back program, demonstrating the importance of selection bias in assessing the long-term outcome of HCV infection. C1 Childrens Natl Med Ctr, Ctr Hlth Serv & Community Res, Childrens Res Inst, Dept Gastroenterol & Nutr, Washington, DC 20010 USA. Childrens Natl Med Ctr, Ctr Hlth Serv & Community Res, Childrens Res Inst, Dept Lab Med & Pathol, Washington, DC 20010 USA. Natl Inst Hlth, Dept Tranfus Med, Bethesda, MD USA. NCI, Lab Pathol, Bethesda, MD USA. RP Mohan, P (reprint author), Childrens Natl Med Ctr, Ctr Hlth Serv & Community Res, Childrens Res Inst, Dept Gastroenterol & Nutr, 111 Michigan Ave NW, Washington, DC 20010 USA. EM pmohan@cnmc.org OI Kleiner, David/0000-0003-3442-4453 FU NHLBI NIH HHS [R01 HL 56060, R01 HL056060] NR 40 TC 38 Z9 42 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD FEB PY 2007 VL 150 IS 2 BP 168 EP 174 DI 10.1016/j.jpeds.2006.11.037 PG 7 WC Pediatrics SC Pediatrics GA 134VB UT WOS:000244111300013 PM 17236895 ER PT J AU Cohen-Wolkowiez, M Smith, PB Mangum, B Steinbach, WJ Alexander, BD Cotten, CM Clark, RH Walsh, TJ Benjamin, DK AF Cohen-Wolkowiez, M. Smith, P. B. Mangum, B. Steinbach, W. J. Alexander, B. D. Cotten, C. M. Clark, R. H. Walsh, T. J. Benjamin, D. K., Jr. TI Neonatal Candida meningitis: significance of cerebrospinal fluid parameters and blood cultures SO JOURNAL OF PERINATOLOGY LA English DT Article DE newborn; fungal; prematurity; candidemia; meningoencephalitis ID BIRTH-WEIGHT INFANTS; CENTRAL NERVOUS-SYSTEM; RISK-FACTORS; INFECTIONS; OUTCOMES; SEPSIS AB Objective: The purpose of this study was to examine the frequency of normal cerebrospinal fluid (CSF) parameters in Candida meningitis and the proportion of candidemia associated with Candida meningitis. Study design: We evaluated the initial lumbar puncture results from infants discharged from 150 Neonatal Intensive Care Units between 1997 and 2004. Candida meningitis was diagnosed by a positive CSF culture or positive Gram stain for yeast. We calculated two-tailed P-values using non-parametric testing, Mann - Whitney, Kruskal - Wallis or Fisher's exact tests where appropriate. Results: Twenty infants had culture-positive Candida meningitis. Normal CSF parameters were found in 43% (3/7) of the infants with Candida meningitis and only 37% (7/19) of them had positive blood cultures for Candida. Conclusion: Normal CSF parameters do not exclude the diagnosis of neonatal Candida meningitis. The majority of infants in this cohort with Candida meningitis did not have evidence of candidemia at the time of diagnosis. C1 Duke Univ, Clin Res Inst, Dept Pediat, Durham, NC 27705 USA. Duke Univ, Dept Med, Durham, NC USA. Pediat Obstet Ctr Res & Educ, Sunrise, FL USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Benjamin, DK (reprint author), Duke Univ, Clin Res Inst, Dept Pediat, POB 17969, Durham, NC 27705 USA. EM danny.benjamin@duke.edu RI Smith, Phillip/I-5565-2014 FU NIAID NIH HHS [T32 AI052080]; NICHD NIH HHS [HD044799-01] NR 12 TC 24 Z9 26 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD FEB PY 2007 VL 27 IS 2 BP 97 EP 100 DI 10.1038/sj.jp.7211628 PG 4 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 131AE UT WOS:000243839300007 PM 17080094 ER PT J AU Smith, PB Steinbach, WJ Cotten, CM Schell, WA Perfect, JR Walsh, TJ Benjamin, DK AF Smith, P. B. Steinbach, W. J. Cotten, C. M. Schell, W. A. Perfect, J. R. Walsh, T. J. Benjamin, D. K., Jr. TI Caspofungin for the treatment of azole resistant candidemia in a premature infant SO JOURNAL OF PERINATOLOGY LA English DT Article DE caspofungin; candidiasis; hypercalcemia ID CANDIDIASIS; CHILDREN; SAFETY AB Candidemia is common in extremely low birth weight infants and is associated with substantial mortality and morbidity. Treatment options have traditionally been limited to amphotericin B deoxycholate or fluconazole. We present a case of a premature infant with persistent candidemia despite antifungal treatment that responded to therapy with caspofungin, an echinocandin antifungal. The infant's Candida isolate developed resistance to azoles during fluconazole administration and also suffered from severe hypercalcemia during the initiation of caspofungin therapy. C1 Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Clin Res Inst, Durham, NC USA. Duke Univ, Dept Mol Genet & Microbiol, Durham, NC USA. Duke Univ, Dept Med, Durham, NC USA. NCI, Bethesda, MD 20892 USA. RP Smith, PB (reprint author), Duke Univ, Med Ctr, Dept Pediat, Box 3179, Durham, NC 27710 USA. EM smith466@mc.duke.edu RI Smith, Phillip/I-5565-2014 NR 8 TC 23 Z9 27 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD FEB PY 2007 VL 27 IS 2 BP 127 EP 129 DI 10.1038/sj.jp.7211637 PG 3 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 131AE UT WOS:000243839300014 PM 17262048 ER PT J AU Negus, SS Mello, NK Blough, BE Baumann, MH Rothman, RB AF Negus, S. S. Mello, N. K. Blough, B. E. Baumann, M. H. Rothman, R. B. TI Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate "agonist" medications for cocaine dependence: Studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CHRONIC D-AMPHETAMINE; STIMULUS PROPERTIES; OPIOID AGONISTS; CROSS-TOLERANCE; ABUSE; FOOD; DOPAMINE; PHARMACOTHERAPIES; SUBSTITUTION; SCHEDULE AB Monoamine releasers constitute one class of drugs under investigation as candidate medications for the treatment of cocaine abuse. Promising preclinical and clinical results have been obtained with amphetamine, which has high selectivity for releasing dopamine/norepinephrine versus serotonin. However, use of amphetamine as a pharmacotherapy is complicated by its high abuse potential. Recent preclinical studies suggest that nonselective monoamine releasers or serotonin-selective releasers have lower abuse liability and may warrant evaluation as alternatives to amphetamine. To address this issue, the present study evaluated the effects of five monoamine releasers in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. The releasers varied along a continuum from dopamine/norepinephrine-selective to serotonin- selective [ m- fluoroamphetamine ( PAL- 353), methamphetamine, m- methylamphetamine ( PAL- 314), 1-napthyl- 2- aminopropane ( PAL- 287), fenfluramine]. In drug discrimination studies, rhesus monkeys were trained to discriminate saline from cocaine ( 0.4 mg/ kg i.m.) in a two-key, food-reinforced drug discrimination procedure. Substitution for cocaine was positively associated with selectivity for dopamine/ norepinephrine versus serotonin release. In drug self-administration studies, rhesus monkeys responded for cocaine (0.01 and 0.032 mg/kg/injection) and food ( 1-g pellets) under a second- order fixed- ratio 2 ( variable-ratio 16: S) schedule. In general, monoamine releasers produced dose-dependent and sustained decreases in cocaine self-administration. However, the dopamine/ norepinephrine-selective releasers decreased cocaine self- administration with minimal effects on food-maintained responding, whereas the more serotonin- selective releasers produced nonselective reductions in both cocaine-and food-maintained responding. These results are consistent with the conclusion that dopamine/ norepinephrine- selective releasers retain cocaine- like abuse- related effects but may also be capable of producing relatively selective reductions in the reinforcing effects of cocaine. C1 Harvard Univ, Sch Med, McLean Hosp, Alcohol & Drug Abuse Res Ctr, Belmont, MA 02478 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 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 Intramural NIH HHS; NIDA NIH HHS [P01-DA14528, K05-DA00101, R01-DA02519, R01-DA12970] NR 34 TC 54 Z9 54 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2007 VL 320 IS 2 BP 627 EP 636 DI 10.1124/jpet.106.107383 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 127SA UT WOS:000243605400016 PM 17071819 ER PT J AU Rothman, RB Murphy, DL Xu, H Godin, JA Dersch, CM Partilla, JS Tidgewell, K Schmidt, M Prisinzano, TE AF Rothman, Richard B. Murphy, Daniel L. Xu, Heng Godin, Jonathan A. Dersch, Christina M. Partilla, John S. Tidgewell, Kevin Schmidt, Matthew Prisinzano, Thomas E. TI Salvinorin A: Allosteric interactions at the mu-opioid receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PSEUDOALLOSTERIC MODULATION; PEPTIDE RECEPTOR; BINDING-SITES; RAT-BRAIN; IN-VIVO; LIGANDS; AGONIST; IDENTIFICATION; ANTAGONISTS; ANALOGS AB Salvinorin A [(2S, 4aR, 6aR, 7R, 9S, 10aS, 10bR)-9-(acetyloxy)-2(3-furanyl)-dodecahydro-6a, 10b-dimethyl-4,10-dioxo-2h-naphtho[2,1-c] pyran-7-carboxylic acid methyl ester] is a hallucinogenic kappa-opioid receptor agonist that lacks the usual basic nitrogen atom present in other known opioid ligands. Our first published studies indicated that Salvinorin A weakly inhibited mu-receptor binding, and subsequent experiments revealed that Salvinorin A partially inhibited mu-receptor binding. Therefore, we hypothesized that Salvinorin A allosterically modulates mu-receptor binding. To test this hypothesis, we used Chinese hamster ovary cells expressing the cloned human opioid receptor. Salvinorin A partially inhibited [H-3] Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (0.5, 2.0, and 8.0 nM) binding with E-MAX values of 78.6, 72.1, and 45.7%, respectively, and EC50 values of 955, 1124, and 4527 nM, respectively. Salvinorin A also partially inhibited [H-3] diprenorphine (0.02, 0.1, and 0.5 nM) binding with E-MAX values of 86.2, 64, and 33.6%, respectively, and EC50 values of 1231, 866, and 3078 nM, respectively. Saturation binding studies with [H-3] DAMGO showed that Salvinorin A (10 and 30 mu M) decreased the mu-receptor B-max and increased the K-d in a dose-dependent nonlinear manner. Saturation binding studies with [H-3] diprenorphine showed that Salvinorin A (10 and 40 mu M) decreased the mu-receptor B-max and increased the K-d in a dose-dependent nonlinear manner. Similar findings were observed in rat brain with [H-3] DAMGO. Kinetic experiments demonstrated that Salvinorin A altered the dissociation kinetics of both [H-3] DAMGO and [H-3] diprenorphine binding to mu receptors. Furthermore, Salvinorin A acted as an uncompetitive inhibitor of DAMGO-stimulated guanosine 5'-O-(3-[S-35]thio)-triphosphate binding. Viewed collectively, these data support the hypothesis that Salvinorin A allosterically modulates the mu-opioid receptor. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov RI Prisinzano, Thomas/B-7877-2010 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA018151, R01 DA018151-01A2] NR 28 TC 31 Z9 32 U1 2 U2 14 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2007 VL 320 IS 2 BP 801 EP 810 DI 10.1124/jpet.106.113167 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 127SA UT WOS:000243605400036 PM 17060492 ER PT J AU Britton, AF Vann, RE Robinson, SE AF Britton, Angela F. Vann, Robert E. Robinson, Susan E. TI Perinatal nicotine exposure eliminates peak in nicotinic acetylcholine receptor response in adolescent rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Society-for-Neuroscience CY NOV 12-16, 2005 CL Washington, DC SP Soc Neurosci ID CONDITIONED PLACE PREFERENCE; MATERNAL SMOKING; BRAIN-REGIONS; CIGARETTE-SMOKING; MESSENGER-RNAS; ADULT RATS; PREGNANCY; DEPENDENCE; AGE; EXPRESSION AB Maternal smoking is a risk factor associated with nicotine abuse, so the effect of perinatal nicotine exposure was studied on the responsiveness to nicotine across adolescence in the rat. Pregnant Sprague-Dawley rats were implanted with s.c. Alzet osmotic minipumps delivering nicotine (L-nicotine hydrogen tartrate, 2 mg/kg/day free base) or vehicle (0.9% saline) on gestational day 7. There was no effect of nicotine on dam weight gain, food consumption, or water consumption or on the number of live pups or weights at the time of birth. Pups were cross-fostered to obtain the following prenatal/postnatal exposure groups: control/control, nicotine/nicotine, nicotine/control, and control/nicotine. On postnatal days 28, 35, 49, and 63, nicotine-stimulated Rb-86(+) efflux was measured in synaptosomes prepared from the frontal cortex, hippocampus, striatum STR), and thalamus (THL), using a previously developed method. Significant effects of treatment and concentration were detected in all four brain regions, and significant effects of age were observed in the STR and THL. Significant interactions of age and treatment were observed in each of the four brain regions. Nicotine-stimulated Rb-86(+) efflux peaked during adolescence in control rats. However, perinatal exposure to nicotine eliminated this peak during adolescence. These results are consistent with recent behavioral and receptor binding results from other laboratories and are the first direct evidence at the cellular level that the nicotinic acetylcholine receptor response varies during adolescence and is affected by perinatal nicotine exposure. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIA, Neurogenet Lab, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Robinson, SE (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, POB 980613, Richmond, VA 23298 USA. EM serobins@vcu.edu NR 43 TC 26 Z9 26 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD FEB PY 2007 VL 320 IS 2 BP 871 EP 876 DI 10.1124/jpet.106.112730 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 127SA UT WOS:000243605400044 PM 17105825 ER PT J AU McCrae, RR Costa, PT Martin, TA Oryol, VE Senin, IG O'Cleirigh, C AF McCrae, Robert R. Costa, Paul T., Jr. Martin, Thomas A. Oryol, Valery E. Senin, Ivan G. O'Cleirigh, Conall TI Personality correlates of HIV stigmatization in Russia and the United States SO JOURNAL OF RESEARCH IN PERSONALITY LA English DT Article DE personality; stigmatization; cross-cultural comparisons; openness to experience ID INJECTION-DRUG USERS; STIGMA; DISCLOSURE; MODEL; RISK; AIDS; ATTITUDES; AFRICA; TRAITS; PEOPLE AB To determine whether stigmatizing attitudes towards HlV/AIDS are associated with personality traits, and whether these associations are generalizable across two cultures, we administered the English and the brief Russian version of the Revised NEO Personality Inventory, a standardized measure of a comprehensive model of personality traits, together with items assessing HIV stigmatization. We hypothesized that stigmatization would be associated chiefly with low Openness to Experience. Self-reports and observer ratings of personality and self-reports of HIV attitudes were collected from volunteers recruited by research assistants. HIV stigmatization was more pronounced in Russia than in the United States, but it was similarly related to personality traits, chiefly low Openness to Experience, a variable associated with other forms of prejudice, and low Agreeableness, suggesting a lack of altruism and sympathy. HIV stigmatization is especially likely to be a problem with people, and in cultures, low in Openness to Experience. Published by Elsevier Inc. C1 NIA, Gerontol Res Ctr, NIH, DHHS, Baltimore, MD 21224 USA. Susquehanna Univ, Selinsgrove, PA USA. Yaroslavl State Univ, Yaroslavl, Russia. Univ Miami, Miami, FL 33152 USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, NIH, DHHS, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mccraej@grc.nia.nih.gov OI Costa, Paul/0000-0003-4375-1712 NR 29 TC 9 Z9 9 U1 4 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0092-6566 J9 J RES PERS JI J. Res. Pers. PD FEB PY 2007 VL 41 IS 1 BP 190 EP 196 DI 10.1016/j.jrp.2005.11.002 PG 7 WC Psychology, Social SC Psychology GA 145BQ UT WOS:000244840700013 ER PT J AU Mavragani, CP Patronas, N Dalakas, M Moutsopoulos, HM AF Mavragani, Clio P. Patronas, Nicholas Dalakas, Marinos Moutsopoulos, Haralampos M. TI Ill-defined neurological syndromes with autoimmune background: A diagnostic challenge SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE multiple sclerosis-like disease; MTHFR reductase mutations; autoimmune thyroid disease; ill-defined neurological syndromes ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; MULTIPLE-SCLEROSIS; ANTIPHOSPHOLIPID SYNDROME; CLASSIFICATION CRITERIA; PLASMA HOMOCYSTEINE; RISK-FACTORS; REDUCTASE; LESIONS; GENE AB Objective. To define the diagnostic features of a cohort of patients presenting with autoimmune manifestations and atypical neurological features not fulfilling criteria for a well defined neurological or connective tissue disorder. Methods. Twenty-nine such patients were referred to our institution for evaluation. Nine were excluded from this study since they were diagnosed with antiphospholipid syndrome. The remaining 20 patients underwent complete clinical and laboratory evaluation, spinal fluid analysis, minor salivary gland biopsy (if sicca features were present), and were tested for evoked potentials. Magnetic resonance imaging (MRI) scans of the brain were performed in all patients and of the spine in 7. Results. Brain and/or spinal cord MRI abnormalities were found in all 20 patients. Based on morphologic criteria and distribution, these lesions were classified into 3 subsets: (1) multiple sclerosis (MS)like (4 patients); (2) vasculitic (8 patients); and (3) nonspecific (8 patients). The most frequent underlying abnormality in patients with subgroups 1 and 2 were the presence of homozygous methylenetetrahydrofolate reductase (MTHFR) mutations (5 of 12,41.6%). The most common findings among subgroup 3 were the presence of antithyroid antibodies (6 of 8 patients, 75%). Conclusion. Homozygous MTHFR mutations are frequently encountered in patients presenting with neurological features and MS-like or vasculitic type MRI abnormalities in a setting of autoimmune disease. Nonspecific MRI changes are frequently associated with antibodies against thyroid antigens. C1 Natl Univ Athens, Sch Med, Dept Pathophysiol, Athens 11527, Greece. NINDS, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Moutsopoulos, HM (reprint author), Natl Univ Athens, Sch Med, Dept Pathophysiol, M Asias 75, Athens 11527, Greece. EM hmoutsop@med.uoa.gr NR 15 TC 7 Z9 7 U1 0 U2 0 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 FEB PY 2007 VL 34 IS 2 BP 341 EP 345 PG 5 WC Rheumatology SC Rheumatology GA 134VQ UT WOS:000244112900019 PM 17304657 ER PT J AU Weiss, JM Stojilkovic, SS Diedrich, K Ortmann, O AF Weiss, Juergen M. Stojilkovic, Stanko S. Diedrich, Klaus Ortmann, Olaf TI Effects of testosterone on hormonal content and calcium-dependent basal secretion in female rat pituitary cells SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE testosterone; anterior pituitary cells; calcium signalling; basal release; hormonal content ID GONADOTROPIN-RELEASING-HORMONE; SEX STEROID-HORMONES; MESSENGER-RNA LEVELS; PROTEIN-KINASE-C; ANTERIOR-PITUITARY; GONADAL-STEROIDS; EXTRACELLULAR CALCIUM; TRANSCRIPTION FACTOR; GH SECRETION; BETA-SUBUNIT AB In vivo and in vitro effects of elevated androgens on agonist-induced gonadotropin secretion have been addressed, previously. Here we investigated the effects of testosterone on hormonal content and basal (in the absence of agonists) hormone release in pituitary lactotrophs, somatotrophs and gonadotrophs from female rats. Furthermore we tested the hypothesis that testosterone action is dependent on the pattern of spontaneous and Bay K 8644 (a L-type calcium channel agonist) -induced calcium signalling. Mixed anterior pituitary cells were cultured in steroid containing or depleted media, and testosterone (1 pM to 10 nM) was added for 48 h. Cells were studied for their spontaneous and Bay K 8644-induced calcium signalling pattern and total hormone levels (release and hormonal content). In lactotrophs, somatotrophs and gonadotrophs testosterone did not affect the pattern of spontaneous calcium signalling. Bay K 8644-induced calcium signalling and hormone release were not affected by testosterone. In both steroid-depleted and -containing medium, testosterone inhibited prolactin (PRL), luteinizing hormone (LH) and growth hormone (GH) cellular content and release in a dose-dependent manner, with IC(50)s in a sub-nanomolar concentration range. These results indicate that testosterone inhibits basal hormone release from lactotrophs, somatotrophs and gonadotrophs without affecting intracellular calcium signalling. This action of testosterone is not dependent on the presence of other steroid hormones. (c) 2006 Elsevier Ltd. All rights reserved. C1 Med Univ Lubeck, Dept Obstet & Gynecol, D-23538 Lubeck, Germany. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Univ Regensburg, Dept Obstet & Gynecol, Caritas St Josef Hosp, D-93006 Regensburg, Germany. RP Weiss, JM (reprint author), Med Univ Lubeck, Dept Obstet & Gynecol, Ratzeburger Allee 160, D-23538 Lubeck, Germany. EM jmweiss1@hotmail.com NR 46 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD FEB PY 2007 VL 103 IS 2 BP 149 EP 157 DI 10.1016/j.jsbmb.2006.09.038 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 138SO UT WOS:000244382800006 PM 17084076 ER PT J AU Mehta, KM Yaffe, K Brenes, GA Newman, AB Shorr, RI Simonsick, EM Ayonayon, HN Rubin, SM Covinsky, KE AF Mehta, Kala M. Yaffe, Kristine Brenes, Gretchen A. Newman, Anne B. Shorr, Ronald I. Simonsick, Eleanor M. Ayonayon, Hilsa N. Rubin, Susan M. Covinsky, Kenneth E. TI Anxiety symptoms and decline in physical function over 5 years in the health, aging and body composition study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY MAY 03-07, 2006 CL Chicago, IL SP Amer Geriatr Soc DE aged; anxiety symptoms; depressive symptoms; functional decline ID OLDER-ADULTS; RISK-FACTORS; CARDIOVASCULAR HEALTH; PROGNOSTIC INDEX; MORTALITY; DISABILITY; DEPRESSION; FALLS; ASSOCIATION; PEOPLE AB OBJECTIVES: To examine the relationship between anxiety and functional decline. DESIGN: A 5-year longitudinal cohort study of well-functioning adults. SETTING: The Health, Aging and Body Composition (Health ABC) Study. PARTICIPANTS: Two thousand nine hundred forty adults aged 70 to 79 (48% male, 41% black), initially free of self-reported mobility difficulty. MEASUREMENTS: In 1997/98, presence of three anxiety symptoms (feeling fearful, tense or keyed up, or shaky or nervous) from the Hopkins Symptom Checklist were ascertained. Physical function was examined over 5 years using the Health ABC performance battery (continuous range 0-4) consisting of chair stands, usual and narrow course gait speed, and difficulty with standing balance and self-reported mobility, defined as difficulty walking one-quarter of a mile or difficulty climbing 10 steps. RESULTS: Participants with anxiety symptoms had similar baseline physical performance scores. After adjustment for potential confounders, subjects with anxiety symptoms had similar declines in physical performance over 5 years as participants without anxiety symptoms. Adults with anxiety symptoms were more likely to report incident mobility difficulty, with a hazard ratio of 1.4 (95% confidence interval=1.3-1.6), compared with adults without anxiety symptoms. These results persisted after adjustment for depressive symptoms, demographics, comorbidity, and use of antianxiety, depressant, and sedative hypnotic medications. CONCLUSION: Anxiety symptoms are not associated with declines in objectively measured physical performance over 5 years but are associated with declines in self-reported functioning. Future studies are needed to determine why anxiety has a differential effect on performance-based and self-reported measures of functioning. C1 Univ Calif San Francisco, Div Geriatr, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Geriatr, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Div Geriatr, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Wake Forest Univ, Sch Med, Dept Psychiat & Behav Med, Winston Salem, NC 27109 USA. Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. Univ Tennessee, Coll Med, Dept Prevent Med, Knoxville, TN 37996 USA. NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Mehta, KM (reprint author), 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. EM kala.mehta@ucsf.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Intramural NIH HHS; NIA NIH HHS [N01 AG062101, K-01AG025444-01A1, K01 AG025444, K01 AG025444-03, K24 AG029812, N01 AG062103, N01 AG062106, P30 AG 15272, P30 AG015272] NR 29 TC 24 Z9 24 U1 2 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD FEB PY 2007 VL 55 IS 2 BP 265 EP 270 DI 10.1111/j.1532-5415.2007.01041.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 131LH UT WOS:000243869900017 PM 17302665 ER PT J AU Gogichaeva, NV Williams, T Alterman, MA AF Gogichaeva, Natalia V. Williams, Todd Alterman, Michail A. TI MALDI TOF/TOF tandem mass spectrometry as a new tool for amino acid analysis SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID ELECTROSPRAY-IONIZATION; QUANTITATIVE-ANALYSIS; FRAGMENTATION; PERFORMANCE; MOLECULES; SPECTRA; QUANTIFICATION; IDENTIFICATION; METABOLISM; DISORDERS AB This is the first report of an application of collisionally induced fragmentation of amino acids (AA) and their derivatives by MALDI TOF/TOF tandem mass spectrometry (MS). In this work, we collected the data on high-energy fragmentation reactions of a large group of protonated amino acids and their derivatives with the goal of determining which product ions are analyte specific and if yields of these fragment could be used for quantitative analysis. From 34 different amino acids (20 alpha-amino acids, beta-amino acids, homocysteine, GABA, and modified AA Met sulfone and sulfoxide, hydroxyproline, etc.) we observed that high yields of the target specific immonium ions and fragmentation patterns are most similar to EI or FAB CID on sector instruments. The major exceptions were two highly basic amino acids, Arg and Orn. It is noted that neither beta-, gamma-, nor delta-amino acids produce immonium ions. As might be predicted from high-energy CID work on peptides from the sectors and TOF/TOF, the presence of specific indicator ions in MALDI tandem MS allows distinguishing isomeric and isobaric amino acids. These indicator ions, in combination with careful control of data acquisition, ensure quantitative analysis of amino acids. We believe our data provide strong basis for the application of MALDI TOF/TOF MS/MS in qualitative and quantitative analysis of amino and organic acids, including application in clinical medicine. C1 US FDA, Tumor Vaccines & Biotechnol Branch, CBER, NIH, Bethesda, MD 20892 USA. Univ Kansas, Analyt Proteom Lab, Lawrence, KS 66045 USA. RP Alterman, MA (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, CBER, NIH, Bldg 29A,Room 2D12,HFM 735,8800 Rockville Pike, Bethesda, MD 20892 USA. EM Michail.Alterman@fda.hhs.gov NR 26 TC 31 Z9 35 U1 3 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD FEB PY 2007 VL 18 IS 2 BP 279 EP 284 DI 10.1016/j.jasms.2006.09.013 PG 6 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 134UJ UT WOS:000244109300014 PM 17074506 ER PT J AU Zhang, DL Meyron-Holtz, E Rouault, TA AF Zhang, Deliang Meyron-Holtz, Esther Rouault, Tracey A. TI Renal iron metabolism: Transferrin iron delivery and the role of iron regulatory proteins SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MESSENGER-RNA; IN-VIVO; TARGETED DELETION; RAT-KIDNEY; EXPRESSION; CELLS; HOMEOSTASIS; RECEPTOR; MICE; TRANSPORTER C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. EM trou@helix.nih.gov RI Meyron-Holtz, Esther/B-5991-2013; Zhang, Deliang/F-7848-2013; OI Zhang, Deliang/0000-0001-9478-5344 FU Intramural NIH HHS NR 52 TC 31 Z9 33 U1 2 U2 6 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2007 VL 18 IS 2 BP 401 EP 406 DI 10.1681/ASN.2006080908 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 132BP UT WOS:000243917300010 PM 17229905 ER PT J AU Oppermann, M Mizel, D Kim, SM Chen, LM Faulhaber-Walter, R Huang, YN Li, CL Deng, CX Briggs, J Schnermann, J Castrop, H AF Oppermann, Mona Mizel, Diane Kim, Soo Mi Chen, Limeng Faulhaber-Walter, Robert Huang, Yuning Li, Cuiling Deng, Chuxia Briggs, Josie Schnermann, Jurgen Castrop, Hayo TI Renal function in mice with targeted disruption of the A isoform of the Na-K-2Cl co-transporter SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MACULA DENSA CELLS; K-CL COTRANSPORTER; RENIN SECRETION; DEPENDENT INHIBITION; NA; TRANSPORT; ADENOSINE; FUROSEMIDE; DELETION; MOUSE AB Three different full-length splice isoforms of the Na-K-2Cl co-transporter (NKCC2/BSC1) are expressed along the thick ascending limb of Henle (TAL), designated NKCC2A, NKCC2B, and NKCC2F. NKCC2F is expressed in the medullary, NKCC2B mainly in the cortical, and NKCC2A in medullary and cortical portions of the TAL. NKCC2B and NKCC2A were shown to be coexpressed in the macula densa (MD) segment of the mouse TAL. The functional consequences of the existence of three different isoforms of NKCC2 are unclear. For studying the specific role of NKCC2A in kidney function, NKCC2A-/- mice were generated by homologous recombination. NKCC2A-/- mice were viable and showed no gross abnormalities. Ambient urine osmolarity was reduced significantly in NKCC2A-/- compared with wild-type mice, but water deprivation elevated urine osmolarity to similar levels in both genotypes. Baseline plasma renin concentration and the effects of a high- and a low-salt diet on plasma renin concentration were similar in NKCC2A+/+ and -/- mice. However, suppression of renin secretion by acute intravenous saline loading (5% of body weight), a measure of MD-dependent inhibition of renin secretion, was reduced markedly in NKCC2A-/mice compared with wild-type mice. Cl and water absorption along microperfused loops of Henle of NKCC2A-/- mice were unchanged at normal flow rates but significantly reduced at supranormal flow. Tubuloglomerular feedback function curve as determined by stop flow pressure measurements was left-shifted in NKCC2A-/- compared with wild-type mice, with maximum responses being significantly diminished. In summary, NKCC2A activity seems to be required for MD salt sensing in the high Cl concentration range. Coexpression of both high- and low-affinity isoforms of NKCC2 may permit transport and Cl-dependent tubuloglomerular feedback regulation to occur over a wider Cl concentration range. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Chevy Chase, MD USA. Univ Regensburg, Inst Physiol, D-8400 Regensburg, Germany. RP Castrop, H (reprint author), NIDDK, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC-1370, Bethesda, MD 20892 USA. EM hayo@castrop.com RI Briggs, Josephine/B-9394-2009; deng, chuxia/N-6713-2016; OI Briggs, Josephine/0000-0003-0798-1190; Faulhaber-Walter, Robert/0000-0002-7769-9652 FU Intramural NIH HHS NR 28 TC 48 Z9 48 U1 0 U2 0 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2007 VL 18 IS 2 BP 440 EP 448 DI 10.1681/ASN.2006091070 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 132BP UT WOS:000243917300015 PM 17215439 ER PT J AU Hiramatsu, N Hiromura, K Shigehara, T Kuroiwa, T Ideura, H Sakurai, N Takeuchi, S Tomioka, M Ikeuchi, H Kaneko, Y Ueki, K Kopp, JB Nojima, Y AF Hiramatsu, Noriyuki Hiromura, Keiju Shigehara, Tetsuya Kuroiwa, Takashi Ideura, Hiroshi Sakurai, Noriyuki Takeuchi, Shigeru Tomioka, Mai Ikeuchi, Hidekazu Kaneko, Yoriaki Ueki, Kazue Kopp, Jeffrey B. Nojima, Yoshihisa TI Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSGENIC MICE; SEGMENTAL GLOMERULOSCLEROSIS; RENAL-DISEASE; DIABETIC GLOMERULOPATHY; UNILATERAL NEPHRECTOMY; PODOCYTE PHENOTYPE; EPITHELIAL-CELLS; MESANGIAL CELLS; INFECTION AB HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension. C1 Gunma Univ, Grad Sch Med, Dept Med & Clin Sci, Maebashi, Gumma 3718511, Japan. NIDDKD, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hiromura, K (reprint author), Gunma Univ, Grad Sch Med, Dept Med & Clin Sci, 3-39-22 Showa, Maebashi, Gumma 3718511, Japan. EM hiromura@med.gunma-u.ac.jp OI Kopp, Jeffrey/0000-0001-9052-186X NR 55 TC 28 Z9 28 U1 0 U2 0 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD FEB PY 2007 VL 18 IS 2 BP 515 EP 527 DI 10.1681/ASN.2006030217 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA 132BP UT WOS:000243917300022 PM 17229913 ER PT J AU Baccarelli, A Zanobetti, A Martinelli, I Grillo, P Hou, L Giacomini, S Bonzini, M Lanzani, G Mannucci, PM Bertazzi, PA Schwartz, J AF Baccarelli, A. Zanobetti, A. Martinelli, I. Grillo, P. Hou, L. Giacomini, S. Bonzini, M. Lanzani, G. Mannucci, P. M. Bertazzi, P. A. Schwartz, J. TI Effects of exposure to air pollution on blood coagulation SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE activated partial thromboplastin time; air pollution; epidemiology; generalized additive models; particulate matter; prothrombin time ID MYOCARDIAL-INFARCTION; PARTICULATE MATTER; AMBIENT PARTICLES; HEART-DISEASE; TISSUE FACTOR; ASSOCIATION; MORTALITY; MARKERS; INHALATION; GESTODENE AB Background: Consistent evidence has indicated that air pollution increases the risk of cardiovascular diseases. The underlying mechanisms linking air pollutants to increased cardiovascular risk are unclear. Objectives: We investigated the association between the pollution levels and changes in such global coagulation tests as the prothrombin time (PT) and the activated partial thromboplastin time (APTT) in 1218 normal subjects from the Lombardia Region, Italy. Plasma fibrinogen and naturally occurring anticoagulant proteins were also evaluated. Methods: Hourly concentrations of particulate (PM10) and gaseous pollutants (CO, NO2, SO2, and O-3) were obtained from 53 monitoring sites covering the study area. Generalized additive models were applied to compute standardized regression coefficients controlled for age, gender, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends. Results: The PT became shorter with higher ambient air concentrations at the time of the study of PM10 (coefficient=-0.06; P < 0.05), CO (coefficient=-0.11; P < 0.001) and NO2 (coefficient=-0.06; P < 0.05). In the 30 days before blood sampling, the PT was also negatively associated with the average PM10 (coefficient=-0.08; P < 0.05) and NO2 (coefficient=-0.08; P < 0.05). No association was found between the APTT and air pollutant levels. In addition, no consistent relations with air pollution were found for fibrinogen, antithrombin, protein C and protein S. Conclusions: This investigation shows that air pollution is associated with changes in the global coagulation function, suggesting a tendency towards hypercoagulability after short-term exposure to air pollution. Whether these changes contribute to trigger cardiovascular events remains to be established. C1 Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Dept Environm Hlth, Boston, MA 02215 USA. Univ Milan, Dept Prevent Med, Milan, Italy. Univ Milan, EPOCA Epidemiol Res Ctr, Milan, Italy. IRCCS Maggiore Hosp, Mangiagalli & Regina Elena Fdn, Milan, Italy. Univ Milan, A Bianchi Bonomi Haemophilia & Thrombosis Ctr, Dept Internal Med & Med Specialties, Milan, Italy. NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. Reg Environm Protect Agcy ARPA Lombardia, Air Qual Unit, Milan, Italy. RP Baccarelli, A (reprint author), Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Dept Environm Hlth, 401 Pk Dr,Landmark Ctr,Suite 412F W,POB 15698, Boston, MA 02215 USA. EM abaccare@hsph.harvard.edu RI Mannucci, Pier/C-3102-2014; Martinelli, ida/J-2287-2015; Bonzini, Matteo/K-7540-2016; bertazzi, pietro alberto/D-5039-2017 OI Martinelli, ida/0000-0001-9218-3622; Bonzini, Matteo/0000-0002-6405-7554; bertazzi, pietro alberto/0000-0003-3475-2449 NR 43 TC 110 Z9 116 U1 0 U2 13 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD FEB PY 2007 VL 5 IS 2 BP 252 EP 260 DI 10.1111/j.1538-7836.2007.02300.x PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 127CN UT WOS:000243563000008 PM 17083648 ER PT J AU Zbar, B Glenn, G Merino, M Middelton, L Peterson, J Toro, J Coleman, J Pinto, P Schmidt, LS Choyke, P Linehan, WM AF Zbar, Berton Glenn, Gladys Merino, Maria Middelton, Lindsay Peterson, James Toro, Jorge Coleman, Jonathan Pinto, Peter Schmidt, Laura S. Choyke, Peter Linehan, W. Marston TI Familial renal carcinoma: Clinical evaluation, clinical subtypes and risk of renal carcinoma development SO JOURNAL OF UROLOGY LA English DT Article DE kidney; kidney neoplasms; neoplastic syndromes, hereditary; gene expression ID HOGG-DUBE-SYNDROME; CELL CANCER; KIDNEY CANCER; GENETIC-BASIS; MUTATIONS; GERMLINE; COMPONENT AB Purpose: Familial renal carcinoma is defined as families with 2 or more individuals with renal cell carcinoma without evidence of known hereditary renal carcinoma syndromes. To better characterize this familial cancer we reviewed renal carcinoma families evaluated at the National Cancer Institute between 1990 and 2004 to identify distinctive features of these families. We also determined the risk of renal carcinoma in first-degree relatives of affected family members. Materials and Methods: We evaluated 141 at risk asymptomatic relatives of affected individuals from 50 families with 2 or more members with renal carcinoma. Histology slides of renal tumors from affected family members were reviewed. At risk members from renal carcinoma families were screened for occult renal neoplasms by renal ultrasound and computerized tomography. DNA from select families was tested for germline mutations of known renal carcinoma genes when clinically indicated and constitutional cytogenetic analysis was performed to search for germline chromosome alterations. Results: Familial renal carcinoma families could be subdivided into subtypes based on tumor multiplicity and renal tumor histology. Of 141 at risk members of renal carcinoma families screened for occult renal tumors 2 were found to have occult renal tumors, which were identified as renal oncocytoma and a solid tumor that was not resected, respectively. No histologically confirmed occult renal carcinomas were detected in at risk family members. Several families previously classified as having familial renal carcinoma were found on further evaluation to have hereditary renal cancer syndromes. Conclusions: Familial renal carcinoma is a heterogeneous clinical and pathological entity. Familial renal carcinoma was subdivided into groups based on tumor multiplicity and tumor pathology. The empirical risk of histologically documented renal carcinoma in first-degree relatives who were members of familial renal carcinoma families was less than 1:141. One renal oncocytoma and 1 small solid renal tumor were detected. C1 NCI, Urol Oncol Branch, CRC, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. SAIC Frederick, Basic Res Program, Frederick, MD USA. RP Zbar, B (reprint author), NCI, Urol Oncol Branch, CRC, 10 Ctr Dr,MSC 1107,Bldg 10,Room 1W-5940, Bethesda, MD 20892 USA. EM zbarb@ncifcrf.gov OI Coleman, Jonathan/0000-0002-6428-7835 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 17 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2007 VL 177 IS 2 BP 461 EP 465 DI 10.1016/j.juro.2006.09.037 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 125PI UT WOS:000243453900009 PM 17222609 ER PT J AU Cannon, GW Mullins, C Lucia, MS Hayward, SW Lin, V Liu, BCS Slawin, K Rubin, MA Getzenberg, RH AF Cannon, Grant W. Mullins, Chris Lucia, M. Scott Hayward, Simon W. Lin, Victor Liu, Brian C. -S. Slawin, Kevin Rubin, Mark A. Getzenberg, Robert H. TI A preliminary study of JM-27: A serum marker that can specifically identify men with symptomatic benign prostatic hyperplasia SO JOURNAL OF UROLOGY LA English DT Article DE prostatic hyperplasia; urinary tract; biological markers; immunoassay AB Purpose: Benign prostatic hyperplasia is a common disease in men that until recently was considered a single disease with varying symptoms. Our recent analysis has revealed that a molecular marker, JM-27, is able to distinguish at the tissue level between highly symptomatic individuals and those with histological disease. The goal of these studies was to determine if a serum based assay to detect JM-27 could distinguish men with different forms of benign prostatic hyperplasia. Materials and Methods: A serum based enzyme-linked immunosorbent assay was developed using a novel anti-JM-27 monoclonal antibody. The assay was sensitive, detecting JM-27 at the low ng/ml level within the serum. A quantitative measurement of serum JM-27 levels was performed in 68 patients. The patients consisted of 3 groups of 29 patients with asymptomatic benign prostatic hyperplasia (American Urological Association symptom score of 15 or less), 39 with symptomatic benign prostatic hyperplasia (American Urological Association symptom score 16 to 32) and 17 with confirmed prostate cancer. The assay cutoff was determined after a pilot run of samples and applied prospectively. Results: Using the determined cutoff, serum levels of JM-27 can distinguish between symptomatic and asymptomatic patient sets. The sensitivity and specificity of the assay are 90% and 77%, respectively. The presence of prostate cancer in these men does not appear to alter the marker levels. Conclusions: The present study is believed to represent the first characterization of a serum based marker for severe benign prostatic hyperplasia. C1 Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Colorado, Dept Pathol, Prostate Diagnost Lab, Denver, CO 80202 USA. Univ Colorado, Dept Pathol, MTOPS Prostate Samples Anal Consortium Pathol Coo, Denver, CO 80202 USA. Hlth Sci Ctr, Aurora, CO USA. Vanderbilt Univ, Med Ctr, Dept Urol Surg, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN USA. Univ Texas, SW Med Ctr, Dept Urol, Dallas, TX 75230 USA. Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA. Brigham & Womens Hosp, Mol Urol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Getzenberg, RH (reprint author), Johns Hopkins Univ Hosp, James Buchanan Brady Urol Inst, Marburg 121,600 N Wolfe St, Baltimore, MD 21287 USA. EM rgetzen1@jhmi.edu OI Rubin, Mark/0000-0002-8321-9950 NR 12 TC 4 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2007 VL 177 IS 2 BP 610 EP 614 DI 10.1016/j.juro.2006.09.023 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 125PI UT WOS:000243453900044 PM 17222644 ER PT J AU Harris, SS Link, CL Tennstedt, SL Kusek, JW McKinlay, JB AF Harris, Susan S. Link, Carol L. Tennstedt, Sharon L. Kusek, John W. McKinlay, John B. TI Care seeking and treatment for urinary incontinence in a diverse population SO JOURNAL OF UROLOGY LA English DT Article; Proceedings Paper CT 100th Annual Meeting of the American-Urological-Association CY MAY 21-26, 2005 CL San Antonio, TX SP Amer Urol Assoc DE bladder; urinary incontinence; questionnaires; patient acceptance of health care ID HEALTH-CARE; NEGLECTED PROBLEM; HELP-SEEKING; COMMUNITY; PREVALENCE; WOMEN; BEHAVIOR; SERVICES; PEOPLE AB Purpose: We examined care seeking and treatment for urine leakage in the Boston Area Community Health Survey, a racially and ethnically diverse, community based study of urological and gynecological symptoms and their correlates. Materials and Methods: Boston Area Community Health Survey used a multistage, stratified cluster design to enroll 5,506 black, Hispanic and white adults. Subjects were 30 to 79 years old and residents of Boston, Massachusetts. Data were obtained during a 2-hour in home interview. Analyses for this report include the 331 women and 128 men who reported weekly incontinence, defined as urine leakage that occurred 1 or more times weekly in the last year. Results: Of women 45% and 22% of men with weekly incontinence reported ever having sought care for it. Of those who sought care 60% reported receiving treatment and half of those who were treated continued to have daily leakage. Of treated women 50% and 40% of treated men reported moderate to great frustration with continued urine leakage. Conclusions: This study demonstrates that the majority of men and women who experience weekly urinary incontinence do not seek care for it, many who sought treatment believe that none was provided and many who received treatment continue to have troubling symptoms. The public should be educated to seek care for urine leakage, health care providers should take the initiative to ask their patients about urinary symptoms and more attention should be given to ensuring that, when treatment is given, it is appropriate and effective. C1 New England Res Inst, Inst Community Hlth Studies, Watertown, MA 02472 USA. Tufts Univ, USDA, Jean Mayer Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NIDDKD, Bethesda, MD USA. RP McKinlay, JB (reprint author), New England Res Inst, Inst Community Hlth Studies, 9 Galen St, Watertown, MA 02472 USA. EM jmckinlay@neriscience.com FU NIDDK NIH HHS [U01 DK 56842] NR 20 TC 40 Z9 40 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD FEB PY 2007 VL 177 IS 2 BP 680 EP 684 DI 10.1016/j.juro.2006.09.045 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 125PI UT WOS:000243453900056 PM 17222656 ER PT J AU Levy, EB Zhang, H Lindisch, D Wood, BJ Cleary, K AF Levy, Elliot B. Zhang, Hui Lindisch, David Wood, Bradford J. Cleary, Kevin TI Electromagnetic tracking-guided percutaneous intrahepatic portosystemic shunt creation in a swine model SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article AB Electromagnetic tracking potentially may be used to guide percutaneous needle-based interventional procedures. This brief report describes our initial experience with an electromagnetic guidance system featuring real-time tracking of respiratory-related target motion using an internal fiducial. An algorithm based on a "freehand" needle puncture technique was employed to puncture the right portal vein and a right hepatic vein for percutaneous intrahepatic portosystemic shunt in a swine model. Preoperative computed tomographic images registered with the electromagnetically tracked needle position were displayed for guidance. Successful puncture was confirmed angiographically. Simultaneous percutaneous transhepatic puncture of the targeted veins was accomplished on the initial attempt. C1 Medstar Georgetown Univ Hosp, Washington, DC 20007 USA. Georgetown Univ, Imaging Sci & Informat Syst Ctr, Washington, DC USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Levy, EB (reprint author), Medstar Georgetown Univ Hosp, 300 Reservoir Rd NW, Washington, DC 20007 USA. EM levye@gunet.georgetown.edu NR 6 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD FEB PY 2007 VL 18 IS 2 BP 303 EP 307 DI 10.1016/j.jvir.2006.12.716 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 143PY UT WOS:000244736200018 PM 17327566 ER PT J AU Aboyans, V Criqui, MH McClelland, RL Allison, MA McDermott, MM Goff, DC Manolio, TA AF Aboyans, Victor Criqui, Michael H. McClelland, Robyn L. Allison, Matthew A. McDermott, Mary McGrae Goff, David C., Jr. Manolio, Teri A. TI Intrinsic contribution of gender and ethnicity to normal anlde-brachial index values: The Multi-Ethnic Study of Atherosclerosis (MESA) SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID PERIPHERAL ARTERIAL-DISEASE; NUTRITION EXAMINATION SURVEY; MIDDLE-AGED POPULATION; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; NATIONAL-HEALTH; BLOOD-PRESSURE; UNITED-STATES; AFRICAN-AMERICANS; OCCLUSIVE DISEASE AB Objective: Several studies report a higher prevalence of peripheral arterial disease (PAD) in women and among blacks. These studies based their PAD definition on an ankle-brachial index (ABI) < 0.90. We hypothesized that there is an inherent contribution of gender and ethnicity to normal ABI values, independent of biologic and social disparities that exist between gender and ethnic groups. Consequently, an ABI threshold that disregards these fundamental gender-related and ethnicity-related differences could partly contribute to reported prevalence differences. Methods: A cross-sectional study was designed as part of the Multi-Ethnic Study of Atherosclerosis (MESA), a multicenter United States population study. We selected a subgroup of participants with unequivocally normal ABIs (1.00 to 1.30), and additionally excluded participants with any major PAD risk factor (smoking, diabetes, dyslipidemia, hypertension). In a linear model with ABI as the dependent variable, demographic, clinical, biologic, and social variables were introduced as independent factors. Results: Among 1775 healthy participants, there was no association between ABI level and subclinical cardiovascular disease (coronary calcium or carotid plaque). Male gender, weight, and high education level were positively correlated with ABI, whereas black race, triglycerides, pack-years (in past smokers), and pulse pressure were negatively correlated. In the fully adjusted model, women had about 0.02 lower ABI values than men, and blacks showed ABI values about 0.02 lower than non-Hispanic whites. Conclusion: These data suggest intrinsic ethnic and gender differences in ABI. Such differences, although small in magnitude, are highly significant and can distort population estimates of disease burden. C1 Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, Sch Med, La Jolla, CA 92093 USA. Dupuytren Univ Hosp, Dept Thorac & Cardiovasc Surg & Vasc Med, Limoges, France. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Aboyans, V (reprint author), Dupuytren Univ Hosp, Dept Thorac & Cardiovasc Surg & Angiol, 2 Ave Martin Luther King, F-87042 Limoges, France. EM aboyans@unilim.fr OI Allison, Matthew/0000-0003-0777-8272 FU NHLBI NIH HHS [N01-HC-95159, N01-HC-95169, N01-HC-95165] NR 57 TC 67 Z9 70 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD FEB PY 2007 VL 45 IS 2 BP 319 EP 327 DI 10.1016/j.jvs.2006.10.032 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 133BS UT WOS:000243987200020 PM 17264011 ER PT J AU Majerciak, V Pripuzova, N McCoy, JP Gao, SJ Zheng, ZM AF Majerciak, Vladimir Pripuzova, Natalia McCoy, J. Philip Gao, Shou-Jiang Zheng, Zhi-Ming TI Targeted disruption of Kaposi's sarcoma-associated herpesvirus ORF57 in the viral genome is detrimental for the expression of ORF59, K8 alpha, and K8.1 and the production of infectious virus SO JOURNAL OF VIROLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; LYTIC GENE-EXPRESSION; RNA EXPORT FACTOR; DNA-REPLICATION; NUCLEAR ANTIGEN; MESSENGER-RNA; TRANSCRIPTIONAL ACTIVATION; EPISOME PERSISTENCE; PROCESSIVITY FACTOR; PROTEIN AB Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 regulates viral gene expression at the posttranscriptional level during viral lytic infection. To study its function in the context of the viral genome, we disrupted KSHV ORF57 in the KSHV genome by transposon-based mutagenesis. The insertion of the transposon into the ORF57 exon 2 region also interrupted the 3' untranslated region of KSHV ORF56, which overlaps with the ORF57 coding region. The disrupted viral genome, Bac36-Delta 57, did not express ORF57, ORF59, K8 alpha, K8.1, or a higher level of polyadenylated nuclear RNA after butyrate induction and could not be induced to produce infectious viruses in the presence of valproic acid, a histone deacetylase inhibitor and a novel KSHV lytic cycle inducer. The ectopic expression of ORF57 partially complemented the replication deficiency of the disrupted KSHV genome and the expression of the lytic gene ORF59. The induced production of infectious virus particles from the disrupted KSHV genome was also substantially restored by the simultaneous expression of both ORF57 and ORF56; complementation by ORF57 alone only partially restored the production of virus, and expression of ORF56 alone showed no effect. Altogether, our data indicate that in the context of the viral genome, KSHV ORF57 is essential for ORF59, K8 alpha, and K8.1 expression and infectious virus production. C1 NCI, HIV & AIDS Malingnancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Childrens Canc Res Inst, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78229 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malingnancy Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Rm 10 S255,MSC-1868, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov RI Gao, Shou-Jiang/B-8641-2012 FU Intramural NIH HHS NR 57 TC 47 Z9 48 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2007 VL 81 IS 3 BP 1062 EP 1071 DI 10.1128/JVI.01558-06 PG 10 WC Virology SC Virology GA 129YU UT WOS:000243766800002 PM 17108026 ER PT J AU Zampieri, CA Fortin, JF Nolan, GP Nabel, GJ AF Zampieri, Carisa A. Fortin, Jean-Francois Nolan, Garry P. Nabel, Gary J. TI The ERK mitogen-activated protein kinase pathway contributes to Ebola virus glycoprotein-induced cytotoxicity SO JOURNAL OF VIROLOGY LA English DT Article ID SIGNAL-REGULATED KINASE; CELL-CYCLE PROGRESSION; ENVELOPE GLYCOPROTEINS; ZAIRE VIRUSES; MECHANISMS; DISTINCT; MARBURG; ENTRY; INTERNALIZATION; IDENTIFICATION AB Ebola virus is a highly lethal pathogen that causes hemorrhagic fever in humans and nonhuman primates. Among the seven known viral gene products, the envelope glycoprotein (GP) alone induces cell rounding and detachment that ultimately leads to cell death. Cellular cytoxicity is not seen with comparable levels of expression of a mutant form of GP lacking a mucin-like domain (GP Delta muc). GP-induced cell death is nonapoptotic and is preceded by downmodulation of cell surface molecules involved in signaling pathways, including certain integrins and epidermal growth factor receptor. To investigate the mechanism of GP-induced cellular toxicity, we analyzed the activation of several signal transduction pathways involved in cell growth and survival. The active form of extracellular signal-regulated kinases types 1 and 2 (ERK1/2), phospho-ERK1/2, was reduced in cells expressing GP compared to those expressing GP Delta muc as determined by flow cytometry, in contrast to the case for several other signaling proteins. Subsequent analysis of the activation states and kinase activities of related kinases revealed a more pronounced effect on the ERK2 kinase isoform. Disruption of ERK2 activity by a dominant negative ERK or by small interfering RNA-mediated ERK2 knockdown potentiated the decrease in alpha V integrin-expression associated with toxicity. Conversely, activation of the pathway through the expression of a constitutively active form of ERK2 significantly protected against this effect. These results indicate that the ERK signaling cascade mediates GP-mediated cytotoxicity and plays a role in pathogenicity induced by this gene product. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Microbiol & Immunol, Baxter Lab Genet Pharmacol, Stanford, CA 94305 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Room 4502,Bldg 40,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [N01 HV028183, N01 HV28183] NR 49 TC 38 Z9 41 U1 1 U2 13 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 FEB PY 2007 VL 81 IS 3 BP 1230 EP 1240 DI 10.1128/JVI.01586-06 PG 11 WC Virology SC Virology GA 129YU UT WOS:000243766800017 PM 17108034 ER PT J AU Kim, JO Chakrabarti, BK Guha-Niyogi, A Louder, MK Mascola, JR Ganesh, L Nabel, GJ AF Kim, Jae-Ouk Chakrabarti, Bimal K. Guha-Niyogi, Anuradha Louder, Mark K. Mascola, John R. Ganesh, Lakshmanan Nabel, Gary J. TI Lysis of human immunodeficiency virus type 1 by a specific secreted human phospholipase A(2) SO JOURNAL OF VIROLOGY LA English DT Article ID COMPLEMENT-MEDIATED LYSIS; ARACHIDONIC-ACID RELEASE; GROUP-X; GROUP-II; GROUP-V; MAMMALIAN-CELLS; BACTERICIDAL PROPERTIES; INFECTION; ANTIBODY; HIV AB Phospholipase A(2) (PLA(2)) proteins affect cellular activation, signal transduction, and possibly innate immunity. A specific secretory PLA(2), sPLA(2)-X, is shown here to neutralize human immunodeficiency virus type 1 (HIV-1) through degradation of the viral membrane. Catalytic function was required for antiviral activity, and the target cells of infection were unaffected. sPLA2-X potently reduced gene transfer of HIV-1 Env-pseudotyped lentivirus vectors and inhibited the replication of both CCR5- and CXCR4-tropic HIV-1 in human CD4(+) T cells. Virions resistant to damage by antibody and complement were sensitive to lysis by sPLA2-X, suggesting a novel mechanism of antiviral surveillance independent of the acquired immune system. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Room 4502,Bldg 40,MSC 3005,40 Convent Dr, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS NR 28 TC 16 Z9 16 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 FEB PY 2007 VL 81 IS 3 BP 1444 EP 1450 DI 10.1128/JVI.01790-06 PG 7 WC Virology SC Virology GA 129YU UT WOS:000243766800038 PM 17093191 ER PT J AU Takenouchi, N Jones, KS Lisinski, I Fugo, K Yao, K Cushman, SW Ruscetti, FW Jacobson, S AF Takenouchi, Norihiro Jones, Kathryn S. Lisinski, Ivonne Fugo, Kazunori Yao, Karen Cushman, Samuel W. Ruscetti, Francis W. Jacobson, Steven TI GLUT1 is not the primary binding receptor but is associated with cell-to-cell transmission of human T-cell leukemia virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; GLUCOSE-TRANSPORTER GLUT-1; ADIPOSE-CELLS; HOST-RANGE; HTLV-I; EXPRESSION; LYMPHOCYTES; ACTIVATION; LINES; RETROVIRUS AB GLUT1 has recently been suggested to be a binding receptor for human T-cell leukemia virus type 1 (HTLV-1). We used a novel, short-term assay to define the role of GLUT1 in cell-to-cell transmission. Although increasing cell surface levels of GLUT1 enhanced HTLV-1 transfer, efficient virus spread correlated largely with heparan sulfate proteoglycan (HSPG) expression on target cells. Moreover, since activated CD4(+) T cells and cord blood lymphocytes that are susceptible to HTLV-1 infection expressed undetectable levels of surface GLUT1, these results indicate that GLUT1 and HSPGs are important for efficient cell-to-cell transmission of HTLV-1 but raise concerns on the role of GLUT1 as the HTLV-1 primary binding receptor. C1 NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20982 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21702 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20982 USA. EM jacobsons@ninds.nih.gov FU Intramural NIH HHS; NCI NIH HHS [CO-12400, N01CO12400] NR 23 TC 36 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 FEB PY 2007 VL 81 IS 3 BP 1506 EP 1510 DI 10.1128/JVI.01522-06 PG 5 WC Virology SC Virology GA 129YU UT WOS:000243766800045 PM 17108050 ER PT J AU Cohen, JI Krogmann, T Pesnicak, L Ali, MA AF Cohen, Jeffrey I. Krogmann, Tammy Pesnicak, Lesley Ali, Mir A. TI Absence or overexpression of the Varicella-Zoster virus (VZV) ORF29 latency-associated protein impairs late gene expression and reduces VZV latency in a rodent model SO JOURNAL OF VIROLOGY LA English DT Article ID DNA-BINDING PROTEIN; REPLICATION-DEFECTIVE MUTANTS; HUMAN TRIGEMINAL GANGLIA; ESTABLISHMENT; INFECTION; CELLS; TRANSCRIPTION; LOCALIZATION; RAT; IMMUNIZATION AB Varicella-zoster virus (VZV) ORF29 encodes the viral single-stranded DNA binding protein and is expressed during latency in human ganglia. We constructed an ORF29 deletion mutant virus and showed that the virus could replicate only in cells expressing ORF29. An ORF29-repaired virus, in which ORF29 was driven by a cytomegalovirus promoter, grew to peak titers similar to those seen with the parental virus. The level of ORF29 protein in cells infected with the repaired virus was greater than that seen with parental virus. Infection of cells with either the ORF29 deletion or repaired virus resulted in similar levels of VZV immediate-early proteins but reduced levels of glycoprotein E compared to those observed with parental virus. Cotton rats infected with the ORF29 deletion mutant had a markedly reduced frequency of latent infection in dorsal root ganglia compared with those infected with parental virus (P < 0.00001). In contrast, infection of animals with the ORF29 deletion mutant resulted in a frequency of ganglionic infection at 3 days similar to that seen with the parental virus. Animals infected with the ORF29-repaired virus, which overexpresses ORF29, also had a reduced frequency of latent infection compared with those infected with parental virus (P = 0.0044). These studies indicate that regulation of ORF29 at appropriate levels is critical for VZV latency in a rodent model. C1 NIH, Med Viorl Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Med Viorl Sect, Lab Clin Infect Dis, Bldg 10,Room 11N234,10 Ctr Dr, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU Intramural NIH HHS NR 41 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 FEB PY 2007 VL 81 IS 4 BP 1586 EP 1591 DI 10.1128/JVI.01220-06 PG 6 WC Virology SC Virology GA 136RI UT WOS:000244241400005 PM 17151102 ER PT J AU DeDiego, ML Alvarez, E Almazan, F Rejas, MT Lamirande, E Roberts, A Shieh, WJ Zaki, SR Subbarao, K Enjuanes, L AF DeDiego, Marta L. Alvarez, Enrique Almazan, Fernando Rejas, Maria Teresa Lamirande, Elaine Roberts, Anjeanette Shieh, Wun-Ju Zaki, Sherif R. Subbarao, Kanta Enjuanes, Luis TI A severe acute respiratory syndrome coronavirus that lacks the E gene is attenuated in vitro and in vivo SO JOURNAL OF VIROLOGY LA English DT Article ID BRONCHITIS-VIRUS-E; VIRAL STRUCTURAL PROTEIN; GOLDEN SYRIAN-HAMSTERS; SARS-CORONAVIRUS; MEMBRANE-PROTEIN; ENVELOPE PROTEIN; RNA-SYNTHESIS; ION CHANNELS; CELL-LINES; REPLICATION AB A deletion mutant of severe acute respiratory syndrome coronavirus (SARS-CoV) has been engineered by deleting the structural E gene in an infectious cDNA clone that was constructed as a bacterial artificial chromosome (BAC). The recombinant virus lacking the E gene (rSARS-CoV-Delta E) was rescued in Vero E6 cells. The recovered deletion mutant grew in Vero E6, Huh-7, and CaCo-2 cells to titers 20-, 200-, and 200-fold lower than the recombinant wild-type virus, respectively, indicating that although the E protein has an effect on growth, it is not essential for virus replication. No differences in virion stability under a wide range of pH and temperature were detected between the deletion mutant and recombinant wild-type viruses. Although both viruses showed the same morphology by electron microscopy, the process of morphogenesis seemed to be less efficient with the defective virus than with the recombinant wild-type one. The rSARS-CoV-AE virus replicated to titers 100- to 1,000-fold lower than the recombinant wild-type virus in the upper and lower respiratory tract of hamsters, and the lower viral load was accompanied by less inflammation in the lungs of hamsters infected with rSARS-CoV-Delta E virus than with the recombinant wild-type virus. Therefore, the SARS-CoV that lacks the E gene is attenuated in hamsters, might be a safer research tool, and may be a good candidate for the development of a live attenuated SARS-CoV vaccine. C1 CSIC, Dept Mol & Cell Biol, Ctr Nacl Biotecnol, Madrid 28049, Spain. UAM, CSIC, Ctr Biol Mol, Fac Ciencias, Madrid 28049, Spain. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. RP Enjuanes, L (reprint author), CSIC, Dept Mol & Cell Biol, Ctr Nacl Biotecnol, Darwin 3,Campus Univ Autonoma, Madrid 28049, Spain. EM L.Enjuanes@cnb.uam.es RI Almazan, Fernando/K-8781-2015; OI Almazan, Fernando/0000-0002-5752-8469; Enjuanes, Luis/0000-0002-0854-0226 FU Intramural NIH HHS NR 60 TC 90 Z9 92 U1 1 U2 6 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 FEB PY 2007 VL 81 IS 4 BP 1701 EP 1713 DI 10.1128/JVI.01467-06 PG 13 WC Virology SC Virology GA 136RI UT WOS:000244241400017 PM 17108030 ER PT J AU Melar, M Ott, DE Hope, TJ AF Melar, Marta Ott, David E. Hope, Thomas J. TI Physiological levels of virion-associated human immunodeficiency virus type 1 envelope induce coreceptor-dependent calcium flux SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; MEK/ERK SIGNALING PATHWAY; CHEMOKINE RECEPTOR CXCR4; MEMBRANE-FUSION; HIV-1 GP120; TROPIC HIV; ANTIRETROVIRAL THERAPY; CONFORMATIONAL-CHANGES; SURFACE ASSOCIATION; GENE-EXPRESSION AB Human immunodeficiency virus (HIV) entry into target cells requires the engagement of receptor and coreceptor by envelope glycoprotein (Env). Coreceptors CCR5 and CXCR4 are chemokine receptors that generate signals manifested as calcium fluxes in response to binding of the appropriate ligand. It has previously been shown that engagement of the coreceptors by HIV Env can also generate Ca2+ fluxing. Since the sensitivity and therefore the physiological consequence of signaling activation in target cells is not well understood, we addressed it by using a microscopy-based approach to measure Ca2+ levels in individual CD4(+) T cells in response to low Env concentrations. Monomeric Env subunit gp120 and virion-bound Env were able to activate a signaling cascade that is qualitatively different from the one induced by chemokines. Env-mediated Ca2+ fluxing was coreceptor mediated, coreceptor specific, and CD4 dependent. Comparison of the observed virion-mediated Ca2+ fluxing with the exact number of viral particles revealed that the viral threshold necessary for coreceptor activation of signaling in CD4(+) T cells was quite low, as few as two virions. These results indicate that the physiological levels of virion binding can activate signaling in CD4(+) T cells in vivo and therefore might contribute to HIV-induced pathogenesis. C1 Northwestern Univ, Dept Cell & Mol Biol, Feinberg Sch Med, Chicago, IL 60611 USA. Univ Illinois, Dept Microbiol & Immunol, Chicago, IL 60612 USA. NCI, Retroviral Assembly Lab, SAIC Frederick, Frederick, MD 21702 USA. RP Hope, TJ (reprint author), Northwestern Univ, Dept Cell & Mol Biol, Feinberg Sch Med, Ward 8-140,303 E Chicago Ave, Chicago, IL 60611 USA. EM thope@northwestern.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI52051, R01 AI052051] NR 77 TC 24 Z9 26 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 FEB PY 2007 VL 81 IS 4 BP 1773 EP 1785 DI 10.1128/JVI.01316-06 PG 13 WC Virology SC Virology GA 136RI UT WOS:000244241400023 PM 17121788 ER PT J AU von Gegerfelt, AS Rosati, M Alicea, C Valentin, A Roth, P Bear, J Franchini, G Albert, PS Bischofberger, N Boyer, JD Weiner, DB Markham, P Israel, ZR Eldridge, JH Pavlakis, GN Felber, BK AF von Gegerfelt, Agneta S. Rosati, Margherita Alicea, Candido Valentin, Antonio Roth, Patricia Bear, Jenifer Franchini, Genoveffa Albert, Paul S. Bischofberger, Norbert Boyer, Jean D. Weiner, David B. Markham, Phillip Israel, Zimra R. Eldridge, John H. Pavlakis, George N. Felber, Barbara K. TI Long-lasting decrease in viremia in macaques chronically infected with simian immunodeficiency virus SIVmac251 after therapeutic DNA immunization SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; DENDRITIC-CELL VACCINE; LATENT RESERVOIR; AIDS VACCINE; HIV-1; REV; GAG; DISCONTINUATION; EXPRESSION; RNA AB Rhesus macaques chronically infected with highly pathogenic simian immunodeficiency virus (SIV) SIVmac251 were treated with antiretroviral drugs and vaccinated with combinations of DNA vectors expressing SIV antigens. Vaccination during therapy increased cellular immune responses. After the animals were released from therapy, the virus levels of 12 immunized animals were significantly lower (P = 0.001) compared to those of 11 animals treated with only antiretroviral drugs. Vaccinated animals showed a persistent increase in immune responses, thus indicating both a virological and an immunological benefit following DNA therapeutic vaccination. Several animals show a long-lasting decrease in viremia, suggesting that therapeutic vaccination may provide an additional benefit to antiretroviral therapy. C1 NCI, Human Retrovirus Sect, Vaccine Branch, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Anim Models & Retroviral Vaccines Sect, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Gilead Sci Inc, Foster City, CA 94404 USA. Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Adv BioSci Labs Inc, Kensington, MD 20895 USA. Wyeth Vaccines Res, Pearl River, NY 10965 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Canc Res Ctr, 1050 Boyles St,Bldg 535,Room 210, Frederick, MD 21702 USA. EM pavlakis@ncifcrf.gov RI Weiner, David/H-8579-2014 FU Intramural NIH HHS NR 38 TC 31 Z9 31 U1 1 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 FEB PY 2007 VL 81 IS 4 BP 1972 EP 1979 DI 10.1128/JVI.01990-06 PG 8 WC Virology SC Virology GA 136RI UT WOS:000244241400040 PM 17135321 ER PT J AU Keller, CR Odden, MC Fried, LF Newman, AB Angleman, S Green, CA Cummings, SR Harris, TB Shlipak, MG AF Keller, C. R. Odden, M. C. Fried, L. F. Newman, A. B. Angleman, S. Green, C. A. Cummings, S. R. Harris, T. B. Shlipak, M. G. TI Kidney function and markers of inflammation in elderly persons without chronic kidney disease: The health, aging, and body composition study SO KIDNEY INTERNATIONAL LA English DT Article DE inflammation; biomarkers; cystatin; kidney; epidemiology ID SERUM CYSTATIN-C; GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; CHRONIC-RENAL-FAILURE; REACTIVE PROTEIN; HEMODIALYSIS-PATIENTS; CARDIOVASCULAR EVENTS; PLASMA; RISK; INTERLEUKIN-6 AB Inflammatory markers are elevated in persons with estimated glomerular filtration rates less than 60ml/min/1.73m(2). As cystatin C may detect small changes in kidney function not detected by estimated glomerular filtration rate, we evaluated the association between cystatin C and serum markers of inflammation in older adults with estimated glomerular filtration rate >= 60. This is an analysis using measures from the Health, Aging, and Body Composition Study, a cohort of well-functioning adults aged 70-79 years. Cystatin C correlated with all five inflammatory biomarkers: C-reactive protein ( r = 0.08), interleukin-6 ( r = 0.19), tumor necrosis factor alpha ( TNF-alpha) ( r = 0.41), soluble TNF receptor 1 ( STNF-R1) ( r = 0.61), and soluble TNF receptor 2 ( STNF-R2) ( r = 0.54); P < 0.0005 for all. In adjusted analyses, cystatin C concentrations appeared to have stronger associations with each biomarker compared with estimated glomerular filtration rate or serum creatinine. Participants with a cystatin C >= 1.0mg/l had significantly higher levels of all five biomarkers compared to those with a cystatin C < 1.0 ( mean differences ranging 16-29%, all P < 0.05). Cystatin C has a linear association with inflammatory biomarkers in an ambulatory elderly cohort with estimated glomerular filtration rates >= 60; associations are particularly strong with TNF-alpha and the STNF-R. C1 Vet Adm Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Pittsburgh, Sch Med, Renal Sect, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Renal Sect, Renal Electrolyte Div, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. Univ Tennessee, Dept Med, Div Nephrol, Knoxville, TN 37996 USA. Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94115 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Shlipak, MG (reprint author), Vet Adm Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM shlip@itsa.ucsf.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Angleman, Sara/0000-0002-9520-5716 FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL073208-01]; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; NIDDK NIH HHS [R01 DK066488-01] NR 42 TC 77 Z9 79 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2007 VL 71 IS 3 BP 239 EP 244 DI 10.1038/sj.ki.5002042 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 129LK UT WOS:000243730800011 PM 17183246 ER PT J AU Suri, RS Garg, AX Chertow, GM Levin, NW Rocco, MV Greene, T Beck, GJ Gassman, JJ Eggers, PW Star, RA Ornt, DB Kliger, AS AF Suri, R. S. Garg, A. X. Chertow, G. M. Levin, N. W. Rocco, M. V. Greene, T. Beck, G. J. Gassman, J. J. Eggers, P. W. Star, R. A. Ornt, D. B. Kliger, A. S. CA Frequent Hemodialysis Network TI Frequent Hemodialysis Network (FHN) randomized trials: Study design SO KIDNEY INTERNATIONAL LA English DT Article DE quality of life; randomized controlled trials; frequent hemodialysis; left ventricular hypertrophy ID LEFT-VENTRICULAR HYPERTROPHY; QUALITY-OF-LIFE; STAGE RENAL-DISEASE; HOME HEMODIALYSIS; NOCTURNAL HEMODIALYSIS; MAGNETIC-RESONANCE; BLOOD-PRESSURE; FOLLOW-UP; DIALYSIS; SURVIVAL AB Observational studies suggest improvements with frequent hemodialysis ( HD), but its true efficacy and safety remain uncertain. The Frequent Hemodialysis Network Trials Group is conducting two multicenter randomized trials of 250 subjects each, comparing conventional three times weekly HD with ( 1) in-center daily HD and ( 2) home nocturnal HD. Daily HD will be delivered for 1.5-2.75 h, 6 days/ week, with target eK(t)/ V-n >= 0.9/ session, whereas nocturnal HD will be delivered for >= 6 h, 6 nights/ week, with target stdK(t)/ V of >= 4.0/ week. Subjects will be followed for 1 year. The composite of mortality with the 12-month change in ( i) left ventricular mass index ( LVMI) by magnetic resonance imaging, and ( ii) SF- 36 RAND Physical Health Composite ( PHC) are specified as co-primary outcomes. The seven main secondary outcomes are between group comparisons of: change in LVMI, change in PHC, change in Beck Depression Inventory score, change in Trail Making Test B score, change in pre-HD serum albumin, change in pre-HD serum phosphorus, and rates of non-access hospitalization or death. Changes in blood pressure and erythropoeisis will also be assessed. Safety outcomes will focus on vascular access complications and burden of treatment. Data will be obtained on the cost of delivering frequent HD compared to conventional HD. Efforts will be made to reduce bias, including blinding assessment of subjective outcomes. Because no large-scale randomized trials of frequent HD have been previously conducted, the first year has been designated a Vanguard Phase, during which feasibility of randomization, ability to deliver the interventions, and adherence will be evaluated. C1 Univ Western Ontario, Div Nephrol, London, ON, Canada. Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. Renal Res Inst, New York, NY USA. Wake Forest Univ, Baptist Med Ctr, Nephrol Sect, Winston Salem, NC 27109 USA. Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. NIDDK, NIH, Bethesda, MD USA. Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. Hosp St Raphael, New Haven, CT USA. RP Suri, RS (reprint author), London Hlth Sci Ctr, Kidney Clin Res Unit, Room ELL-119,800 Commissioners Rd E, London, ON N6A 4G5, Canada. EM rita.suri@lhsc.on.ca RI Suri, Rita/G-3348-2011 OI Suri, Rita/0000-0002-0519-3927 NR 41 TC 139 Z9 141 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2007 VL 71 IS 4 BP 349 EP 359 DI 10.1038/sj.ki.5002032 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 134KP UT WOS:000244082200018 PM 17164834 ER PT J AU Saika, S Shirai, K Yamanaka, O Miyazaki, K Okada, Y Kitano, A Flanders, KC Kon, S Uede, T Kao, WWY Rittling, SR Denhardt, DT Ohnishi, Y AF Saika, Shizuya Shirai, Kumi Yamanaka, Osamu Miyazaki, Ken-ichi Okada, Yuka Kitano, Ai Flanders, Kathleen C. Kon, Shigeyuki Uede, Toshimitsu Kao, Winston Whei-Yang Rittling, Susan R. Denhardt, David T. Ohnishi, Yoshitaka TI Loss of osteopontin perturbs the epithelial-mesenchymal mouse lens epithelium transition in an injured SO LABORATORY INVESTIGATION LA English DT Article DE lens epithelium; epithelial-mesenchymal transition; osteopontin; wound healing; Smad ID POSTERIOR CAPSULE OPACIFICATION; GROWTH-FACTOR-BETA; CELL-MEDIATED-IMMUNITY; DEFICIENT MICE; AQUEOUS-HUMOR; FIBROSIS; MATRIX; TRANSDIFFERENTIATION; EXPRESSION; LUMICAN AB We previously reported that osteopontin (OPN), a matrix structural glycophosphoprotein, is upregulated in the injured mouse lens prior to the epithelial-mesenchymal transition (EMT). Here, we investigated the role of this protein in EMT of the lens epithelium during wound healing. The crystalline lens was injured by needle puncture in OPN-null (KO, n = 40) and wild-type (WT, n = 40) mice. The animals were killed at day 1, 2, 5, and 10 postinjury. Immunohistochemistry was employed to detect alpha-smooth muscle action (alpha SMA), a marker of EMT, collagen type 1, transforming growth factor beta 1 (TGF beta I), TGF beta 2, and phospho-Smad2/3. Cell proliferation was assayed by examining uptake of bromodeoxyuridine (BrdU). The results showed that injury-induced EMT of mouse lens epithelium, as evaluated by histology, expression pattern of alpha SMA and collagen I, was altered in the absence of OPN with reduced phospho-Smad2/3 signaling. Upregulation of TGF beta 1 and TGF beta 2 in the epithelium was also inhibited. Cell proliferation was more active in KO mice as compared with WT mice at day 1 and 2, but not at day 5 and 10. An in vitro experiment shows OPN facilitates cell adhesion of lens epithelial cell line. OPN is required for activation of Smad2/3 signal in an injured lens epithelium and lens cell EMT. C1 Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Hokkaido Univ, Inst Med Genet, Div Mol Immunol, Kita Ku, Sapporo, Hokkaido, Japan. Univ Cincinnati, Med Ctr, Dept Ophthalmol, Cincinnati, OH 45267 USA. Rutgers State Univ, Dept Genet, Piscataway, NJ USA. Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ USA. RP Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM shizuya@wakayama-med.ac.jp RI Kon, Shigeyuki/A-3809-2012; uede, toshimitsu/A-4273-2012 FU NEI NIH HHS [EY13755] NR 52 TC 19 Z9 22 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2007 VL 87 IS 2 BP 130 EP 138 DI 10.1038/labinvest.3700508; PG 9 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 136IP UT WOS:000244216100004 PM 17211411 ER PT J AU Koutros, S Holford, TR Hahn, T Lantos, PM McCarthy, PL Risch, HA Swede, H AF Koutros, Stella Holford, Teodore R. Hahn, Theresa Lantos, Paul M. McCarthy, Philip L., Jr. Risch, Harvey A. Swede, Helen TI Excess diagnosis of non-Hodgkin's lymphoma during spring in the USA SO LEUKEMIA & LYMPHOMA LA English DT Article DE non-Hodgkin's lymphoma; etiology; seasonality; periodicity; infectious cancer; SEER Program; hematologic neoplasms ID UNITED-STATES; SEASONAL-VARIATION; LEUKEMIA; DISEASE; CANCER; SUBTYPE; EPIDEMIOLOGY; CONNECTICUT; HEPATITIS; ETIOLOGY AB A seasonal peak in hematologic malignancies may support hypotheses of infection-related precipitating events. Moderately increased incidence rates have been observed during the spring for leukemias and Hodgkin's disease but few studies have been conducted of non-Hodgkin's lymphoma (NHL). Our study consisted of 77,173 NHL patients in the Surveillance, Epidemiology, and End Results database diagnosed during 1973-99. Chi-square analyses showed excess observed-vs.-expected diagnoses during March, April, and June (P < 0.0001). B-cell origin subtype, but not T-cell/NK, was diagnosed more frequently in March. Controlling for age, sex, geographical location, and diagnosis year, multivariate Poisson regression revealed peaks in both March and April (P < 0.0001). Excluding cases in December, due to consistent troughs, regression uncovered greater-than-expected incidence during spring months for patients aged 20-39 years and 40-64 years (P = 0.043, P = 0.0001) but not among patients > 65 years. Future studies are needed to discern if a spring peak is due to diagnostic bias or other uncontrolled factors. C1 Univ Connecticut, Ctr Hlth, Dept Community Med & Hlth Care, Div Epidemiol & Biostat, Farmington, CT 06030 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Div Chron Dis Epidemiol, New Haven, CT USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT USA. Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. Childrens Hosp, Div Infect Dis, Boston, MA USA. Harvard Univ, Dept Pediat, Boston, MA 02115 USA. Univ Connecticut, Neag Canc Ctr, Ctr Hlth, Farmington, CT USA. RP Swede, H (reprint author), Univ Connecticut, Ctr Hlth, Dept Community Med & Hlth Care, Div Epidemiol & Biostat, 263 Farmington Ave, Farmington, CT 06030 USA. EM hswede@uchc.edu FU NCI NIH HHS [R25 CA47883, N01-CN-67005] NR 38 TC 6 Z9 6 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD FEB PY 2007 VL 48 IS 2 BP 357 EP 366 DI 10.1080/10428190601076799 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 140SZ UT WOS:000244528300023 PM 17325897 ER PT J AU Dracheva, T Philip, R Xiao, WM Gee, AG McCarthy, J Yang, P Wang, Y Dong, G Yang, HJ Jen, J AF Dracheva, Tatiana Philip, Reena Xiao, Wenming Gee, Alexander G. McCarthy, John Yang, Ping Wang, Yue Dong, Gang Yang, Hongjun Jen, Jin TI Distinguishing lung tumours from normal lung based on a small set of genes SO LUNG CANCER LA English DT Article DE cancer detection; class prediction; expression profiling; gene chip; non-small cell lung cancer; Flow-Thru Chip (R) ID HUMAN BREAST-CANCER; SERIAL ANALYSIS; EXPRESSION PROFILES; PREDICT SURVIVAL; SUPPRESSOR GENE; CELL-GROWTH; ADENOCARCINOMA; METASTASIS; CARCINOMAS; CLASSIFICATION AB Identifying specific molecular markers and developing sensitive detection methods are two of the fundamental requirements for detection and differential diagnosis of cancer. Toward this goal, we first performed cDNA array analysis using 65 non-small cell lung cancer and non-involved normal lung tissues. We then used several complementary statistical and analytical methods to examine gene expression profiles generated by us and others from four independent sets of normal and neoplastic lung tissues. We report here that several sets of roughly 20 genes were sufficient to provide a robust distinction between normal and neoptastic tissues of the lung. Next we assessed the predictive ability of these gene sets by using Flow-Thru Chips (R) (FrC) (MetriGenix, Baltimore, MD) containing 20 genes to screen 48 primary lung tumours and normal lung tissues. Gene expression changes detected by FTC distinguished lung cancers from the normal lung tissues using an RNA amount equivalent to that present in as few as 300 cells. We also used an independent set of 24 genes and showed that their expression profile was equally effective when measured by quantitative polymerase chain reaction (Q-PCR). Our results demonstrate that lung cancers can be identified based on the expression patterns of just 20 genes and that this approach is applicable for cancer diagnosis, prognosis, and monitoring using small amount of tumour or biopsy samples. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NCI, Lab Populat Gent, Ctr Canc Res, Bethesda, MD 20892 USA. MetriGenix US Inc, Baltimore, MD 21227 USA. AnVil Inc, Burlington, MA 01803 USA. Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. RP Jen, J (reprint author), 41 Lib Dr,Room D702, Bethesda, MD 20892 USA. EM jenj@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010164-05, Z01 CP010162-05] NR 33 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD FEB PY 2007 VL 55 IS 2 BP 157 EP 164 DI 10.1016/j.lungcan.2006.10.025 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 134SC UT WOS:000244103300004 PM 17161497 ER PT J AU Sampath, S Prince, JL AF Sampath, Smita Prince, Jerry L. TI Automatic 3D tracking of cardiac material markers using slice-following and harmonic-phase MRI SO MAGNETIC RESONANCE IMAGING LA English DT Article DE magnetic resonance tagging; HARP; slice-following; cardiac motion; cardiac strain ID HYPERTROPHIC CARDIOMYOPATHY; MYOCARDIAL MOTION; WALL-MOTION; TAGGED MRI; CONTRAST; HEART; DEFORMATION; MODULATION; ECHOES AB A method to track a grid of cardiac material points in three dimensions using slice-following (SF) tagged magnetic resonance imaging (MRI) and harmonic-phase MRI is presented. A three-dimensional grid of material points on the lines of intersections of short-axis (SA) and long-axis (LA) planes is automatically tracked by combining two-dimensional pathlines that are computed on both SA and LA image planes. This process yields the true three-dimensional motion of points originating on the image plane intersections. Experimental data from normal volunteers, each obtained in four short breath-holds using the SF harmonic phase MRI pulse sequence, is presented. A validation of two-dimensional in-plane tracks using this pulse sequence on a moving phantom is also presented. (c) 2007 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. RP Sampath, S (reprint author), NHLBI, Lab Cardiac Energet, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sampaths@mail.nih.gov RI Prince, Jerry/A-3281-2010 OI Prince, Jerry/0000-0002-6553-0876 FU NHLBI NIH HHS [R01 HL047405-13, R01 HL047405, R01HL47405] NR 35 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD FEB PY 2007 VL 25 IS 2 BP 197 EP 208 DI 10.1016/j.mri.2006.09.033 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 136YZ UT WOS:000244261300007 PM 17275614 ER PT J AU Xu, S Yang, J Shen, J AF Xu, Su Yang, Jehoon Shen, Jun TI In vivo C-13 saturation transfer effect of the lactate dehydrogenase reaction SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE lactate dehydrogenase; cancer; in vivo spectroscopy; C-13; saturation transfer ID MAGNETIZATION-TRANSFER; RAT-BRAIN; METABOLIC-CHANGES; PANIC DISORDER; 11.7 TESLA; SPECTROSCOPY; ACID; RELAXATION; ASTROCYTES; ISOENZYMES AB Lactate dehydrogenase (LDH, EC 1.1.1.27) catalyzes an exchange reaction between pyruvate and lactate. It is demonstrated here that this reaction is sufficiently fast to cause a significant magnetization (saturation) transfer effect when the C-13 resonance of pyruvate is saturated by a continuous-wave (CW) RF pulse. Infusion of [2- 13C]glucose was used to allow labeling of pyruvate C2 at 207.9 ppm to determine the pseudo first-order rate constant of the unidirectional lactate -> pyruvate flux in vivo. During systemic administration of GABA(A) receptor antagonist bicuculline, this pseudo first-order rate constant was determined to be 0.08 0.01 s-1 (mean SD, N = 4) in halothane-anesthetized adult rat brains. In 9L and C6 rat glioma models, the 13C saturation transfer effect of the LDH reaction was also detected in vivo. Our results demonstrate that the 13C magnetization transfer effect of the LDH reaction may be useful as a novel marker for utilizing noninvasive in vivo MRS to study many physiological and pathological conditions, such as cancer. Magn Reson Med 57:258-264, 2007. (c) 2007 Wiley-Liss, Inc.(+) C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU Intramural NIH HHS NR 41 TC 11 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2007 VL 57 IS 2 BP 258 EP 264 DI 10.1002/mrm.21137 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 132MG UT WOS:000243946300004 PM 17260357 ER PT J AU Li, SZ Yang, J Shen, J AF Li, Shizhe Yang, Jehoon Shen, Jun TI Novel strategy for cerebral C-13 MRS using very low RF power for proton decoupling SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE decoupling; in vivo C-13 MRS; glutamate; glutamine; stochastic pulses ID MAGNETIC-RESONANCE-SPECTROSCOPY; TRICARBOXYLIC-ACID CYCLE; IN-VIVO; HUMAN BRAIN; RAT-BRAIN; OXIDATIVE-METABOLISM; NMR-SPECTROSCOPY; 4 TESLA; GLUTAMATE; HUMANS AB One of the major difficulties of in vivo C-13 MRS is the need to decouple the large, one-bond, H-1-C-13 scalar couplings in order to obtain useful signal-to-noise ratios (SNRs) and spectral resolution at magnetic field strengths that are accessible to clinical studies. In this report a new strategy for in vivo cerebral MRS is proposed. We realized that the turnover kinetics of glutamate (Glu) C5 from exogenous [2-C-13]glucose (Glc) is identical to that of Glu C4 from exogenous [1-C-13]Glc. The carboxylic/amide carbons are only coupled to protons via very weak long-range H-1-C-13 scalar couplings. As such, they can be effectively decoupled at very low RF power. Therefore, decoupling of the large H-1-C-13 scalar couplings can be avoided by the use of [2-C-13]Glc. An additional advantage of this strategy is the lack of contamination from subcutaneous lipids because there are no overlapping fat signals in the vicinity of the Glu C5 and glutamine (Gin) C5 peaks. The feasibility of this strategy was demonstrated using 13C MRS on rhesus monkey brains at 4.7T. Magn Reson Med 57:265-271, 2007. (c) 2007 Wiley-Liss, Inc. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NIMH, Magnet Resonance Spect Core Facil, NIH, Bethesda, MD 20892 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU Intramural NIH HHS NR 39 TC 20 Z9 20 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2007 VL 57 IS 2 BP 265 EP 271 DI 10.1002/mrm.21148 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 132MG UT WOS:000243946300005 PM 17260369 ER PT J AU van Gelderen, P de Zwart, JA Starewicz, P Hinks, RS Duyn, JH AF van Gelderen, P. de Zwart, J. A. Starewicz, P. Hinks, R. S. Duyn, J. H. TI Real-time shimming to compensate for respiration-induced B-0 fluctuations SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE high field imaging; image artifacts; respiration; phase stability; shimming ID ECHO-PLANAR; RETROSPECTIVE ESTIMATION; PHYSIOLOGICAL ARTIFACTS; FUNCTIONAL MRI; FMRI AB In MRI of human brain, the respiratory cycle can induce B-0-field fluctuations through motion of the chest and fluctuations in local oxygen concentration. The associated NMR frequency changes can affect the MRI data in various ways and lead to temporal signal fluctuations, and image artifacts such as ghosting and blurring. Since the size of the effect scales with magnetic field strength, artifacts become particularly problematic at fields above 3.0T. Furthermore, the spatial dependence of the B-0-field fluctuations complicates their correction. In this work, a new method is presented that allows compensation of field fluctuations by modulating the B. shims in real time. In this method, a reference scan is acquired to measure the spatial distribution of the B-0 effect related to chest motion. During the actual scan, this information is then used, together with chest motion data, to apply compensating B0 shims in real time. The method can be combined with any type of scan without modifications to the pulse sequence. Real-time B0 shimming is demonstrated to substantially improve the phase stability of EPI data and the image quality of multishot gradient-echo (GRE) MRI at 7T. Magn Reson Med 57:362-368, 2007. (c) 2007 Wiley Liss, Inc. C1 NINDS, Lab Funct & Mol Imaging, Adv MRI, NIH, Bethesda, MD 20892 USA. Resonance Res Inc, Billerica, MA USA. GE Healthcare, Milwaukee, WI USA. RP van Gelderen, P (reprint author), NINDS, Lab Funct & Mol Imaging, Adv MRI, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-725, Bethesda, MD 20892 USA. EM gelderen@nih.gov RI Duyn, Jozef/F-2483-2010 FU Intramural NIH HHS NR 11 TC 78 Z9 78 U1 1 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2007 VL 57 IS 2 BP 362 EP 368 DI 10.1002/mrm.21136 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 132MG UT WOS:000243946300015 PM 17260378 ER PT J AU Hama, Y Bernardo, M Regino, CAS Koyama, Y Brechbiel, MW Krishna, MC Choyke, PL Kobayashi, H AF Hama, Yukihiro Bernardo, Marcelino Regino, Celeste A. S. Koyama, Yoshinori Brechbiel, Martin W. Krishna, Murali C. Choyke, Peter L. Kobayashi, Hisataka TI MR lymphangiography using dendrimer-based contrast agents: A comparison at 1.5T and 3.0T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE contrast media; sentinel lymph node; lymphatic; relaxivity; macromolecule ID MAGNETIC RESONANCE LYMPHANGIOGRAPHY; MICE; LYMPHOGRAPHY; EXPERIENCE AB Most macromolecular contrast agents (CAs) show lower r(1) and higher r(2) relaxivities at 3.0T than at 1.5T. MR lymphangiography in mice using a macromolecular G6 dendrimer-based CA was serially performed and compared at both 1.5T and 3.0T. The r(1) and r(2) relaxivities of the G6 CA were 25 and 78/s/mM at 1.5T and 17 and 82/s/mM at 3.0T, respectively. The lymph node (LN)-to-fat ratios (LN signal intensity (SI)/fat SI) of T-1-weighted 3D-fast spoiled gradient-echo (3D-FSPGR) were 3.2 +/- 0.4 (mean standard deviation (SD)) at 1.5T and 2.7 +/- 0.3 at 3.0T (P = 0.021), and the LN-to-fat ratios of T-2/T-1-weighted 3D-fast imaging employing steady-state acquisition with phase cycling (3D-FIESTA-C) were 1.8 +/- 0.2 at 1.5T and 1.2 +/- 0.4 at 3.0T (P = 0.003). Although 3D-FSPGR successfully delineated the LNs at both 1.5T and 3.0T, 3D-FIESTA-C at 3.0T failed to visualize the LNs. C1 NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room 1B40,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural NIH HHS NR 19 TC 10 Z9 11 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD FEB PY 2007 VL 57 IS 2 BP 431 EP 436 DI 10.1002/mrm.21126 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 132MG UT WOS:000243946300024 PM 17260373 ER PT J AU Zou, SG Sinclair, J Wilson, MA Carey, JR Liedo, P Oropeza, A Kalra, A de Cabo, R Ingram, DK Longo, DL Wolkow, CA AF Zou, Sige Sinclair, Jason Wilson, Mark A. Carey, James R. Liedo, Pablo Oropeza, Azucena Kalra, Avash de Cabo, Rafael Ingram, Donald K. Longo, Dan L. Wolkow, Catherine A. TI Comparative approaches to facilitate the discovery of prolongevity interventions: Effects of tocopherols on lifespan of three invertebrate species SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE aging; longevity; Caenorhabditis elegans; Drosophila melanogaster; Anastrepha ludens; tocopherol; vitamin E ID VITAMIN-E SUPPLEMENTATION; DROSOPHILA-MELANOGASTER; CAENORHABDITIS-ELEGANS; DIETARY RESTRICTION; LONGEVITY; DISEASE; STRESS; ANTIOXIDANTS; REPRODUCTION; PREVENTION AB Many compounds hold promise for pharmacologic manipulation of aging. However, such claims are difficult to investigate due to time and budget constraints. Here, we took a comparative approach, using short-lived invertebrate species, to directly test the effects of two tocopherols (Vitamin E) on longevity. gamma-Tocopherol represents the most abundant tocopherol in the Western diet, while alpha-tocopherol is selectively enriched in human plasma. Both isoforms demonstrate antioxidant activity and are proposed to have anti-aging activities. We compared the effects of alpha- and ytocopherol supplementation on lifespan in three invertebrate species. gamma-Tocopherol, but not alpha-tocopherol, slightly extended lifespan in nematodes, but neither significantly affected lifespan in two fly species. This study shows that a comparative approach, utilizing multiple invertebrate species, can increase the robustness of invertebrate-based pilot screens for prolongevity interventions. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Natl Inst Aging, Lab Neurosci, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. El Colegio Frontera Sur, Chiapas, Mexico. RP Wolkow, CA (reprint author), Natl Inst Aging, Lab Neurosci, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wolkowca@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; Trejo, Yesenia/D-9257-2012; Liedo, Pablo/E-9313-2010; de Cabo, Rafael/J-5230-2016; OI Liedo, Pablo/0000-0002-0004-1721; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS; NIA NIH HHS [P01 AG008761, P01 AG008761-170003, P01 AG022500, P01 AG08761] NR 30 TC 37 Z9 37 U1 1 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD FEB PY 2007 VL 128 IS 2 BP 222 EP 226 DI 10.1016/j.mad.2006.11.026 PG 5 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 140FI UT WOS:000244489500007 PM 17169403 ER PT J AU Lewis, SL Khoo, PL De Young, RA Bildsoe, H Wakamiya, M Behringer, RR Mukhopadhyay, M Westphal, H Tam, PPL AF Lewis, Samara L. Khoo, Poh-Lynn De Young, R. Andrea Bildsoe, Heidi Wakamiya, Maki Behringer, Richard R. Mukhopadhyay, Mahua Westphal, Heiner Tam, Patrick P. L. TI Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse SO MECHANISMS OF DEVELOPMENT LA English DT Article DE tissue patterning; anterior mesendoderm; Gsc; Dkk1; WNT signalling; mouse embryo ID FOREBRAIN DEVELOPMENT; ANTERIOR NEUROECTODERM; GASTRULA ORGANIZER; RETINOIC ACID; INDUCTION; MESENDODERM; REPRESSION; EMBRYOS; NOGGIN; EMBRYOGENESIS AB Mouse embryos lacking Gsc and Dkk1 function display severe deficiencies in craniofacial structures which are not found in either Dkk1 homozygous null or Gsc homozygous null mutant embryos. Loss of Gsc has a dosage-related effect on the severity of head truncation phenotype in Dkk1 heterozygous embryos. The synergistic effect of these mutations in enhancing head truncation provides direct evidence of a genetic interaction between Gsc and Dkk1, which display overlapping expression in the prechordal mesoderm. In the absence of Gsc activity, the expression of Dkk1, WNT genes and a transgenic reporter for WNT signalling are altered. Our results show that Gsc and Dkk1 functions are non-redundant in the anterior mesendoderm for normal anterior development and Gsc may influence Wnt signalling as a negative regulator. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Childrens Med Res Inst, Embryol Unit, Wentworthville, NSW 2145, Australia. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Tam, PPL (reprint author), Childrens Med Res Inst, Embryol Unit, Locked Bag 23, Wentworthville, NSW 2145, Australia. EM ptam@cmri.usyd.edu.au NR 36 TC 15 Z9 16 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2007 VL 124 IS 2 BP 157 EP 165 DI 10.1016/j.mod.2006.10.001 PG 9 WC Developmental Biology SC Developmental Biology GA 140XI UT WOS:000244539700006 ER PT J AU Zeliadt, SB Etzioni, R Ramsey, SD Penson, DF Potosky, AL AF Zeliadt, Steven B. Etzioni, Ruth Ramsey, Scott D. Penson, David F. Potosky, Arnold L. TI Trends in treatment costs for localized prostate cancer - The healthy screenee effect SO MEDICAL CARE LA English DT Article DE prostate; prostatic neoplasms; costs; cancer-attributable costs; healthy screenee bias; SEER-Medicare ID SEER-MEDICARE DATA; RADICAL PROSTATECTOMY; COLORECTAL-CANCER; CARE; STAGE; COMORBIDITY; POPULATION; IMPACT; BREAST; AGE AB Objective: We sought to obtain estimates of trends in initial treatment costs during the prostate-specific antigen (PSA) era that account for the changing patient case-mix associated with screening. Subjects: We used reimbursement claims for Medicare-eligible subjects diagnosed with nonmetastatic prostate cancer between 1991 and 1999. Patients were grouped by initial treatment, with 17,846 receiving radical prostatectomy (RP), 25,933 receiving external beam radiotherapy (XRT), and 4525 receiving brachytherapy (BT). Methods: Cancer-attributable costs were computed by subtracting noncancer costs from total Medicare reimbursements among newly diagnosed cancer patients. Noncancer costs were estimated in 2 ways: (1) average costs among age-matched, cancer-free control subjects (control method) and (2) projections based on claims from subjects before diagnosis (prediagnosis method). Adjusted annual percent change in cancer-attributable costs was calculated using multivariate generalized linear models. Results: Noncancer costs increased at a much lower rate among men prior to diagnosis (3.8% annually) than among the general Medicare population (10.9%). The 2 approaches yielded different results; RP costs declined by 2.4% annually (prediagnosis method) versus 6.2% (control method); XRT costs declined by 1.5% versus 5.8%; and BT costs declined by 4.1% versus 8.3%. Conclusions: Because of self-selection of PSA screening, men diagnosed with prostate cancer today are now healthier overall than men in the general population and are considerably healthier than men diagnosed previously. Estimates of cancer-attributable costs that do not account for this healthy selection effect are likely to be biased. Declines in cancer-attributable treatment costs are evident even after accounting for a healthy screenee effect, suggesting that there has been a real reduction in cancer treatment costs. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Hlth Serv, Seattle, WA 98195 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Urol & Prevent Med, Los Angeles, CA 90033 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Zeliadt, SB (reprint author), Fred Hutchinson Canc Res Ctr, POB 19024,M2-230, Seattle, WA 98109 USA. EM szeliadt@fhcrc.org FU NCI NIH HHS [CA-92408, CA-88160] NR 21 TC 33 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD FEB PY 2007 VL 45 IS 2 BP 154 EP 159 DI 10.1097/01.mlr.0000241044.09778.3f PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 138GR UT WOS:000244351600008 PM 17224778 ER PT J AU Pendrak, ML Roberts, DD AF Pendrak, Michael L. Roberts, David D. TI Hemoglobin is an effective inducer of hyphal differentiation in Candida albicans SO MEDICAL MYCOLOGY LA English DT Article DE Candida albicans; hemoglobin; hyphal morphogenesis ID GERM-TUBE FORMATION; YEAST SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION FACTOR; FILAMENTOUS GROWTH; FUNGAL PATHOGEN; BINDING DOMAIN; HEME OXYGENASE; MORPHOGENESIS; FIBRONECTIN; SERUM AB Hemoglobin is an abundant protein in the host vascular compartment and a source of iron, heme, and amino acids for many pathogens. The human fungal pathogen Candida albicans uses hemoglobin as an iron source as well as a signaling molecule to alter gene expression and induce adhesion to several extracellular matrix proteins. We now report that hemoglobin can promote true hyphal morphogenesis. Hemoglobin added to yeast cells at 37 degrees C rapidly induced expression of the hypha-specific genes HWP1 and ECE1 coincident with the pattern of hyphal development. A synthetic medium buffered with phosphate at pH 7.2 and containing physiological glucose (5 mM) and low ammonium Ion (0.1 mM) was optimal for the response to hemoglobin. High glucose (110 mM), high ammonium Ion (20 mM), and 0.1 mM glutamine were all inhibitory. Heme, free globin, or immobilized hemoglobin could not replicate the activity of hemoglobin to induce germ tubes or hypha-specific gene expression at 37 degrees C under optimized conditions. This implicates the previously described Hb-signaling receptor in hyphal formation. This response was also dependent upon the presence of the morphogenesis regulator Efg1p, but the MAP-kinase specific transcription factor Cph1p was not required. These data define a role for the host-factor hemoglobin in Efg1p-dependent hyphal development. C1 NCI, NIH, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Pendrak, ML (reprint author), Bldg 10,Room 2A33, Bethesda, MD 20892 USA. EM mpendrak@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS NR 55 TC 9 Z9 14 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 FEB PY 2007 VL 45 IS 1 BP 61 EP 71 DI 10.1080/13693780601028691 PG 11 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 140VJ UT WOS:000244534500009 PM 17325946 ER PT J AU Van Uitert, R Bitter, I AF Van Uitert, Robert Bitter, Ingmar TI Subvoxel precise skeletons of volumetric data based on fast marching methods SO MEDICAL PHYSICS LA English DT Article DE skeleton; centerline; level sets; subvoxel accuracy ID CENTERLINE EXTRACTION; THINNING ALGORITHM; LEVEL SETS AB The accurate calculation of the skeleton of an object is a problem not satisfactorily solved by existing approaches. Most algorithms require a significant amount of user interaction and use a voxel grid to compute discrete and often coarse approximations of this representation of the data. We present a novel, automatic algorithm for computing subvoxel precise skeletons of volumetric data based on subvoxel precise distance fields. Most voxel based centerline and skeleton algorithms start with a binary mask and end with a list of voxels that define the centerline or skeleton. Even though subsequent smoothing may be applied, the results are inherently discrete. Our skeletonization algorithm uses as input a subvoxel precise distance field and employs a number of fast marching method propagations to extract the skeleton at subvoxel precision. We present the skeletons of various three-dimensional (3D) data sets and digital phantom models as validations of our algorithm. (c) 2007 American Association of Physicists in Medicine. C1 NIH, Bethesda, MD 20892 USA. Claron Technol Inc, Toronto, ON M5G 1L7, Canada. RP Van Uitert, R (reprint author), NIH, 10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM uitertr@cc.nih.gov; ingmar@clarontech.com FU Intramural NIH HHS NR 29 TC 35 Z9 35 U1 1 U2 9 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 FEB PY 2007 VL 34 IS 2 BP 627 EP 638 DI 10.1118/1.2409238 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 139HZ UT WOS:000244424200028 PM 17388180 ER PT J AU Liang, HY Badano, A AF Liang, Hongye Badano, Aldo TI Temporal response of medical liquid crystal displays SO MEDICAL PHYSICS LA English DT Article DE liquid crystal display; gray level resolution; temporal blur; temporal response; motion artifact ID AAPM/RSNA TUTORIAL; PACS EQUIPMENT; SELECTION AB Displays based on liquid crystal technology suffer from slow temporal response due to the dynamics of the molecular rearrangement in response to a pixel voltage change. A slow display can affect the visualization by the human observer of subtle contrast in dynamic presentation of volumetric image datasets or real-time image sequences. In this paper, we describe a measurement method for the characterization of the temporal response of medical liquid crystal displays (LCDs). The ratio of luminance difference to noise at the gray levels of concern determines the reliability of measurements. Coefficients of variations are used to represent the measurement reliability. We optimized the repeatability of most response time measurements to less than 10%. However, poor repeatability is encountered for the response of adjacent gray levels. 256 x 255 inter-gray-level transition time matrices were measured for four medical displays and one high-definition TV LCD display. Response times range from below 20 ms to above 150 ms. For each display, response times are not uniformly distributed, with a faster response for large gray-level transitions. Transition times are smaller when the starting gray level is between 10 and 20 for a target between 25 and 150. The difference could be over 100 ms for different transitions within a display. For transitions with poor temporal response, the luminance after 1, 3, and 5 frames reaches only 12, 45, and 75% of the target value, respectively. We also found that LCD response time depends on temperature, with I h warm-up reducing the response time by a factor of 2. C1 NIBIB Lab Assesment Med Imaging Syst, CDRH, US FDA, Rockville, MD 20857 USA. RP Liang, HY (reprint author), NIBIB Lab Assesment Med Imaging Syst, CDRH, US FDA, 12720 Twinbrook Pkwy,HFZ 142, Rockville, MD 20857 USA. OI badano, aldo/0000-0003-3712-6670 NR 14 TC 17 Z9 17 U1 0 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 FEB PY 2007 VL 34 IS 2 BP 639 EP 646 DI 10.1118/1.2428403 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 139HZ UT WOS:000244424200029 PM 17388181 ER PT J AU Elmore, E Jain, A Siddiqui, S Tohidlan, N Meyskens, FL Steele, VE Redpath, JL AF Elmore, Eugene Jain, Aarti Siddiqui, Shazia Tohidlan, Nilou Meyskens, Frank L. Steele, Vernon E. Redpath, John L. TI Development and characteristics of a human cell assay for screening agents for melanoma prevention SO MELANOMA RESEARCH LA English DT Article DE apoptosis; cancer prevention; E-cadherin/N-cadherin; melanoma; screening ID NORMAL HUMAN MELANOCYTES; MALIGNANT-MELANOMA; IN-VITRO; PROLIFERATION; PLASMA; PHARMACOKINETICS; PROGRESSION; FENRETINIDE; SURVIVAL; BIOLOGY AB This paper describes the development and initial evaluation of a human cell assay to identify potentially efficacious agents for preventing melanoma. Four human cell lines were used: normal melanocytes, a radial growth-phase-like melanoma cell line (WM3211), a vertical growth-phase-like melanoma cell line (Lull 205), and 83-2c, a cell strain cloned from metastatic melanoma. Four endpoints were evaluated in ultraviolet B-treated cells: annexin V, human leukocyte antigen-DR; E-cadherin, and N-cadherin. Annexin V was induced by nimesulide, 4-hydroxyphenylretinamide, and difluoromethylornithine in ultraviolet-B-treated radial growth-phase-like melanoma cells. None of the agents inhibited human leukocyte antigen-DR expression in ultraviolet-B-treated radial growth-phase-like melanoma cells, the only cells that strongly expressed human leukocyte antigen-DR. E-cadherin was overexpressed only in radial growth-phase-like melanoma cells relative to melanocytes, and ultraviolet B exposure dramatically reduced this expression. E-cadherin was only induced by difluoromethylornithine in ultraviolet-B-treated radial growth-phase-like melanoma cells. N-cadherin was overexpressed in all melanoma cell lines relative to melanocytes. In this study, all candidate preventive agents inhibited N-cadherin in ultraviolet B-treated radial growth-phase-like melanoma cells. Four agents inhibited N-cadherin in ultraviolet B-treated vertical growth-phase-like melanoma cells. The mean ratios of N-cadherin to E-cadherin levels and specific endpoint responses for both the radial growth-phase-like melanoma and vertical growth-phase-like melanoma cells were used to rank the agents. Agents were evaluated at clinically relevant concentrations. The rankings were difluoromethylornithine > 4-hydroxyphenylretinamide > nimesulide > 9-cis-retinoic acid > polyphenon E. Diphenylhydramine, D-mannitol, and nordihydroguaiaretic acid were inactive. The results of these initial studies suggest that ultraviolet-B-treated radial growth-phase-like melanoma cells are the most responsive to chemopreventive agents, and may be the cell line of choice for screening melanoma prevention agents. C1 Univ Calif Irvine, Dept Radiat Oncol, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Med, Irvine, CA 92697 USA. Univ Calif Irvine, Chao Family Comprehens Canc Ctr, Irvine, CA 92697 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Elmore, E (reprint author), Univ Calif Irvine, Dept Radiat Oncol, Med Sci 1,B149, Irvine, CA 92697 USA. EM eelmore@uci.edu FU NCI NIH HHS [N01-CN-15030, CA62203] NR 28 TC 3 Z9 3 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-8931 J9 MELANOMA RES JI Melanoma Res. PD FEB PY 2007 VL 17 IS 1 BP 42 EP 50 DI 10.1097/CMR.0b013e3280142f96 PG 9 WC Oncology; Dermatology; Medicine, Research & Experimental SC Oncology; Dermatology; Research & Experimental Medicine GA 132YO UT WOS:000243979000006 PM 17235241 ER PT J AU Solomon, M Cohen-Fix, O AF Solomon, Mark Cohen-Fix, Orna TI Methods in cell cycle research SO METHODS LA English DT Editorial Material C1 NIDDK, Lab Mol & Cellular Biol, NIH, Bethesda, MD 20892 USA. Yale Univ, Mol Biophys & Biochem, New Haven, CT 06520 USA. RP Solomon, M (reprint author), NIDDK, Lab Mol & Cellular Biol, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM Mark.Solomon@Yale.edu; ornacf@helix.nih.gov NR 0 TC 0 Z9 0 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 1046-2023 J9 METHODS JI Methods PD FEB PY 2007 VL 41 IS 2 BP 141 EP 142 DI 10.1016/j.ymeth.2006.07.021 PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 129VL UT WOS:000243758100001 PM 17189855 ER PT J AU Motegi, A Myung, K AF Motegi, Akira Myung, Kyungjae TI Measuring the rate of gross chromosomal rearrangements in Saccharomyces cerevisiae: A practical approach to study genomic rearrangements observed in cancer SO METHODS LA English DT Article DE cancer; genome instability; GCR; DNA repair; yeast model ID DNA-DAMAGE; INSTABILITY; YEAST; REPLICATION; SUPPRESSION; RECOMBINATION; STABILITY; COMPLEX; SYSTEM; TRANSLOCATIONS AB Gross chromosomal rearrangements (GCRs), including translocations, deletions, amplifications and aneuploidy are frequently observed in various types of human cancers. Despite their clear importance in carcinogenesis, the molecular mechanisms by which GCRs are generated and held in check are poorly understood. By using a GCR assay, which can measure the rate of accumulation of spontaneous GCRs in Saccharomyces cerevisiae, we have found that many proteins involved in DNA replication, DNA repair, DNA recombination, checkpoints, chromosome remodeling, and telomere maintenance, play crucial roles in GCR metabolism. We describe here the theoretical background and practical procedures of this GCR assay. We will explain the breakpoint structure and DNA damage that lead to GCR formation. We will also summarize the pathways that suppress and enhance GCR formation. Finally, we will briefly describe similar assays developed by others and discuss their potential in studying GCR metabolism. (c) 2006 Elsevier Inc. All rights reserved. C1 Natl Human Genome Res Inst, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, K (reprint author), Natl Human Genome Res Inst, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov FU Intramural NIH HHS NR 42 TC 16 Z9 16 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 1046-2023 J9 METHODS JI Methods PD FEB PY 2007 VL 41 IS 2 BP 168 EP 176 DI 10.1016/j.ymeth.2006.07.025 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 129VL UT WOS:000243758100005 PM 17189859 ER PT J AU Golden, A O'Connell, KF AF Golden, Andy O'Connell, Kevin F. TI Silence is Golden: Combining RNAi and live cell imaging to study cell cycle regulatory genes during Caenorhabditis elegans development SO METHODS LA English DT Article DE C. elegans; RNAi; oocyte maturation; Wee1 ID TO-EMBRYO TRANSITION; FUNCTIONAL GENOMIC ANALYSIS; ZINC-FINGER PROTEINS; C-ELEGANS; OOCYTE MATURATION; WIDE RNAI; INTERFERENCE; DEGRADATION; KINASE; OMA-1 AB Much of the pioneering work on the genetics of cell cycle regulation was accomplished using budding and fission yeast. The relative simplicity of these single-celled organisms allowed investigators to readily identify and assign roles to individual genes. While the molecular mechanisms worked out in yeast are more or less identical to those operating in higher organisms, additional layers of control must exist in multicellular organisms to coordinate the timing of developmental events occurring in different cells and tissues. Here we discuss experimental approaches for studying cell cycle processes in the nematode Caenorhabditis elegans. Published by Elsevier Inc. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Golden, A (reprint author), NIDDK, Lab Biochem & Genet, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. EM andyg@mail.nih.gov NR 49 TC 5 Z9 7 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 1046-2023 J9 METHODS JI Methods PD FEB PY 2007 VL 41 IS 2 BP 190 EP 197 DI 10.1016/j.ymeth.2006.07.029 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 129VL UT WOS:000243758100007 PM 17189861 ER PT J AU Samuel, LP Song, CH Wei, J Roberts, EA Dahl, JL Barry, CE Jo, EK Friedman, RL AF Samuel, Linoj P. Song, Chang-Hwa Wei, Jun Roberts, Esteban A. Dahl, John L. Barry, Clifton E., III Jo, Eun-Kyeong Friedman, Richard L. TI Expression, production and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion SO MICROBIOLOGY-SGM LA English DT Article ID TUMOR-NECROSIS-FACTOR; BLOOD MONONUCLEAR-CELLS; FACTOR-ALPHA; HUMAN MONOCYTES; INTERLEUKIN-12 PRODUCTION; INTRACELLULAR SURVIVAL; N-ACETYLTRANSFERASES; GENE-EXPRESSION; 30-KDA ANTIGEN; IDENTIFICATION AB The eis gene of Mycobacterium tuberculosis has been shown to play a role in the survival of the avirulent Mycobacterium smegmatis within the macrophage. In vitro and in vivo analysis of Delta eis deletion mutants and complemented strains showed no effect on survival of M. tuberculosis in U-937 macrophages or in a mouse aerosol infection model, respectively. Further studies were done in an attempt to determine the role of eis in M. tuberculosis intracellular survival and to define a phenotypic difference between wild-type and the Delta eis deletion mutant. Bioinformatic analysis indicated that Eis is an acetyltransferase of the GCN5-related family of N-acetyltransferases. Immunofluorescence microscopy and Western blot analysis studies demonstrated that Eis is released into the cytoplasm of M. tuberculosis-infected U-937 macrophages. Eis was also found in the extravesicular fraction and culture supernatant of M. tuberculosis-infected macrophages. The effect of Eis on human macrophage cytokine secretion was also examined. Eis modulated the secretion of IL-10 and TNF-alpha by primary human monocytes in response both to infection with M. tuberculosis and to stimulation with recombinant Eis protein. These results suggest that Eis is a mycobacterial effector that is released into the host cell to modulate inflammatory responses, possibly via transcriptional or post-translational means. C1 Univ Arizona, Dept Microbiol & Immunol, Tucson, AZ 85724 USA. Chungnam Natl Univ, Coll Med, Dept Microbiol, Taejon 301747, South Korea. Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. NIAAA, TB Res Sect, Rockville, MD 20852 USA. RP Samuel, LP (reprint author), Univ Rochester, Dept Clin Microbiol, 601 Elmwood Ave,Box 710, Rochester, NY 14642 USA. EM Linoj_Samuel@urmc.rochester.edu RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI45537-01A2] NR 48 TC 24 Z9 26 U1 0 U2 3 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 FEB PY 2007 VL 153 BP 529 EP 540 DI 10.1099/mic.0.2006/002642-0 PN 2 PG 12 WC Microbiology SC Microbiology GA 139HK UT WOS:000244422700026 PM 17259625 ER PT J AU Miska, KB Fetterer, RH Lillehoj, HS Jenkins, MC Allen, PC Harper, SB AF Miska, Katarzyna B. Fetterer, Raymond H. Lillehoj, Hyun S. Jenkins, Mark C. Allen, Patricia C. Harper, Susan B. TI Characterisation of macrophage migration inhibitory factor from Eimeria species infectious to chickens SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Eimeria; macrophage migration inhibitory factor; MIF; coccidiosis ID T-CELL-ACTIVATION; FACTOR MIF; LYMPHATIC FILARIASIS; PARASITIC NEMATODE; CRYSTAL-STRUCTURE; BOVINE BRAIN; SWISS-MODEL; PROTEIN; IDENTIFICATION; EXPRESSION AB Macrophage migration inhibitory factor (MIF) was the first cytokine to be identified almost 40 years ago. Homologues of MIF have been isolated recently from invertebrates, making it an interesting molecule from an evolutionary as well as functional perspective. The present study represents the first report of MIF homologues in apicomplexan parasites, belonging to the genus Eimeria. A single full-length clone was isolated from Eimeria acervulina that shared between 35 and 38% amino acid identity with MIFs of vertebrates. A MIF cDNA from Eimeria tenella shared 64% amino acid identity with E. acervulina MIF. The mRNA expression was highest in merozoites, whereas developing oocysts and sporozoites expressed low to undetectable levels. Protein expression patterns were nearly identical to that observed by reverse transcriptase polymerase chain reaction (RT-PCR), suggesting strong developmental regulation. Immunofluorescence staining and co-localisation studies of E. acervulina merozoites indicated that MIF is distributed throughout the cytosol, and appears to be concentrated in the apical end of the parasite. The presence of MIF was detected in excretory/secretory (ES) products collected from E. acervulina merozoites, and isoelectric focusing indicated that three MIF isoforms are present in this stage. Phylogenetic analysis revealed that apicomplexan MIF sequences form a sister relationship to MIF-like molecules from Arabidopsis thaliana. (c) 2006 Published by Elsevier B.V. C1 USDA, ARS, Anim Parasit Dis Lab, Beltsville, MD 20705 USA. NIH, Off Biotechnol Act, Bethesda, MD 20892 USA. RP Miska, KB (reprint author), USDA, ARS, Anim Parasit Dis Lab, 10300 Baltimore Ave,BARC East, Beltsville, MD 20705 USA. EM kmiska@anri.barc.usdau.gov NR 53 TC 27 Z9 35 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD FEB PY 2007 VL 151 IS 2 BP 173 EP 183 DI 10.1016/j.molbiopara.2006.10.020 PG 11 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 135LO UT WOS:000244155300004 PM 17194492 ER PT J AU Limtrakul, P Chearwae, W Shukla, S Phisalphong, C Ambudkar, SV AF Limtrakul, Pornngarm Chearwae, Wanida Shukla, Suneet Phisalphong, Chada Ambudkar, Suresh V. TI Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE ABC transporter; ATP hydrolysis; chemosensitivity; drug transport; multidrug resistance; P-glycoprotein; tetrahydrocurcumin ID CHEMOPREVENTIVE AGENT CURCUMIN; CATALYTIC TRANSITION-STATE; BREAST-CANCER CELLS; ATP HYDROLYSIS; PROTECTIVE ROLE; IN-VITRO; MECHANISM; MICROORGANISMS; INVOLVEMENT; INHIBITION AB Many studies have been performed with the aim of developing effective resistance modulators to overcome the multidrug resistance (MDR) of human cancers. Potent MDR modulators are being investigated in clinical trials. Many current studies are focused on dietary herbs due to the fact that these have been used for centuries without producing any harmful side effects. In this study, the effect of tetrahydrocurcumin (THC) on three ABC drug transporter proteins, P-glycoprotein (P-gp or ABCB1), mitoxantrone resistance protein (MXR or ABCG2) and multidrug resistance protein 1 (MRP1 or ABCC1) was investigated, to assess whether an ultimate metabolite form of curcuminoids (THC) is able to modulate MDR in cancer cells. Two different types of cell lines were used for P-gp study, human cervical carcinoma KB-3-1 (wild type) and KB-V-1 and human breast cancer MCF-7 (wild type) and MCF-7 MDR, whereas, pcDNA3.1 and pcDNA3.1-MRP1 transfected HEK 293 and MXR overexpressing MCF7AdrVp3000 or MCF7FL1000 and its parental MCF-7 were used for MRP1 and MXR study, respectively. We report here for the first time that THC is able to inhibit the function of P-gp, MXR and MRP1. The results of flow cytometry assay indicated that THC is able to inhibit the function of P-gp and thereby significantly increase the accumulation of rhodamine and calcein AM in KB-V-1 cells. The result was confirmed by the effect of THC on [H-3]-vinblastine accumulation and efflux in MCF-7 and MCF-7MDR. THC significantly increased the accumulation and inhibited the efflux of [H-3]-vinblastine in MCF-7 MDR in a concentration-dependent manner. This effect was not found in wild type MCF-7 cell line. The interaction of THC with the P-gp molecule was clearly indicated by ATPase assay and photoaffinity labeling of P-gp with transport substrate. THC stimulated P-gp ATPase activity and inhibited the incorporation of [I-125]-iodoarylazidoprazosin (IAAP) into P-gp in a concentration-dependent manner. The binding of [I-125]-IAAP to MXR was also inhibited by THC suggesting that THC interacted with drug binding site of the transporter. THC dose dependently inhibited the efflux of mitoxantrone and pheophorbide A from MXR expressing cells (MCF7AdrVp3000 and MCF7FL1000). Similarly with MRP1, the efflux of a fluorescent substrate calcein AM was inhibited effectively by THC thereby the accumulation of calcein was increased in MRP1-HEK 293 and not its parental pcDNA3.1-HEK 293 cells. The MDR reversing properties of THC on P-gp, MRP1, and MXR were determined by MTT assay. THC significantly increased the sensitivity of vinblastine, mitoxantrone and etoposide in drug resistance KB-V-1, MCF7AdrVp3000 and MRP1-HEK 293 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Taken together, this study clearly showed that THC inhibits the efflux function of P-gp, MXR and MRP1 and it is able to extend the MDR reversing activity of curcuminoids in vivo. C1 Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50200, Thailand. NCI, Cell Biol Lab, Canc Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. Govt Pharmaceut Org, Inst Res & Dev, Bangkok 10400, Thailand. RP Limtrakul, P (reprint author), Chiang Mai Univ, Fac Med, Dept Biochem, Chiang Mai 50200, Thailand. EM plimtrak@mail.med.cmu.ac.th; ambudkar@helix.hih.gov RI shukla, suneet/B-4626-2012 FU Intramural NIH HHS NR 44 TC 115 Z9 120 U1 4 U2 21 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD FEB PY 2007 VL 296 IS 1-2 BP 85 EP 95 DI 10.1007/s11010-006-9302-8 PG 11 WC Cell Biology SC Cell Biology GA 143AH UT WOS:000244691900011 PM 16960658 ER PT J AU DeBell, K Graham, L Reischl, I Serrano, C Bonvini, E Rellahan, B AF DeBell, Karen Graham, Laurie Reischl, Ilona Serrano, Carmen Bonvini, Ezio Rellahan, Barbara TI Intramolecular regulation of phospholipase C-gamma 1 by its C-terminal Src homology 2 domain SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; PLECKSTRIN HOMOLOGY DOMAIN; PLC-GAMMA-L; SH2 DOMAIN; TYROSINE PHOSPHORYLATION; PH DOMAIN; CELL-LINE; C-GAMMA-1; RECEPTOR; ACTIVATION AB Phosphoinositide-specific phospholipase C-gamma 1 (PLC-gamma 1) is a key enzyme that governs cellular functions such as gene transcription, secretion, proliferation, motility, and development. Here, we show that PLC-gamma 1 is regulated via a novel autoinhibitory mechanism involving its carboxy-terminal Src homology (SH2C) domain. Mutation of the SH2C domain tyrosine binding site led to constitutive PLC-gamma 1 activation. The amino-terminal split pleckstrin homology (sPHN) domain was found to regulate the accessibility of the SH2C domain. PLC-gamma 1 constructs with mutations in tyrosine 509 and phenylalanine 510 in the sPHN domain no longer required an intact amino-terminal Src homology (SH2N) domain or phosphorylation of tyrosine 775 or 783 for activation. These data are consistent with a model in which the SH2C domain is blocked by an intramolecular interaction(s) that is released upon cellular activation by occupancy of the SH2N domain. C1 FDA, DMA OPS, CDER, Lab Immunobiol, Bethesda, MD 20892 USA. MacroGenetics Inc, Rockville, MD USA. RP Rellahan, B (reprint author), FDA, DMA OPS, CDER, Lab Immunobiol, NIH Bldg 29B,3NN06,29 Lincoln Dr, Bethesda, MD 20892 USA. EM barbara.rellahan@fda.hhs.gov NR 42 TC 21 Z9 22 U1 0 U2 1 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 FEB PY 2007 VL 27 IS 3 BP 854 EP 863 DI 10.1128/MCB.01400-06 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 132MD UT WOS:000243946000006 PM 17116690 ER PT J AU Rojas, R Kametaka, S Haft, CR Bonifacino, JS AF Rojas, Raul Kametaka, Satoshi Haft, Carol R. Bonifacino, Juan S. TI Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the tracking of mannose 6-phosphate receptors SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; GOLGI RETROGRADE TRANSPORT; PROTEIN-SORTING RECEPTOR; TO-TGN TRANSPORT; MAMMALIAN RETROMER; MEMBRANE-PROTEINS; NEXIN-1; YEAST; TRAFFICKING; COMPLEX AB The retromer is a cytosolic/peripheral membrane protein complex that mediates the retrieval of the cation-independent mannose 6-phosphate receptor from endosomes to the trans-Golgi network (TGN) in mammalian cells. Previous studies showed that the mammalian retromer comprises three proteins, named Vps26, Vps29, and Vps35, plus the sorting nexin, SNX1. There is conflicting evidence, however, as to whether a homologous sorting nexin, SNX2, is truly a component of the retromer. In addition, the nature of the subunit interactions and assembly of the mammalian retromer complex are poorly understood. We have addressed these issues by performing biochemical and functional analyses of endogenous retromers in the human cell line HeLa. We found that the mammalian retromer complex consists of two autonomously assembling subcomplexes, namely, a Vps26-Vps29-Vps35 obligate heterotrimer and a SNX1/2 alternative heterodimer or homodimer. The association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. We also found that the presence of either SNX1 or SNX2 is essential for the retrieval of the cation-independent mannose 6-phosphate receptor to the TGN. These observations indicate that the mammalian retromer complex assembles by sequential association of SNX1/2 and Vps26-Vps29-Vps35 subcomplexes on endosomal membranes and that SNX1 and SNX2 play interchangeable but essential roles in retromer structure and function. C1 NICHHD, Cell Biol & Metab Branch, Natl Inst Child Hlth, NIH, Bethesda, MD 20892 USA. NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, Natl Inst Child Hlth, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov FU Intramural NIH HHS NR 45 TC 117 Z9 121 U1 2 U2 9 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 FEB PY 2007 VL 27 IS 3 BP 1112 EP 1124 DI 10.1128/MCB.00156-06 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 132MD UT WOS:000243946000027 PM 17101778 ER PT J AU Kim, A Kiefer, CM Dean, A AF Kim, AeRi Kiefer, Christine M. Dean, Ann TI Distinctive signatures of histone methylation in transcribed coding and noncoding human beta-globin sequences SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LOCUS-CONTROL REGION; RNA-POLYMERASE-II; LYSINE METHYLATION; INTERGENIC TRANSCRIPTION; H3 METHYLATION; ACTIVE GENES; ERYTHROID-DIFFERENTIATION; SACCHAROMYCES-CEREVISIAE; CHROMATIN SUBDOMAINS; MAMMALIAN CHROMATIN AB The establishment of epigenetic marks, such as methylation on histone tails, is mechanistically linked to RNA polymerase II within active genes. To explore the interplay between these modifications in transcribed noncoding as well as coding sequences, we analyzed epigenetic modification and chromatin structure at high resolution across 300 kb of human chromosome 11, including the beta-globin locus which is extensively transcribed in intergenic regions. Monomethylated H3K4, K9, and K36 were broadly distributed, while hypermethylated forms appeared to different extents across the region in a manner reflecting transcriptional activity. The trimethylation of H3K4 and H3K9 correlated within the most highly transcribed sequences. The H3K36me3 mark was more broadly detected in transcribed coding and noncoding sequences, suggesting that K36me3 is a stable mark on sequences transcribed at any level. Most epigenetic and chromatin structural features did not undergo transitions at the presumed borders of the globin domain where the insulator factor CTCF interacts, raising questions about the function of the borders. C1 Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan 609735, South Korea. NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Kim, A (reprint author), Bldg 50,Room 3154,50 S Dr,MSC 8028, Bethesda, MD 20892 USA. EM kimaeri@pusan.ac.kr; anndean@helix.nih.gov FU Intramural NIH HHS NR 68 TC 61 Z9 65 U1 0 U2 1 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 FEB PY 2007 VL 27 IS 4 BP 1271 EP 1279 DI 10.1128/MCB.01684-06 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 136OE UT WOS:000244233200008 PM 17158930 ER PT J AU He, YZ Simons, SS AF He, Yuanzheng Simons, S. Stoney, Jr. TI STAMP, a novel predicted factor assisting TIF2 actions in glucocorticoid receptor-mediated induction and repression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FACTOR-BINDING PROTEIN-1; DOSE-RESPONSE CURVE; MOLECULAR-MECHANISMS; HORMONE-RECEPTOR; GENE-EXPRESSION; TRANSCRIPTION FACTORS; ANTAGONIST COMPLEXES; INTERACTING PROTEIN; ESTROGEN-RECEPTORS; STEROID-RECEPTORS AB The coactivator TIF2 was predicted to interact with an unknown factor to modify both the relative inhibition in glueocorticoid receptor (GR)-mediated gene repression and several parameters of agonists and antisteroids in GR-regulated induction. Here, we describe the isolation and characterization of the predicted factor as a new 1,277-amino-acid endogenous protein (STAMP). STAMP associates with coactivators (TIF2 and SRC-1) and is selective for a subset of the steroid/nuclear receptors including GRs. Transfected STAMP increases the effects of TIF2 in GR-mediated repression and induction. Conversely, the levels of both induction and repression of endogenous genes are reduced when STAMP small interfering RNAs are used to lower the level of endogenous STAMP. Endogenous STAMP colocalizes with GR in intact cells and is recruited to the promoters of endogenous GR-induced and -repressed genes. We suggest that STAMP is an important new, downstream component of GR action in both gene activation and gene repression. C1 NIDDK, Clin Endocrinol Branch, NIH, Steroid Hormones Sect, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Steroid Hormones Sect, Bldg 10,Room 8N307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU Intramural NIH HHS NR 63 TC 30 Z9 34 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 FEB PY 2007 VL 27 IS 4 BP 1467 EP 1485 DI 10.1128/MCB.01360-06 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 136OE UT WOS:000244233200024 PM 17116691 ER PT J AU Trotter, KW Archer, TK AF Trotter, Kevin W. Archer, Trevor K. TI Nuclear receptors and chromatin remodeling machinery SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Joint Meeting of the 6th Conference on the Adrenal Cortex/Molecular Steroidogenesis Workshop CY JUN 20-23, 2006 CL Boston, MA DE GR; chromatin; epigenetics; SWI/SNF; BRG1; transcriptional activation ID TRANSCRIPTION IN-VIVO; RNA-POLYMERASE-II; GLUCOCORTICOID-RECEPTOR; DEPENDENT TRANSCRIPTION; MODIFYING COMPLEXES; ESTROGEN-RECEPTOR; RESPONSIVE GENES; HUMAN HOMOLOGS; SWI/SNF; ACTIVATION AB Eukaryotic genetic information is stored within the association of DNA and histone proteins resulting in a dynamic polymer called chromatin. The fundamental structural unit of chromatin is the nucleosome which consists of similar to 146 bp of DNA wrapped around an octamer of histones containing two copies each of four core histones, H2A, H2B, H3 and H4. It is this DNA/protein fiber that transcription factors and other agents of chromatin metabolism must access and regulate. We have developed model systems to study the mechanisms by which steroid receptors control physiological activities by regulating gene expression within a higher order chromatin organization. Our studies have focused on the glucocorticoid receptor and its ability to remodel chromatin which is mediated by the BRG1 complex. Using novel cell systems, we demonstrate that GR-mediated transactivation from chromatin templates requires BRG1 remodeling activity and that other ATP-dependent remodeling proteins cannot substitute for this activity. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Natl Inst Environm Hlth Sci, Chromatin & Gene Express Sect, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), Natl Inst Environm Hlth Sci, Chromatin & Gene Express Sect, Mol Carcinogenesis Lab, NIH, 111 TW Alexander Dr,POB 12233 MD C4-06, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES071006-09] NR 52 TC 55 Z9 57 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB PY 2007 VL 265 BP 162 EP 167 DI 10.1016/j.mce.2006.12.015 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 148AH UT WOS:000245046400028 PM 17240047 ER PT J AU Cheadle, C Becker, KG Cho-Chung, YS Nesterova, M Watkins, T Wood, W Prabhu, V Barnes, KC AF Cheadle, Chris Becker, Kevin G. Cho-Chung, Yoon S. Nesterova, Maria Watkins, Tonya Wood, William, III Prabhu, Vinayakumar Barnes, Kathleen C. TI A rapid method for microarray cross platform comparisons using gene expression signatures SO MOLECULAR AND CELLULAR PROBES LA English DT Article ID OLIGONUCLEOTIDE ARRAY DATA; SET ENRICHMENT; AFFYMETRIX; CDNA AB Microarray technology has become highly valuable for identifying complex changes in global gene expression patterns. The inevitable use of a variety of different platforms has compounded the difficulty of effectively comparing data between projects, laboratories, and public access databases. The need for consistent, believable results across platforms is fundamental and methods for comparing results across platforms should be as straightforward as possible. We present the results of a study comparing three major, commercially available, microarray platforms (Affymetrix, Agilent, and Illumina). Concordance estimates between platforms was based on mapping of probes to Human Gene Organization (HUGO) gene names. Appropriate data normalization procedures were applied to each dataset followed by the generation of lists of regulated genes using a common significance threshold for all three platforms. As expected, concordance measured by directly comparing genelists was relatively low (an average 22.8% for all platforms across all possible comparisons). However, when statistical tests (gene set enrichment analysis-GSEA, parametric analysis of gene enrichment-PAGE) which align genelists with continuous measures of differential gene expression were applied to the cross platform datasets using significant genelists to poll entire datasets, the relatedness of the results from all three platforms was specific, obvious, and profound. (c) 2006 Elsevier Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Genom Core, Baltimore, MD 21224 USA. NIA, Gene Express & Genom Unit, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NCI, Cellular Biochem Sect, Basic Res Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Cheadle, C (reprint author), Johns Hopkins Univ, Sch Med, Div Allergy & Clin Immunol, Genom Core, Mason Lord Bldg,Ctr Tower,Rm 664,5200 Eastern Ave, Baltimore, MD 21224 USA. EM echeadl1@jhmi.edu; beckerk@grc.nia.nih.gov; chochuny@mail.nih.gov; nesterom@mail.nih.gov; twatkin2@jhem.jhmi.edu; WoodW@grc.nia.nih.gov; prabhuvi@grc.nia.nih.gov; kbarnes@jhmi.edu OI Becker, Kevin/0000-0002-6794-6656 NR 21 TC 27 Z9 29 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0890-8508 J9 MOL CELL PROBE JI Mol. Cell. Probes PD FEB PY 2007 VL 21 IS 1 BP 35 EP 46 DI 10.1016/j.mcp.2006.07.004 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology GA 127MO UT WOS:000243590600007 PM 16982174 ER PT J AU Zheng, YL Li, BS Kanungo, J Kesavapany, S Amin, N Grant, P Pant, HC AF Zheng, Ya-Li Li, Bing-Sheng Kanungo, Jyotshna Kesavapany, Sashi Amin, Niranjana Grant, Philip Pant, Harish C. TI Cdk5 modulation of mitogen-activated protein kinase signaling regulates neuronal survival SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; N-TERMINAL KINASE; TAU-PROTEIN; PC12 CELLS; GRANULE NEURONS; PHOSPHORYLATION; P35; DIFFERENTIATION; ROLES; DEATH AB Cdk5, a cyclin-dependent kinase, is critical for neuronal development, neuronal migration, cortical lamination, and survival. Its survival role is based, in part, on "cross-talk" interactions with apoptotic and survival signaling pathways. Previously, we showed that Cdk5 phosphorylation of mitogen-activated protein kinase kinase (MEK)1 inhibits transient activation induced by nerve growth factor (NGF) in PC12 cells. To further explore the nature of this inhibition, we studied the kinetics of NGF activation of extracellular signal-regulated kinase (Erk)1/2 in cortical neurons with or without roscovitine, an inhibitor of Cdk5. NGF alone induced an Erk1/2-transient activation that peaked in 15 min and declined rapidly to baseline. Roscovitine, alone or with NGF, reached peak Erk1/2 activation in 30 min that was sustained for 48 h. Moreover, the sustained Erk1/2 activation induced apoptosis in cortical neurons. Significantly, pharmacological application of the MEK1 inhibitor PD98095 to roscovitine-treated cortical neurons prevented apoptosis. These results were also confirmed by knocking down Cdk5 activity in cortical neurons with Cdk5 small interference RNA. Apoptosis was correlated with a significant shift of phosphorylated tau and neurofilaments from axons to neuronal cell bodies. These results suggest that survival of cortical neurons is also dependent on tight Cdk5 modulation of the mitogen-activated protein kinase signaling pathway. C1 Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU Intramural NIH HHS NR 48 TC 49 Z9 53 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2007 VL 18 IS 2 BP 404 EP 413 DI 10.1091/mbc.E06-09-0851 PG 10 WC Cell Biology SC Cell Biology GA 132AJ UT WOS:000243913800007 PM 17108320 ER PT J AU Ueyama, T Tatsuno, T Kawasaki, T Tsujibe, S Shirai, Y Sumimoto, H Leto, TL Saito, N AF Ueyama, Takehiko Tatsuno, Toshihiko Kawasaki, Takumi Tsujibe, Satoshi Shirai, Yasuhito Sumimoto, Hideki Leto, Thomas L. Saito, Naoaki TI A regulated adaptor function of p40(phox): Distinct p67(phox) membrane targeting by p40(phox) and by p47(phox) SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PHAGOCYTE NADPH OXIDASE; CYTOSOLIC PHOSPHOLIPASE A(2); PROTEIN-KINASE-C; ADENINE-DINUCLEOTIDE PHOSPHATE; CELL-FREE SYSTEM; RESPIRATORY BURST OXIDASE; R-MEDIATED PHAGOCYTOSIS; CHRONIC GRANULOMATOUS-DISEASE; EXOGENOUS ARACHIDONIC-ACID; SRC HOMOLOGY-3 DOMAINS AB In the phagocytic cell, NADPH oxidase (Nox2) system, cytoplasmic regulators (p47(phox), p67(phox), p40(phox), and Rac) translocate and associate with the membrane-spanning flavocytochrome b(558), leading to activation of superoxide production. We examined membrane targeting of phox proteins and explored conformational changes in p40(phox) that regulate its translocation to membranes upon stimulation. GFP-p40(phox) translocates to early endosomes, whereas GFP-p47(phox) translocates to the plasma membrane in response to arachidonic acid. In contrast, GFP-p67(phox) does not translocate to membranes when expressed alone, but it is dependent on p40(phox) and p47(phox) for its translocation to early endosomes or the plasma membrane, respectively. Translocation of GFP-p40(phox) or GFP-p47(phox) to their respective membrane-targeting sites is abolished by mutations in their phox (PX) domains that disrupt their interactions with their cognate phospholipid ligands. Furthermore, GFP-p67(phox) translocation to either membrane is abolished by mutations that disrupt its interaction with p40(phox) or p47(phox). Finally, we detected a head-to-tail (PX-Phox and Bem1 [PB1] domain) intramolecular interaction within p40(phox) in its resting state by deletion mutagenesis, cell localization, and binding experiments, suggesting that its PX domain is inaccessible to interact with phosphatidylinositol 3-phosphate without cell stimulation. Thus, both p40(phox) and p47(phox) function as diverse p67(phox) "carrier proteins" regulated by the unmasking of membrane-targeting domains in distinct mechanisms. C1 Kobe Univ, Mol Pharmacol Lab, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. NIAID, Mol Def Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Med Inst Bioregulat, Fukuoka 8128582, Japan. RP Saito, N (reprint author), Kobe Univ, Mol Pharmacol Lab, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. EM naosaito@kobe-u.ac.jp NR 86 TC 52 Z9 53 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2007 VL 18 IS 2 BP 441 EP 454 DI 10.1091/mbc.E06-08-0731 PG 14 WC Cell Biology SC Cell Biology GA 132AJ UT WOS:000243913800010 PM 17122360 ER PT J AU Mahadeo, DC Janka-Junttila, M Smoot, RL Roselova, P Parent, CA AF Mahadeo, Dana C. Janka-Junttila, Mirkka Smoot, Rory L. Roselova, Pavla Parent, Carole A. TI A chemoattractant-mediated G(i)-coupled pathway activates adenylyl cyclase in human neutrophils SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HUMAN POLYMORPHONUCLEAR LEUKOCYTES; FORMYL PEPTIDE RECEPTOR; XENOPUS-LAEVIS OOCYTES; BETA-GAMMA-SUBUNITS; PROTEIN-KINASE-A; SIGNAL-TRANSDUCTION; CYCLIC-AMP; DICTYOSTELIUM-DISCOIDEUM; ALPHA-6-BETA-4 INTEGRIN; DIFFERENTIAL REGULATION AB Neutrophils and Dictyostelium use conserved signal transduction pathways to decipher chemoattractant gradients and migrate directionally. In both cell types, addition of chemoattractants stimulates the production of cAMP, which has been suggested to regulate chemotaxis. We set out to define the mechanism by which chemoattractants increase cAMP levels in human neutrophils. We show that chemoattractants elicit a rapid and transient activation of adenylyl cyclase (AC). This activation is sensitive to pertussis toxin treatment but independent of phosphoinositide-3 kinase activity and an intact cytoskeleton. Remarkably, and in sharp contrast to G alpha(s)-mediated activation, chemoattractant-induced AC activation is lost in cell lysates. Of the nine, differentially regulated transmembrane AC isoforms in the human genome, we find that isoforms III, IV, VII, and IX are expressed in human neutrophils. We conclude that the signal transduction cascade used by chemoattractants to activate AC is conserved in Dictyostelium and human neutrophils and is markedly different from the canonical G alpha(s)-meditated pathway. C1 NCI, Lab Celular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Lab Celular & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM parentc@helix.nih.gov FU Intramural NIH HHS NR 62 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD FEB PY 2007 VL 18 IS 2 BP 512 EP 522 DI 10.1091/mbc.E06-05-0418 PG 11 WC Cell Biology SC Cell Biology GA 132AJ UT WOS:000243913800016 PM 17135293 ER PT J AU Do, TV Symowicz, JC Berman, DM Liotta, LA Petricoin, EF Stack, MS Fishman, DA AF Do, Thuy-Vy Symowicz, Jay C. Berman, David M. Liotta, Lance A. Petricoin, Emanuel F., III Stack, M. Sharon Fishman, David A. TI Lysophosphatidic acid down-regulates stress fibers and up-regulates pro-matrix metalloproteinase-2 activation in ovarian cancer cells SO MOLECULAR CANCER RESEARCH LA English DT Article ID GELATINASE-A ACTIVATION; BINDING PROTEIN RHO; EPITHELIAL-CELLS; FOCAL ADHESIONS; EXTRACELLULAR-MATRIX; ACTIN CYTOSKELETON; COLLAGEN LATTICES; HUMAN-FIBROBLASTS; PHOSPHOLIPASE-D; GROWTH-FACTOR AB Epithelial ovarian cancer (EOC) is asymptomatic at early stages and is often diagnosed late when tumor cells are highly metastatic. Lysophosphatidic acid (LPA) has been implicated in ovarian oncogenesis as levels of this lipid are elevated in patient ascites and plasma. Because the underlying mechanism governing LPA regulation of matrix metalloproteinase-2 (MMP-2) activation remains undefined, we investigated the relationship between LPA-induced changes in actin microfilament organization and MMP-2 enzymatic activity. We report that when cells were cultured at a high density, LPA mediated stress fiber and focal adhesion disassembly and significantly repressed RhoA activity in EOC cells. Inhibition of Rho-kinase/ROCK enhanced both LPA-stimulated loss of stress fibers and pro-MMP-2 activation. In contrast, expression of the constitutively active RhoA(G14V) mutant diminished LPA-induced pro-MMP-2 activation. LPA had no effects on membrane type 1-MMP or tissue inhibitor of metalloproteinase-2 expression, but up-regulated MMP-2 levels, contributing to the induction of MMP-2 activation. Interestingly, when cells were cultured at a low density, stress fibers were present after LPA stimulation, and ROCK activity was required for EOC cell migration. Collectively, these results were consistent with a model in which LPA stimulates the metastatic dissemination of EOC cells by initiating loss of adhesion and metalloproteinase activation. C1 Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, New York, NY 10016 USA. Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, New York, NY 10016 USA. NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Off Director, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Dept Obsted & Gynecol Gynecol Oncol, New York, NY USA. RP Fishman, DA (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Obstet & Gynecol, 550 1st Ave, New York, NY 10016 USA. EM director-gynonc@med.nyu.edu FU NCI NIH HHS [R01 CA82562, R01 CA01015, U01 CA85133, P50 CA83639, R01 CA89503] NR 53 TC 26 Z9 26 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2007 VL 5 IS 2 BP 121 EP 131 DI 10.1158/1541-7786.MCR-06-0319 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 140WT UT WOS:000244538200002 PM 17314270 ER PT J AU Lin, L Czapiga, M Nini, L Zhang, JH Simonds, WF AF Lin, Ling Czapiga, Meggan Nini, Lylia Zhang, Jian-Hua Simonds, William F. TI Nuclear localization of the parafibromin tumor suppressor protein implicated in the hyperparathyroidism-jaw tumor syndrome enhances its proapoptotic function SO MOLECULAR CANCER RESEARCH LA English DT Article ID RNA-POLYMERASE-II; FAMILIAL ISOLATED HYPERPARATHYROIDISM; SPORADIC PARATHYROID TUMORS; HRPT2 GENE; PAF1 COMPLEX; MUTATIONS; IDENTIFICATION; TRANSCRIPTION; GERMLINE; 1Q21-Q32 AB Parafibromin is a tumor suppressor protein encoded by HRPT2, a gene recently implicated in the hereditary hyperparathyroidism-jaw tumor syndrome, parathyroid cancer, and a subset of kindreds with familial isolated hyperparathyroidism. Human parafibromin binds to RNA polymerase 11 as part of a PAP transcriptional regulatory complex. The mechanism by which loss of parafibromin function can lead to neoplastic transformation is poorly understood. Because the subcellular localization of parafibromin is likely to be critical for its function with the nuclear PAF1 complex, we sought to experimentally define the nuclear localization signal (NLS) of parafibromin and examine its potential role in parafibromin function. Using site-directed mutagenesis, we define a dominant bipartite NLS and a secondary NLS, both in the NH2-terminal region of parafibromin whose combined mutation nearly abolishes nuclear targeting. The NLS-mutant parafibromin is significantly impaired in its association with endogenous Paf1 and Leo1. We further report that overexpression of wild-type but not NLS-mutant parafibromin induces apoptosis in transfected cells. Inhibition of endogenous parafibromin expression by RNA interference inhibits the basal rate of apoptosis and apoptosis resulting from DNA damage induced by camptothecin, a topoisomerase I inhibitor. These experiments identify for the first time a proapoptotic activity of endogenous parafibromin likely to be important in its role as a tumor suppressor and show a functional role for the NLS of parafibromin in this activity. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDK, Metab Dis Branch, NIH, Room 8C-101,Bldg 10,10 Ctr Dr,MSC 1752, Bethesda, MD 20892 USA. EM wf@helix.nih.gov FU Intramural NIH HHS NR 28 TC 36 Z9 37 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD FEB PY 2007 VL 5 IS 2 BP 183 EP 193 DI 10.1158/1541-7786.MCR-06-0129 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 140WT UT WOS:000244538200008 PM 17314275 ER PT J AU Reinhold, WC Reimers, MA Maunakea, AK Kim, S Lababidi, S Scherf, U Shankavaram, UT Ziegler, MS Stewart, C Kouros-Mehr, H Cui, HM Dolginow, D Scudiero, DA Pommier, YG Munroe, DJ Feinberg, AP Weinstein, JN AF Reinhold, William C. Reimers, Mark A. Maunakea, Alika K. Kim, Sohyoung Lababidi, Samir Scherf, Uwe Shankavaram, Uma T. Ziegler, Micah S. Stewart, Claudia Kouros-Mehr, Hosein Cui, Hengmi Dolginow, Douglas Scudiero, Dominic A. Pommier, Yves G. Munroe, David J. Feinberg, Andrew P. Weinstein, John N. TI Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID INVASION-SUPPRESSOR GENE; CPG ISLAND METHYLATION; BREAST-CANCER; MOLECULAR PHARMACOLOGY; PROSTATE-CANCER; MALIGNANT PROGRESSION; MULTIDRUG-RESISTANCE; EXPRESSION DATABASE; GASTRIC-CANCER; DRUG SCREEN AB E-cadherin (E-cad) is a transmembrane adhesion glycoprotein, the expression of which is often reduced in invasive or metastatic tumors. To assess E-cad's distribution among different types of cancer cells, we used bisulfite-sequencing for detailed, base-by-base measurement of CpG methylation in E-cad's promoter region in the NCI-60 cell lines. The mean methylation levels of the cell lines were distributed bimodally, with values pushed toward either the high or low end of the methylation scale. The 38 epithelial cell lines showed substantially lower (28%) mean methylation levels compared with the nonepithelial cell lines (58%). The CpG site at -143 with respect to the transcriptional start was commonly methylated at intermediate levels, even in cell lines with low overall DNA methylation. We also profiled the NCI-60 cell lines using Affymetrix U133 microarrays and found E-cad expression to be correlated with E-cad methylation at highly statistically significant levels. Above a threshold of similar to 20% to 30% mean methylation, the expression of E-cad was effectively silenced. Overall, this study provides a type of detailed analysis of methylation that can also be applied to other cancer-related genes. As has been shown in recent years, DNA methylation status can serve as a biomarker for use in choosing therapy. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,Genom & Bioinformat Grp, Bethesda, MD 20892 USA. Gene Logic, Gaithersburg, MD USA. NCI, Sci Applicat Int Corp, Frederick Inc, Frederick, MD 21701 USA. Johns Hopkins Univ, Sch Med, Dept Med, Epigenet Unit, Baltimore, MD 21205 USA. RP Reinhold, WC (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,Genom & Bioinformat Grp, Bldg 37,Room 5056, Bethesda, MD 20892 USA. EM wcr@mail.nih.gov OI Kim, Sohyoung/0000-0002-6140-7918 FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400, R37 CA054358-17, R37 CA054358] NR 61 TC 35 Z9 35 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2007 VL 6 IS 2 BP 391 EP 403 DI 10.1158/1535-7163.MCT-06-0609 PG 13 WC Oncology SC Oncology GA 136ZN UT WOS:000244262700001 PM 17272646 ER PT J AU Goldsmith, ME Aguila, A Steadman, K Martinez, A Steinberg, SM Alley, MC Waud, WR Bates, SE Fojo, T AF Goldsmith, Merrill E. Aguila, Alian Steadman, Kenneth Martinez, Alfredo Steinberg, Seth M. Alley, Michael C. Waud, William R. Bates, Susan E. Fojo, Tito TI The histone deacetylase inhibitor FK228 given prior to adenovirus infection can boost infection in melanoma xenograft model systems SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CANCER GENE-THERAPY; MEDIATED TRANSGENE EXPRESSION; CHROMOBACTERIUM-VIOLACEUM NO-968; DEPSIPEPTIDE FR901228; BLADDER-CANCER; RECEPTOR CAR; MALIGNANT-CELLS; IN-VIVO; COXSACKIE; VECTORS AB A major limitation of adenovirus type 5-mediated cancer gene therapy is the inefficient infection of many cancer cells. Previously, we showed that treatment with low doses of the histone deacetylase inhibitor FK228 (FR901228, depsipeptide) increased coxsackie adenovirus receptor (CAR) levels, histone H3 acetylation, and adenovirus infection efficiencies as measured by viral transgene expression in cancer cell lines but not in cultured normal cells. To evaluate FK228 in vivo, the effects of FK228 therapy in athymic mice bearing LOX IMVI or UACC-62 human melanoma xenografts were examined. Groups of mice were treated with FK228 using several dosing schedules and the differences between treated and control animals were determined. In mice with LOX IMVI xenografts (n = 6), maximum CAR induction was observed 24 h following a single FK228 dose of 3.6 mg/kg with a 13.6 +/- 4.3-fold (mean +/- SD) increase in human CAR mRNA as determined by semiquantitative reverse transcription-PCR analysis. By comparison, mouse CAR levels in liver, kidney, and lung from the same animals showed little to no change. Maximum CAR protein induction of 9.2 +/- 4.8-fold was achieved with these treatment conditions and was associated with increased histone H3 acetylation. Adenovirus carrying a green fluorescent protein (GFP) transgene (2 x 109 viral particles) was injected into the xenografts and GFP mRNA levels were determined. A 7.4 +/- 5.2-fold increase in GFP mRNA was found 24 h following adenovirus injection into optimally FK228-treated mice (n = 10). A 4-fold increase in GFP protein-positive cells was found following FK228 treatment. These studies suggest that FK228 treatment prior to adenovirus infection could increase the efficiency of adenovirus gene therapy in xenograft model systems. C1 NCI, Expt Therapeut Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biol Testing Branch, Div Canc Treatment & Diag, NIH, Frederick, MD 21701 USA. So Res Inst, Birmingham, AL 35255 USA. RP Fojo, T (reprint author), NCI, Expt Therapeut Sect, Med Oncol Branch, Ctr Canc Res,NIH, 10 Ctr Dr,Bldg 10,Room 13N240,MSC 1903, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov RI Martinez, Alfredo/A-3077-2013; Steadman, Kenneth/J-3883-2013 OI Martinez, Alfredo/0000-0003-4882-4044; FU Intramural NIH HHS NR 51 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2007 VL 6 IS 2 BP 496 EP 505 DI 10.1158/1535-7163.MCT-06-0431 PG 10 WC Oncology SC Oncology GA 136ZN UT WOS:000244262700010 PM 17308048 ER PT J AU McNeill, DR Wong, HK Narayana, A Wilson, DM AF McNeill, Daniel R. Wong, Heng-Kuan Narayana, Avinash Wilson, David M., III TI Lead promotes abasic site accumulation and co-mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1 SO MOLECULAR CARCINOGENESIS LA English DT Article DE Ape1; environmental metal lead; abasic site; DNA base excision repair; mutagenesis ID HUMAN APURINIC ENDONUCLEASE; BASE EXCISION-REPAIR; DNA-POLYMERASE-BETA; OCCUPATIONAL-EXPOSURE; COMET ASSAY; METAL-IONS; DAMAGE; MECHANISMS; CADMIUM; PROTEIN AB Lead is a widespread environmental toxin, found in contaminated water sources, household paints, and certain occupational settings. Classified as a probable carcinogen by the international Agency for Research on Cancer (IARC), lead promotes mutagenesis when combined with alkylating and oxidizing DNA-damaging agents. We previously reported that lead inhibits the in vitro repair activity of Ape1, the major endonuclease for repairing mutagenic and cytotoxic abasic sites in DNA. We investigated here whether lead targets Ape1 in cultured mammalian cells. We report a concentration-dependent inhibition of apurinic/apyrimidinic (AP) site incision activity of Chinese hamster ovary (CHO) AA8 whole cell extracts by lead. in addition, lead exposure results in a concentration-dependent accumulation of AP sites in the genomic DNA of AA8 cells. An increase in the oxidative base lesion 8-oxoguanine was observed only at high lead levels (500 mu M), suggesting that non-specific oxidation plays little role in the production of lead-related AP lesions at physiological metal concentrations-a conclusion corroborated by "thiobarbituric acid reactive substances" assays. Notably, Ape1 overexpression in AA8 (hApe1-3 cell line) abrogated the lead-dependent increase in AP site steady-state levels. Moreover, lead functioned cooperatively to promote a further increase in abasic sites with agents known to generate AP sites in DNA (i.e., methyl methansulfonate (MMS) and hydrogen peroxide (H2O2)), but not the DNA crosslinking agent mitomycin C. Hypoxanthine guanine phosphoribosyltransferase (hprt) mutation analysis revealed that, whereas lead alone had no effect on mutation frequencies, mutagenesis increased in MMS treated, and to a greater extent lead/MMS treated, AA8 cells. With the hApe1-3 cell line, the number of mutant colonies in all treatment groups was found to be equal to that of the background level, indicating that Ape1 overexpression reverses MMS- and lead-associated hprt mutagenesis. Our studies in total indicate that Ape1 is a member of an emerging group of DNA surveillance proteins that are inhibited by environmental heavy metals, and suggest an underlying mechanism by which lead promotes co-carcinogenesis. Published 2006 Wiley-Liss, Inc. C1 NIA, Lab Mol Gerontol, GRC, IRP,NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, GRC, IRP,NIH, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. FU Intramural NIH HHS NR 47 TC 12 Z9 17 U1 1 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2007 VL 46 IS 2 BP 91 EP 99 DI 10.1002/mc.20196 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 134JY UT WOS:000244080500002 PM 17013835 ER PT J AU Takahashi, Y Perkins, SN Hursting, SD Wang, TTY AF Takahashi, Yoko Perkins, Susan N. Hursting, Stephen D. Wang, Thomas T. Y. TI 17 beta-estradiol differentially regulates androgen-responsive genes through estrogen receptor-beta- and extracellular-signal regulated kinase-dependent pathways in LNCaP human prostate cancer cells SO MOLECULAR CARCINOGENESIS LA English DT Article DE cell proliferation; estrogen; estrogen-responsive element; quantitative real-time PCR ID STE20/SPS1-RELATED KINASE; REPRODUCTIVE PHENOTYPES; MESSENGER-RNA; NOBLE RATS; NULL MICE; ER-ALPHA; EXPRESSION; HORMONE; ESTRADIOL; ANTIGEN AB The molecular mechanism underlying the actions of estrogens in normal prostate physiology and prostate cancer development remains unclear. In the present study we tested the hypothesis that estrogens modulate androgen-dependent events in prostate cells by examining the effects of 17 beta-estradiol (E2) on androgen-responsive genes (ARGs) in the androgen responsive LNCaP cells. We found that LNCaP cells express estrogen receptor-beta (ER-beta) as the major form of ER and ER treatment with E2 led to an increase in cell growth. The proliferative effect of E2 correlated with induction of several ARGs by E2. Interestingly, some other ARGs did not respond to E2. Consistent with involvement of ER-P, the induction of both cell growth and ARG mRNA levels by E2 was attenuated by the pure antiestrogen vertical bar C vertical bar 182,780. Moreover, we found ER-beta small interfering RNA attenuated induction of ARG mRNAs by E2. However, the effect of E2 on ARG mRNA appeared also to require the androgen receptor and to be mediated through activation of the extracellular-signal regulated kinase (ERK) pathway. These results provide mechanistic evidence supporting a direct effect of estrogen, mediated through ER-beta- and ERK-dependent pathways, on specific molecular targets in human prostate cancer cells. (c) 2006 Wiley-Liss, Inc. C1 USDA ARS, Beltsville Human Nutr Res Ctr, Phytonutrients Lab, Beltsville, MD 20705 USA. Natl Food Res Inst, Tsukuba, Ibaraki 305, Japan. NCI, Ctr Canc Res, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. RP Wang, TTY (reprint author), USDA ARS, Beltsville Human Nutr Res Ctr, Phytonutrients Lab, 10300 Baltimore Ave,Bldg 307C,Room 132, Beltsville, MD 20705 USA. NR 51 TC 20 Z9 20 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2007 VL 46 IS 2 BP 117 EP 129 DI 10.1002/mc.20254 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 134JY UT WOS:000244080500005 PM 17131305 ER PT J AU Tchaicka, L Eizirik, E De Oliveira, TG Candido, JF Freitas, TRO AF Tchaicka, Ligia Eizirik, Eduardo De Oliveira, Tadeu G. Candido, Jose Flavio, Jr. Freitas, Thales R. O. TI Phylogeography and population history of the crab-eating fox (Cerdocyon thous) SO MOLECULAR ECOLOGY LA English DT Article DE Canidae; Carnivora; Cerdocyon thous; demographic history; mitochondrial DNA control region; nuclear introns ID MITOCHONDRIAL-DNA; ATLANTIC FOREST; GEOGRAPHICAL-DISTRIBUTION; HAPLOTYPE RECONSTRUCTION; MOLECULAR ANALYSIS; STATISTICAL-METHOD; CLADISTIC-ANALYSIS; CONTROL REGION; SMALL MAMMALS; MUTATION-RATE AB The crab-eating fox is a medium-sized Neotropical canid with generalist habits and a broad distribution in South America. We have investigated its genetic diversity, population structure and demographic history across most of its geographic range by analysing 512 base pairs (bp) of the mitochondrial DNA (mtDNA) control region, 615 bp of the mtDNA cytochrome b gene and 1573 total nucleotides from three different nuclear fragments. MtDNA data revealed a strong phylogeographic partition between northeastern Brazil and other portions of the species' distribution, with complete separation between southern and northern components of the Atlantic Forest. We estimated that the two groups diverged from each other c. 400 000-600 000 years ago, and have had contrasting population histories. A recent demographic expansion was inferred for the southern group, while northern populations seem to have had a longer history of large population size. Nuclear sequence data did not support this north-south pattern of subdivision, likely due at least in part to secondary male-mediated historical gene flow, inferred from multilocus coalescent-based analyses. We have compared the inferred phylogeographic patterns to those observed for other Neotropical vertebrates, and report evidence for a major north-south demographic discontinuity that seems to have marked the history of the Atlantic Forest biota. C1 Univ Fed Rio Grande Sul, Inst Biociencias, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil. PUCRS, Fac Biociencias, Ctr Biol Genom & Mol, BR-90619900 Porto Alegre, RS, Brazil. NCI Frederick, Lab Genom Divers, NIH, Ft Detrick, MD 21702 USA. Cidade Univ Paulo VI, Dept Biol, UEMA, San Luis, MA, Brazil. RP Eizirik, E (reprint author), Univ Fed Rio Grande Sul, Inst Biociencias, Dept Genet, Campus Vale Bloco III,Ave Bent Goncalves 9500, BR-91501970 Porto Alegre, RS, Brazil. EM eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012; Freitas, Thales/G-1160-2012 OI Eizirik, Eduardo/0000-0002-9658-0999; Freitas, Thales/0000-0002-1019-9303 NR 70 TC 43 Z9 46 U1 4 U2 19 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0962-1083 J9 MOL ECOL JI Mol. Ecol. PD FEB PY 2007 VL 16 IS 4 BP 819 EP 838 DI 10.1111/j.1365-294X.2006.03185.x PG 20 WC Biochemistry & Molecular Biology; Ecology; Evolutionary Biology SC Biochemistry & Molecular Biology; Environmental Sciences & Ecology; Evolutionary Biology GA 133HQ UT WOS:000244004400011 PM 17284214 ER PT J AU Sidransky, E LaMarca, ME Ginns, EI AF Sidransky, Ellen LaMarca, Mary E. Ginns, Edward I. TI Therapy for Gaucher disease: Don't stop thinking about tomorrow SO MOLECULAR GENETICS AND METABOLISM LA English DT Editorial Material DE Gaucher disease; enzyme replacement therapy; lysosomal storage diseases; chaperone therapy; gene therapy; substrate reduction therapy ID ENZYME REPLACEMENT THERAPY; LONG-TERM EXPRESSION; HUMAN GLUCOCEREBROSIDASE GENE; LYSOSOMAL STORAGE DISORDERS; N-BUTYLDEOXYNOJIRIMYCIN; CHEMICAL CHAPERONES; BETA-GLUCOSIDASE; NATURAL-HISTORY; IN-VIVO; CELLS AB While enzyme replacement therapy for Gaucher disease has been widely used and appears to be an efficacious and safe treatment, this success should not be a reason for complacency. Other treatment strategies currently under consideration for patients with Gaucher disease include gene therapy, substrate reduction therapy and chaperone therapy. Furthermore, improvements in enzyme therapy could also have a significant clinical impact. Individuals with Gaucher disease and other lysosomal disorders will greatly benefit from continual refinement and optimization of the current therapy, as well as from the development of new treatment modalities that offer improvements in efficacy, cost, safety and availability. (c) 2007 Published by Elsevier Inc. C1 NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Program Med Genet Pediat Neurol, Shrewsbury, MA 01545 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS NR 31 TC 11 Z9 12 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 FEB PY 2007 VL 90 IS 2 BP 122 EP 125 DI 10.1016/j.ymgme.2006.09.007 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 137ON UT WOS:000244302000002 PM 17084653 ER PT J AU Takahashi, M Jeevan, A Sawant, K McMurray, DN Yoshimura, T AF Takahashi, Munehisa Jeevan, Amminikutty Sawant, Kirti McMurray, David N. Yoshimura, Teizo TI Cloning and characterization of guinea pig CXCR1 SO MOLECULAR IMMUNOLOGY LA English DT Article DE guinea pig; neutrophils; chemokines; cell trafficking; chemotaxis; inflammation ID CHEMOKINE RECEPTOR CXCR1; INTERLEUKIN-8 RECEPTOR; MONOCLONAL-ANTIBODY; NEUTROPHIL; HOMOLOG; EXPRESSION; CYTOKINES; RABBITS; BINDING; GENES AB IL-8/CXCL8 plays a critical role in the trafficking and activation of neutrophils via its receptors, CXCR1 and CXCR2, in humans. CXCR1 is highly selective for IL-8, whereas CXCR2 is activated by all CXC chemokines with an ELR motif. In mice and rats, neither IL-8 nor CXCR1 is present, making it difficult to evaluate the in vivo roles of the IL-8/CXCR1 interactions. We previously demonstrated the presence of IL-8 in the guinea pig (gp), suggesting that its specific receptor CXCR1 is also present in this species. Here, we obtained two gp genomic DNA clones, clones 8 and 10, coding for the potential orthologues of CXCR1 and CXCR2, respectively. Transcripts for these genes were expressed in neutrophils, but not in macrophages. Functionally, both gp and human (h) IL-8 induced cell migration and ERK phosphorylation in HEK 293 cells expressing either receptor, whereas hGRO activated only cells expressing the clone 10 protein, confirming that clone 8 indeed coded for gpCXCR1. I-125-labeled hIL-8 bound to gpCXCR1 and addition of unlabeled hIL-8 completely abolished the binding; however, unlabeled gpIL-8 failed to compete against 121 I-labeled hIL-8, strongly suggesting that the avidity of hIL-8 to gpCXCR1 is higher than that of gpIL-8. Identification and characterization of CXCR1 in the guinea pig will allow us to use this small animal model to evaluate the role of the IL-8/CXCR1 interactions and to examine the efficacy of CXCR1 antagonists in vivo. (c) 2006 Elsevier Ltd. All rights reserved. C1 NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Texas A&M Univ, Hlth Sci Ctr, Dept Microbial & Mol Pathogenesis, College Stn, TX 77843 USA. RP Yoshimura, T (reprint author), NCI, Mol Immunoregulat Lab, Bldg 560,Rm 31-36, Frederick, MD 21702 USA. EM yoshimut@mail.nih.gov RI Sawant, Kirti/L-1602-2013; Sawant, Kirti/H-3778-2013 FU Intramural NIH HHS; NIAID NIH HHS [R01 AI-15495] NR 27 TC 11 Z9 12 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD FEB PY 2007 VL 44 IS 5 BP 878 EP 888 DI 10.1016/j.molimm.2006.03.023 PG 11 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 105HD UT WOS:000242020100023 PM 16712933 ER PT J AU Spooner, CJ Guo, XR Johnson, PF Schwartz, RC AF Spooner, Chauncey J. Guo, Xiangrong Johnson, Peter F. Schwartz, Richard C. TI Differential roles of C/EBP beta regulatory domains in specifviuy MCP-1 and IL-6 transcription SO MOLECULAR IMMUNOLOGY LA English DT Article DE gene regulation; C/EBP beta; IL-6; MCP-1; lipopolysaccharide ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; LYMPHOBLASTIC CELL-LINE; ACUTE-PHASE RESPONSE; BINDING-PROTEIN; NUCLEAR-FACTOR; INDUCIBLE EXPRESSION; INHIBITORY PROTEIN; FAMILY-MEMBERS AB C/EBP beta is a member of the CCAAT/enhancer binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of various proinflammatory genes, including IL-6 and MCP-1. To examine the roles of the C/EBP beta transactivation and regulatory domains in LPS-induced MCP-1 and IL-6 expression, we expressed various N-terminal truncations and deletions of C/EBP beta in P388 murine B lymphoblasts, which lack endogenous C/EBP beta expression and are normally unresponsive to LPS for expression of IL-6 and MCP-1. Unexpectedly, a region between amino acids 105 and 212 of C/EBP beta that includes regulatory domains I and 2 facilitates C/EBP beta activation of IL-6 expression, while having an inhibitory effect on MCP-1 expression. Thus, this region can mediate promoter-specific effects on cytokine and chemokine gene transcription. LIP, the naturally occurring truncated form of C/EBP beta, largely retains these regulatory domains and stimulates IL-6 but not MCP-1 transcription. (c) 2006 Elsevier Ltd. All rights reserved. C1 Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Schwartz, RC (reprint author), Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. EM schwart9@msu.edu RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 56 TC 19 Z9 20 U1 0 U2 1 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 FEB PY 2007 VL 44 IS 6 BP 1384 EP 1392 DI 10.1016/j.molimm.2006.05.004 PG 9 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 118NT UT WOS:000242949700035 PM 16784777 ER PT J AU Mead, S Vaisman, A Valjavec-Gratian, M Karata, K Vandewiele, D Woodgate, R AF Mead, Samantha Vaisman, Alexandra Valjavec-Gratian, Majda Karata, Kiyonobu Vandewiele, Dominique Woodgate, Roger TI Characterization of polV(R391): a Y-family polymerase encoded by rumA'B from the IncJ conjugative transposon, R391 SO MOLECULAR MICROBIOLOGY LA English DT Article ID BASE SUBSTITUTION MUTATIONS; SOS-INDUCED MUTAGENESIS; ESCHERICHIA-COLI; DNA-POLYMERASE; RECA PROTEIN; LESION BYPASS; BIOCHEMICAL BASIS; MUTATOR ACTIVITY; POL-III; UMUD AB Although best characterized for their ability to traverse a variety of DNA lesions, Y-family DNA polymerases can also give rise to elevated spontaneous mutation rates if they are allowed to replicate undamaged DNA. One such enzyme that promotes high levels of spontaneous mutagenesis in Escherichia coli is polV(R391), a polV-like Y-family polymerase encoded by rumA'B from the IncJ conjugative transposon R391. When expressed in a Delta umuDC lexA(Def) recA730 strain, polV(R391) promotes higher levels of spontaneous mutagenesis than the related MucA'B (polR1) or UmuD'C (polV) polymerases respectively. Analysis of the spectrum of polV(R391)-dependent mutations in rpoB revealed a unique genetic fingerprint that is typified by an increase in C:G -> A:T and A:T -> T:A transversions at certain mutagenic hot spots. Biochemical characterization of polV(R391) highlights the exceptional ability of the enzyme to misincorporate T opposite C and T in sequence contexts corresponding to mutagenic hot spots. Purified polV(R391) can also bypass a T-T pyrimidine dimer efficiently and displays greater accuracy opposite the 3'T of the dimer than opposite an undamaged T. Our study therefore provides evidence for the molecular basis for the enhanced spontaneous mutator activity of RumA'B, as well as explains its ability to promote efficient and accurate bypass of T-T pyrimidine dimers in vivo. C1 NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. EM woodgate@nih.gov RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 FU Intramural NIH HHS NR 40 TC 11 Z9 11 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2007 VL 63 IS 3 BP 797 EP 810 DI 10.1111/j.1365-2958.2006.05561.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 126IX UT WOS:000243507700014 PM 17302804 ER PT J AU Cabib, E Blanco, N Grau, C Rodriguez-Pena, JM Arroyo, J AF Cabib, Enrico Blanco, Noelia Grau, Cecilia Rodriguez-Pena, Jose Manuel Arroyo, Javier TI Crh1p and Crh2p are required for the cross-linking of chitin to beta(1-6)glucan in the Saccharomyces cerevisiae cell wall SO MOLECULAR MICROBIOLOGY LA English DT Article ID INTEGRITY SIGNALING PATHWAY; POLARIZED GROWTH SITES; GENOME-WIDE ANALYSIS; CHROMOSOME-VII; YEAST; PROTEINS; ARCHITECTURE; MUTANTS; GENES; DISRUPTION AB In budding yeast, chitin is found in three locations: at the primary septum, largely in free form, at the mother-bud neck, partially linked to beta(1-3)glucan, and in the lateral wall, attached in part to beta(1-6)glucan. By using a recently developed strategy for the study of cell wall cross-links, we have found that chitin linked to beta(1-6)glucan is diminished in mutants of the CRH1 or the CRH2/UTR2 gene and completely absent in a double mutant. This indicates that Crh1p and Crh2p, homologues of glycosyltransferases, ferry chitin chains from chitin synthase III to beta(1-6)glucan. Deletion of CRH1 and/or CRH2 aggravated the defects of fks1 Delta and gas1 Delta mutants, which are impaired in cell wall synthesis. A temperature shift from 30 degrees C to 38 degrees C increased the proportion of chitin attached to beta(1-6)glucan. The expression of CRH1, but not that of CRH2, was also higher at 38 degrees C in a manner dependent on the cell integrity pathway. Furthermore, the localization of both Crh1p and Crh2p at the cell cortex, the area where the chitin-beta(1-6)glucan complex is found, was greatly enhanced at 38 degrees C. Crh1p and Crh2p are the first proteins directly implicated in the formation of cross-links between cell wall components in fungi. C1 NIDDK, Lab Biochem & Genet, Bethesda, MD 20892 USA. Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, Madrid 28040, Spain. RP Cabib, E (reprint author), NIDDK, Lab Biochem & Genet, Bethesda, MD 20892 USA. EM enricoc@bdg10.niddk.nih.gov RI Arroyo, Javier/E-9308-2016; Rodriguez-Pena, Jose/E-9624-2016 OI Arroyo, Javier/0000-0002-1971-1721; Rodriguez-Pena, Jose/0000-0002-8792-362X FU Intramural NIH HHS NR 39 TC 71 Z9 74 U1 1 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2007 VL 63 IS 3 BP 921 EP 935 DI 10.1111/j.1365-2958.2006.05565.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 126IX UT WOS:000243507700024 PM 17302808 ER PT J AU Gerald, NJ Coppens, I Dwyer, DM AF Gerald, Noel J. Coppens, Isabelle Dwyer, Dennis M. TI Molecular dissection and expression of the LdK39 kinesin in the human pathogen, Leishmania donovani SO MOLECULAR MICROBIOLOGY LA English DT Article ID AMERICAN VISCERAL LEISHMANIASIS; CYCLE-DEPENDENT CHANGES; TRYPANOSOMA-BRUCEI; CELL-CYCLE; SUBCELLULAR-LOCALIZATION; CONVENTIONAL KINESIN; RECOMBINANT ANTIGEN; CARGO-BINDING; GAMMA-TUBULIN; MOTOR DOMAIN AB In this study we show for the first time the intracellular distribution of a K39 kinesin homologue in Leishmania donovani, a medically important parasite of humans. Further, we demonstrated that this motor protein is expressed in both the insect and mammalian developmental forms (i.e. promastigote and amastigotes) of this organism. Moreover, in both of these parasite developmental stages, immunofluorescence indicated that the LdK39 kinesin accumulated at anterior and posterior cell poles and that it displayed a peripheral localization consistent with the cortical cytoskeleton. Using a molecular approach, we identified, cloned and characterized the first complete open reading frame for the gene (LdK39) encoding this large (> 358 kDa) motor protein in L. donovani. Based on these observations, we subsequently used a homologous episomal expression system to dissect and express the functional domains that constitute the native molecule. Cell fractionation experiments demonstrated that LdK39 was soluble and that it bound to detergent-extracted cytoskeletons of these parasites in an ATP-dependent manner. The cumulative results of these experiments are consistent with LdK39 functioning as an ATP-dependent kinesin which binds to and travels along the cortical cytoskeleton of this important human pathogen. C1 NIAID, Parasit Dis Lab, Cell Biol Sect, NIH, Bethesda, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Dwyer, DM (reprint author), NIAID, Parasit Dis Lab, Cell Biol Sect, NIH, Bethesda, MD USA. EM ddwyer@niaid.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI060767] NR 72 TC 9 Z9 9 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2007 VL 63 IS 4 BP 962 EP 979 DI 10.1111/j.1365-2958.2006.05487.x PG 18 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 131LW UT WOS:000243871500004 PM 17257310 ER PT J AU Derbise, A Chenal-Francisque, V Pouillot, F Fayolle, C Prevost, MC Medigue, C Hinnebusch, BJ Carniel, E AF Derbise, Anne Chenal-Francisque, Viviane Pouillot, Flavie Fayolle, Corinne Prevost, Marie-Christine Medigue, Claudine Hinnebusch, Bernard Joseph Carniel, Elisabeth TI A horizontally acquired filamentous phage contributes to the pathogenicity of the plague bacillus SO MOLECULAR MICROBIOLOGY LA English DT Article ID COMPLETE GENOME SEQUENCE; YERSINIA-PESTIS; VIBRIO-CHOLERAE; CTX-PHI; INTEGRATION; DNA; PSEUDOTUBERCULOSIS; CHROMOSOME; RECOMBINATION; TRANSMISSION AB Yersinia pestis, the plague bacillus, has an exceptional pathogenicity but the factors responsible for its extreme virulence are still unknown. A genome comparison with its less virulent ancestor Yersinia pseudotuberculosis identified a few Y. pestis-specific regions acquired after their divergence. One of them potentially encodes a prophage (Ypf Phi), similar to filamentous phages associated with virulence in other pathogens. We show here that Ypf Phi forms filamentous phage particles infectious for other Y. pestis isolates. Although it was previously suggested that Ypf Phi is restricted to the Orientalis branch, our results indicate that it was acquired by the Y. pestis ancestor. In Antiqua and Medievalis strains, Ypf Phi genome forms an unstable episome whereas in Orientalis isolates it is stably integrated as tandem repeats. Deletion of the Ypf Phi genome does not affect Y. pestis ability to colonize and block the flea proventriculus, but results in an alteration of Y. pestis pathogenicity in mice. Our results show that transformation of Y. pestis from a classical enteropathogen to the highly virulent plague bacillus was accompanied by the acquisition of an unstable filamentous phage. Continued maintenance of Ypf Phi despite its high in vitro instability suggests that it confers selective advantages to Y. pestis under natural conditions. C1 Inst Pasteur, Yersinia Res Unit, F-75724 Paris 15, France. Inst Pasteur, F-75015 Paris, France. Genoscope, CNRS, UMR 8030, F-91006 Evry, France. NIAID, Lab Zoonot Pathogens, Rocky Mtn Labs, NIH, Hamilton, MT 59840 USA. RP Derbise, A (reprint author), Inst Pasteur, Yersinia Res Unit, 28 Rue Dr Roux, F-75724 Paris 15, France. EM aderbise@pasteur.fr NR 40 TC 42 Z9 46 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2007 VL 63 IS 4 BP 1145 EP 1157 DI 10.1111/j.1365-2958.2006.05570.x PG 13 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 131LW UT WOS:000243871500017 PM 17238929 ER PT J AU Sloan, S Rutkai, E King, RA Velikodvorskaya, T Weisberg, RA AF Sloan, Sieghild Rutkai, Edit King, Rodney A. Velikodvorskaya, Tatyana Weisberg, Robert A. TI Protection of antiterminator RNA by the transcript elongation complex SO MOLECULAR MICROBIOLOGY LA English DT Article ID RHO-DEPENDENT TERMINATION; LAMBDA-N-PROTEIN; ESCHERICHIA-COLI; BACTERIOPHAGE-LAMBDA; MESSENGER-RNA; PHAGE HK022; TRANSLATION REPRESSION; TRYPTOPHAN OPERON; COLIPHAGE-LAMBDA; ANTI-TERMINATION AB Nascent transcripts encoded by the putL and putR sites of phage HK022 bind the transcript elongation complex and suppress termination at downstream transcription terminators. We report here that the chemical stability of putL RNA is considerably greater than that of the typical Escherichia coli message because the elongation complex protects this RNA from degradation. When binding to the elongation complex was prevented by mutation of either putL or RNA polymerase, RNA stability decreased more than 50-fold. The functional modification conferred by putL RNA on the elongation complex is also long-lived: the efficiency of terminator suppression remained high for at least 10 kb from the putL site. We find that RNase III rapidly and efficiently cleaved the transcript just downstream of the putL sequences, but such cleavage changed neither the stability of putL RNA nor the efficiency of antitermination. These results argue that the continuity of the RNA that connects put sequences to the growing point is not required for persistence of the antiterminating modification in vivo. C1 NICHHD, Sect Microbial Genet, Mol Genet Lab, Bethesda, MD 20892 USA. RP Weisberg, RA (reprint author), Acad Sci Czech Republ, Inst Microbiol, Lab Regulat Gene Express, Videnska 1083, CR-14220 Prague, Czech Republic. EM rweisberg@nih.gov FU Intramural NIH HHS NR 48 TC 4 Z9 4 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD FEB PY 2007 VL 63 IS 4 BP 1197 EP 1208 DI 10.1111/j.1365-2958.2006.05579.x PG 12 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 131LW UT WOS:000243871500021 PM 17238921 ER PT J AU Groer, CE Tidgewell, K Moyer, RA Harding, WW Rothman, RB Prisinzano, TE Bohn, LM AF Groer, C. E. Tidgewell, K. Moyer, R. A. Harding, W. W. Rothman, R. B. Prisinzano, T. E. Bohn, L. M. TI An opioid agonist that does not induce mu-opioid receptor - Arrestin interactions or receptor internalization SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BETA-ARRESTIN; ERK1/2 ACTIVATION; SALVINORIN-A; MORPHINE-TOLERANCE; SALVIA-DIVINORUM; KNOCKOUT MICE; DESENSITIZATION; ENDOCYTOSIS; TRAFFICKING AB G protein-coupled receptor desensitization and trafficking are important regulators of opioid receptor signaling that can dictate overall drug responsiveness in vivo. Furthermore, different mu-opioid receptor ( mu OR) ligands can lead to varying degrees of receptor regulation, presumably because of distinct structural conformations conferred by agonist binding. For example, morphine binding produces a mu OR with low affinity for beta-arrestin proteins and limited receptor internalization, whereas enkephalin analogs promote robust trafficking of both beta-arrestins and the receptors. Here, we evaluate mu OR trafficking in response to activation by a novel mu-selective agonist derived from the naturally occurring plant product, salvinorin A. It is interesting that this compound, termed herkinorin, does not promote the recruitment of mu-arrestin-2 to the mu OR and does not lead to receptor internalization. Moreover, whereas G protein- coupled receptor kinase overexpression can promote morphine- induced beta-arrestin interactions and mu OR internalization, such manipulations do not promote herkinorin- induced trafficking. Studies in mice have shown that mu- arrestin- 2 plays an important role in the development of morphine- induced tolerance, constipation, and respiratory depression. Therefore, drugs that can activate the receptor without recruiting the arrestins may be a promising step in the development of opiate analgesics that distinguish between agonist activity and receptor regulation and may ultimately lead to therapeutics designed to provide pain relief without the adverse side effects normally associated with the opiate narcotics. C1 Ohio State Univ, Coll Med, Dept Pharmacol, Columbus, OH 43210 USA. Ohio State Univ, Coll Med, Dept Psychiat, Columbus, OH 43210 USA. Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Prisinzano, TE (reprint author), 333 W 10th Ave,5184A Graves Hall, Columbus, OH 43210 USA. EM thomasprisinzano@uiowa.edu RI Bohn, Laura/A-4412-2008; Prisinzano, Thomas/B-7877-2010; Bohn, Laura/A-7483-2014 OI Bohn, Laura/0000-0002-6474-8179 FU NIDA NIH HHS [DA18151, DA14600, DA18860, K01 DA014600, R01 DA018151, R01 DA018151-01A2, R01 DA018860] NR 42 TC 116 Z9 119 U1 2 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2007 VL 71 IS 2 BP 549 EP 557 DI 10.1124/mol.106.028258 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 127RV UT WOS:000243604900017 PM 17090705 ER PT J AU Rao, JS Ertley, RN Demar, JC Rapoport, SI Bazinet, RP Lee, HJ AF Rao, J. S. Ertley, R. N., Jr. DeMar, J. C. Rapoport, S. I. Bazinet, R. P. Lee, H-J TI Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex SO MOLECULAR PSYCHIATRY LA English DT Article DE arachidonic acid; brain; docosahexaenoic acid; cyclooxygenase; phospholipase A(2); n-3 PUFA ID CYTOSOLIC PHOSPHOLIPASE A(2); POLYUNSATURATED FATTY-ACIDS; GROUP-SPECIFIC ASSAYS; BIPOLAR DISORDER; BRAIN PHOSPHOLIPIDS; GENE-EXPRESSION; CHRONIC LITHIUM; UNANESTHETIZED RAT; CHRONIC VALPROATE; CYCLOOXYGENASE-2 AB The enzymes that regulate the brain arachidonic acid ( AA) cascade have been implicated in bipolar disorder and neuroinflammation. Fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats decreases the concentration of docosahexaenoic acid (DHA) and increases its half-life within the brain. Based on this, we hypothesized that such dietary deprivation would decrease expression of enzymes responsible for the metabolic loss of DHA while increasing expression of those responsible for the metabolism of AA. Fifteen weeks of n-3 PUFA deprivation significantly decreased the activity, protein and mRNA expression of the DHA regulatory phospholipase A(2) (PLA(2)), calcium-independent iPLA(2), in rat frontal cortex. In contrast the activities, protein and mRNA levels of the AA selective calcium-dependent cytosolic phospholipase (cPLA(2)) and secretory sPLA(2) were increased. Cyclooxygenase (COX)-1 protein but not mRNA was decreased in the n-3 PUFA-deprived rats whereas COX-2 protein and mRNA were increased. This study suggests that n-3 PUFA deprivation increases the half-live of brain DHA by downregulating iPLA(2). The finding that n-3 PUFA deprivation increases cPLA(2), sPLA(2) and COX-2 is opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests that n-3 PUFA deprivation may increase susceptibility to bipolar disorder. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov RI Rao, Jagadeesh/C-1250-2009 NR 61 TC 122 Z9 125 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2007 VL 12 IS 2 BP 151 EP 157 DI 10.1038/sj.mp.4001887 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 130EZ UT WOS:000243783700004 PM 16983392 ER PT J AU Addington, AM Gornick, MC Shaw, P Seal, J Gogtay, N Greenstein, D Clasen, L Coffey, M Gochman, P Long, R Rapoport, JL AF Addington, A. M. Gornick, M. C. Shaw, P. Seal, J. Gogtay, N. Greenstein, D. Clasen, L. Coffey, M. Gochman, P. Long, R. Rapoport, J. L. TI Neuregulin 1 (8p12) and childhood-onset schizophrenia: susceptibility haplotypes for diagnosis and brain developmental trajectories SO MOLECULAR PSYCHIATRY LA English DT Article DE endophenotype; neurodevelopment; linkage disequilibrium; child psychosis; TDT; QTDT ID AFFECTIVE-DISORDERS; VOLUME LOSS; K-SADS; CHILDREN; GENE; ASSOCIATION; MATTER; ADOLESCENCE; EXPRESSION; INCREASES AB Childhood-onset schizophrenia (COS), defined as onset of psychosis by the age of 12, is a rare and malignant form of the illness, which may have more salient genetic influence. Since the initial report of association between neuregulin 1 (NRG1) and schizophrenia in 2002, numerous independent replications have been reported. In the current study, we genotyped 56 markers (54 single-nucleotide polymorphisms (SNPs) and two microsatellites) spanning the NRG1 locus on 78 COS patients and their parents. We used family-based association analysis for both diagnostic (extended transmission disequilibrium test) and quantitative phenotypes (quantitative transmission disequilibrium test) and mixed-model regression. Most subjects had prospective anatomic brain magnetic resonance imaging (MRI) scans at 2-year intervals. Further, we genotyped a sample of 165 healthy controls in the MRI study to examine genetic risk effects on normal brain development. Individual markers showed overtransmission of alleles to affecteds (P=0.009-0.05). Further, several novel four-marker haplotypes demonstrated significant transmission distortion. There was no evidence of epistasis with SNPs in erbB4. The risk allele (0) at 420M9-1395 was associated with poorer premorbid social functioning. Further, possession of the risk allele was associated with different trajectories of change in lobar volumes. In the COS group, risk allele carriers had greater total gray and white matter volume in childhood and a steeper rate of subsequent decline in volume into adolescence. By contrast, in healthy children, possession of the risk allele was associated with different trajectories in gray matter only and was confined to frontotemporal regions, reflecting epistatic or other illness-specific effects mediating NRG1 influence on brain development in COS. This replication further documents the role of NRG1 in the abnormal brain development in schizophrenia. This is the first demonstration of a disease-specific pattern of gene action in schizophrenia. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Addington, AM (reprint author), 10 Ctr Dr,Bldg 10 Room 3N202, Bethesda, MD 20892 USA. EM addingta@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 47 TC 82 Z9 83 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD FEB PY 2007 VL 12 IS 2 BP 195 EP 205 DI 10.1038/sj.mp.4001906 PG 11 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 130EZ UT WOS:000243783700008 PM 17033632 ER PT J AU Schmidt, MW Houseman, A Ivanov, AR Wolf, DA AF Schmidt, Michael W. Houseman, Andres Ivanov, Alexander R. Wolf, Dieter A. TI Comparative proteomic and transcriptomic profiling of the fission yeast Schizosaccharomyces pombe SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE fission yeast; LC-MS/MS; mRNA-protein correlation; relative protein quantification; protein profiling ID PROTEIN IDENTIFICATION TECHNOLOGY; CYCLE-REGULATED GENES; SACCHAROMYCES-CEREVISIAE; MASS-SPECTROMETRY; CELL-CYCLE; GLOBAL ANALYSIS; MESSENGER-RNA; EXPRESSION; ABUNDANCE; SCALE AB The fission yeast Schizosaccharomyces pombe is a widely used model organism to study basic mechanisms of eukaryotic biology, but unlike other model organisms, its proteome remains largely uncharacterized. Using a shotgun proteomics approach based on multidimensional prefractionation and tandem mass spectrometry, we have detected similar to 30% of the theoretical fission yeast proteome. Applying statistical modelling to normalize spectral counts to the number of predicted tryptic peptides, we have performed label-free quantification of 1465 proteins. The fission yeast protein data showed considerable correlations with mRNA levels and with the abundance of orthologous proteins in budding yeast. Functional pathway analysis indicated that the mRNA protein correlation is strong for proteins involved in signalling and metabolic processes, but increasingly discordant for components of protein complexes, which clustered in groups with similar mRNA-protein ratios. Self-organizing map clustering of large-scale protein and mRNA data from fission and budding yeast revealed coordinate but not always concordant expression of components of functional pathways and protein complexes. This finding reaffirms at the protein level the considerable divergence in gene expression patterns of the two model organisms that was noticed in previous transcriptomic studies. C1 Harvard Univ, Sch Publ Hlth, NIEHS Environm Hlth Proteom Facil, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. Univ Stuttgart, Inst Biochem, D-7000 Stuttgart, Germany. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Ivanov, AR (reprint author), Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM aivanov@hsph.harvard.edu; dwolf@hsph.harvard.edu OI Wolf, Dieter/0000-0002-3761-1070; Houseman, Eugene Andres/0000-0003-0703-1830 FU NCRR NIH HHS [S10 RR019028]; NIEHS NIH HHS [ES-00002, P30 ES000002]; NIGMS NIH HHS [GM59780, R01 GM059780] NR 43 TC 77 Z9 79 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD FEB PY 2007 VL 3 AR 79 DI 10.1038/msb4100117 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 141IF UT WOS:000244571300003 PM 17299416 ER PT J AU Liu, GM Chen, YH He, XH Martins, I Heth, JA Chiorini, JA Davidson, BL AF Liu, Gumei Chen, Yong Hong He, Xiaohua Martins, Ines Heth, Jason A. Chiorini, John A. Davidson, Beverly L. TI Adeno-associated virus type 5 reduces learning deficits and restores glutamate receptor subunit levels in MPS VII mice CNS SO MOLECULAR THERAPY LA English DT Article ID MUCOPOLYSACCHARIDOSIS TYPE-VII; CENTRAL-NERVOUS-SYSTEM; MEDIATED GENE-TRANSFER; LYSOSOMAL STORAGE DISEASE; BETA-GLUCURONIDASE GENE; MURINE MODEL; FUNCTIONAL CORRECTION; SPATIAL MEMORY; SIALIC-ACID; LONG-TERM AB A major challenge in treating lysosomal storage diseases with enzyme therapy is correcting symptoms in the central nervous system (CNS). This study used a murine model of mucopolysaccharidosis type VII ( MPS VII) to test whether pathological and functional CNS defects could be corrected by expressing beta-glucuronidase via bilateral intrastriatal injection of adeno-associated virus type 5 (AAV5 beta gluc) vectors. After injecting AAV5 beta gluc, different brain regions expressed active beta-glucuronidase, which corrected lysosomal storage defects. Compared to age-matched littermates, adult MPS VII mice were impaired in spatial learning and memory, as measured by the repeated acquisition and performance chamber (RAPC). AAV5 beta gluc-treated MPS VII mice improved significantly in the RAPC assay, relative to saline-injected littermates. Moreover, our studies reveal that cognitive changes in MPS VII mice correlate with decreased N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptor expression. Importantly, AAV5 beta gluc delivery restored glutamate receptor levels. Together, these data demonstrate that AAV5 vectors deliver a therapeutically effective beta-glucuronidase gene to the CNS and further suggest a possible mechanism underlying spatial learning defects in MPS VII mice. C1 Univ Iowa, Program Gene Therapy, Dept Internal Med, Iowa City, IA 52242 USA. Univ Michigan, Dept Neurosurg, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Neurol, Iowa City, IA 52242 USA. Univ Iowa, Dept Physiol & Biophys, Iowa City, IA 52242 USA. RP Davidson, BL (reprint author), Univ Iowa, Program Gene Therapy, Dept Internal Med, 200 EMRB, Iowa City, IA 52242 USA. EM beverly-davidson@uiowa.edu FU NICHD NIH HHS [HD33531] NR 42 TC 19 Z9 20 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD FEB PY 2007 VL 15 IS 2 BP 242 EP 247 DI 10.1038/sj.mt.6300016 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 139AU UT WOS:000244405200005 PM 17235300 ER PT J AU Lupu, VD Mora, CA Dambrosia, J Meer, J Dalakas, M Floeter, MK AF Lupu, Vitalie D. Mora, Carlos A. Dambrosia, Jim Meer, Jacob Dalakas, Marinos Floeter, Mary Kay TI Terminal latency index in neuropathy with antibodies against myelin-associated glycoproteins SO MUSCLE & NERVE LA English DT Article; Proceedings Paper CT 52nd Annual Scientific Meeting of the American-of-Neuromuscular-and-Electrodiagnostic-Medicine CY SEP 21-24, 2005 CL Monterey, CA SP Amer Assoc Neuromuscular & Elect Med DE anti-MAG antibodies; Charcot-Marie-Tooth disease; chronic demyelinating inflammatory polyneuropathy; demyelinating neuropathy; monoclonal gammopathy; terminal latency index ID MARIE-TOOTH-DISEASE; ANTI-MAG ANTIBODIES; INFLAMMATORY DEMYELINATING POLYNEUROPATHY; CARPAL-TUNNEL SYNDROME; DIFFERENTIAL-DIAGNOSIS; HEREDITARY NEUROPATHY; PERIPHERAL NEUROPATHY; IGM PARAPROTEINEMIA; RESIDUAL LATENCY; SGPG ANTIBODIES AB Neuropathy with antibodies against myelin-associated glycoproteins (MAG/SGPG-N) and hereditary sensorimotor neuropathy type 1 (HMSN1) are characterized by chronic demyelination with little conduction block. Electrodiagnostic studies suggest that in HMSN1 conduction slowing occurs uniformly along the nerve, whereas in MAG/SGPG-N it is predominantly distal. Some but not all previous reports have shown that the terminal latency index (TLI) was useful to distinguish MAG/SGPG-N from chronic idiopathic demyelinating polyneuropathy. We compared median TLI from 21 patients with MAG/SGPG-N with those obtained from 26 patients with HMSN1, 20 with HMSN2, and 12 healthy volunteers. All patients with TLI < 0.26 had MAG/SGPG-N, and all patients with TLI >= 0.32 had HMSN1. In the remaining patients with intermediate TLI values, ulnar distal motor latency (DML) aided in differentiation between MAG/SGPG-N and HMSN1 with an overall sensitivity of 100% and specificity of 98%. In conclusion, median TLI in combination with ulnar DML can further guide the demyelinating neuropathy evaluation toward hereditary or autoimmune causes. C1 NINDS, EMG Sect, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuromuscular Sect, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), NINDS, EMG Sect, NIH, Bldg 10,CRC7-5680,10 Ctr Dr, Bethesda, MD 20892 USA. EM floeter@ninds.nih.gov FU Intramural NIH HHS NR 36 TC 17 Z9 17 U1 0 U2 3 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 FEB PY 2007 VL 35 IS 2 BP 196 EP 202 DI 10.1002/mus.20678 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 132LM UT WOS:000243944300008 PM 17068765 ER PT J AU Keiser, MJ Roth, BL Armbruster, BN Ernsberger, P Irwin, JJ Shoichet, BK AF Keiser, Michael J. Roth, Bryan L. Armbruster, Blaine N. Ernsberger, Paul Irwin, John J. Shoichet, Brian K. TI Relating protein pharmacology by ligand chemistry SO NATURE BIOTECHNOLOGY LA English DT Article ID SIMILARITY COEFFICIENTS; RECEPTORS; BINDING; DESCRIPTORS; METHADONE; DRUGS; MOLECULES; DATABASES; TARGETS; CELLS AB The identification of protein function based on biological information is an area of intense research. Here we consider a complementary technique that quantitatively groups and relates proteins based on the chemical similarity of their ligands. We began with 65,000 ligands annotated into sets for hundreds of drug targets. The similarity score between each set was calculated using ligand topology. A statistical model was developed to rank the significance of the resulting similarity scores, which are expressed as a minimum spanning tree to map the sets together. Although these maps are connected solely by chemical similarity, biologically sensible clusters nevertheless emerged. Links among unexpected targets also emerged, among them that methadone, emetine and loperamide ( Imodium) may antagonize muscarinic M3, alpha 2 adrenergic and neurokinin NK2 receptors, respectively. These predictions were subsequently confirmed experimentally. Relating receptors by ligand chemistry organizes biology to reveal unexpected relationships that may be assayed using the ligands themselves. C1 Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Durham, NC 27705 USA. Univ N Carolina, Sch Med, Div Med Chem & Nat Prod BLR, Durham, NC 27705 USA. RP Irwin, JJ (reprint author), Univ Calif San Francisco, Dept Pharmaceut Chem, 1700 4th St, San Francisco, CA 94143 USA. EM irwin@cgl.ucsf.edu; shoichet@cgl.ucsf.edu RI Roth, Bryan/F-3928-2010; Ernsberger, Paul/O-2702-2014; Keiser, Michael/F-2825-2016; OI Ernsberger, Paul/0000-0003-2372-2500; Keiser, Michael/0000-0002-1240-2192; Irwin, John/0000-0002-1195-6417 FU NIGMS NIH HHS [F32-GM074554, GM67547, GM71896] NR 49 TC 577 Z9 598 U1 3 U2 64 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD FEB PY 2007 VL 25 IS 2 BP 197 EP 206 DI 10.1038/nbt1284 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 134DV UT WOS:000244064000025 PM 17287757 ER PT J AU Mikule, K Delaval, B Kaldis, P Jurcyzk, A Hergert, P Doxsey, S AF Mikule, Keith Delaval, Benedicte Kaldis, Philipp Jurcyzk, Agata Hergert, Polla Doxsey, Stephen TI Loss of centrosome integrity induces p38-p53-p21dependent G1-S arrest SO NATURE CELL BIOLOGY LA English DT Article ID CELL-CYCLE PROGRESSION; CENTRIOLE DUPLICATION; C-ELEGANS; S-PHASE; MICROTUBULE NUCLEATION; CANCER PROGRESSION; TUMOR SUPPRESSION; MAMMALIAN-CELLS; DNA-DAMAGE; PROTEIN AB Centrosomes organize the microtubule cytoskeleton for both interphase and mitotic functions. They are implicated in cell-cycle progression but the mechanism is unknown. Here, we show that depletion of 14 out of 15 centrosome proteins arrests human diploid cells in G1 with reduced Cdk2-cyclin A activity and that expression of a centrosome-disrupting dominant-negative construct gives similar results. Cell-cycle arrest is always accompanied by defects in centrosome structure and function (for example, duplication and primary cilia assembly). The arrest occurs from within G1, excluding contributions from mitosis and cytokinesis. The arrest requires p38, p53 and p21, and is preceded by p38-dependent activation and centrosomal recruitment of p53. p53-deficient cells fail to arrest, leading to centrosome and spindle dysfunction and aneuploidy. We propose that loss of centrosome integrity activates a checkpoint that inhibits G1-S progression. This model satisfies the definition of a checkpoint in having three elements: a perturbation that is sensed, a transducer (p53) and a receiver (p21). C1 Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. NCI, Frederick, MD 21702 USA. RP Doxsey, S (reprint author), Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. EM Stephen.Doxsey@umassmed.edu RI Kaldis, Philipp/G-2714-2010 OI Kaldis, Philipp/0000-0002-7247-7591 FU Intramural NIH HHS; NIGMS NIH HHS [GM51994] NR 49 TC 157 Z9 158 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 EI 1476-4679 J9 NAT CELL BIOL JI Nat. Cell Biol. PD FEB PY 2007 VL 9 IS 2 BP 160 EP U49 DI 10.1038/ncb1529 PG 18 WC Cell Biology SC Cell Biology GA 131WR UT WOS:000243903000008 PM 17330329 ER PT J AU Buey, RM Calvo, E Barasoain, I Pineda, O Edler, MC Matesanz, R Cerezo, G Vanderwal, CD Day, BW Sorensen, EJ Lopez, JA Andreu, JM Hamel, E Diaz, JF AF Buey, Ruben M. Calvo, Enrique Barasoain, Isabel Pineda, Oriol Edler, Michael C. Matesanz, Ruth Cerezo, Gemma Vanderwal, Christopher D. Day, Billy W. Sorensen, Erik J. Lopez, Juan Antonio Andreu, Jose Manuel Hamel, Ernest Diaz, J. Fernando TI Cyclostreptin binds covalently to microtubule pores and lumenal taxoid binding sites SO NATURE CHEMICAL BIOLOGY LA English DT Article ID ANTIMITOTIC SUBSTANCE; BETA-TUBULIN; CANCER-CELLS; GDP-TUBULIN; THERMODYNAMICS; FR182877; CYTOTOXICITY; EPOTHILONE; RESISTANCE; INHIBITOR AB Cyclostreptin ( 1), a natural product from Streptomyces sp. 9885, irreversibly stabilizes cellular microtubules, causes cell cycle arrest, evades drug resistance mediated by P- glycoprotein in a tumor cell line and potently inhibits paclitaxel binding to microtubules, yet it only weakly induces tubulin assembly. In trying to understand this paradox, we observed irreversible binding of synthetic cyclostreptin to tubulin. This results from formation of covalent crosslinks to beta- tubulin in cellular microtubules and microtubules formed from purified tubulin in a 1: 1 total stoichiometry distributed between Thr220 ( at the outer surface of a pore in the microtubule wall) and Asn228 ( at the lumenal paclitaxel site). Unpolymerized tubulin was only labeled at Thr220. Thus, the pore region of beta- tubulin is an undescribed binding site that ( i) elucidates the mechanism by which taxoid-site compounds reach the kinetically unfavorable lumenal site and ( ii) explains how taxoid-site drugs induce microtubule formation from dimeric and oligomeric tubulin. C1 CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. Ctr Nacl Invest Cardiovasc, Unidad Proteom, Madrid 28029, Spain. Univ Barcelona, Fac Quim, Dept Quim Organ, E-08028 Barcelona, Spain. NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA. PharmaMar SA, Colmenar Viejo 28770, Spain. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15261 USA. Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. RP Diaz, JF (reprint author), CSIC, Ctr Invest Biol, Ramiro Maeztu 9, E-28040 Madrid, Spain. EM fer@cib.csic.es RI Martinez-Buey, Ruben/K-4296-2014; Lopez, Juan Antonio/G-7750-2015; OI Martinez-Buey, Ruben/0000-0003-1263-0221; Lopez, Juan Antonio/0000-0002-9097-6060; Andreu, Jose M/0000-0001-8064-6933; Diaz, J. Fernando/0000-0003-2743-3319 NR 31 TC 88 Z9 91 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD FEB PY 2007 VL 3 IS 2 BP 117 EP 125 DI 10.1038/nchembio853 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 128UZ UT WOS:000243685800016 PM 17206139 ER PT J AU Herzka, DA Gharib, AM AF Herzka, Daniel A. Gharib, Ahmed M. TI Should all patients with suspected coronary artery disease undergo coronary angiography with 16-row MDCT? SO NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE LA English DT Editorial Material DE coronary angiography; coronary artery disease; diagnosis; imaging; multidetector CT ID COMPUTED-TOMOGRAPHY; ACCURACY AB BACKGROUND Coronary angiography is currently the best diagnostic test for suspected coronary artery disease (CAD), but the risks and patient discomfort associated with this procedure have encouraged research into less invasive alternatives. Multidetector CT (MDCT) has emerged as an effective means of assessing the coronary arteries, but until recently has only been evaluated in single-center studies. OBJECTIVES To evaluate the sensitivity and specificity of 16-row MDCT in the diagnosis of CAD. DESIGN The Coronary Assessment by Computed Tomographic Scanning and Catheter Angiography (CATSCAN) trial was a prospective study conducted at centers in Argentina, Germany, Israel, Japan, The Netherlands, UK, (one center each) and US (five centers) between June 2004 and March 2005. Patients aged 30-70 years scheduled to have coronary angiography for evaluation of chest pain or because of suspected CAD were enrolled in this study. Patients who had undergone previous CABG surgery and women of reproductive age were not enrolled. Other exclusion criteria included the presence of a cardiac pacemaker or defibrillator, renal insufficiency, diabetes requiring medication, a BMI greater than 40, myocardial infarction within the 30 days before enrollment, and contraindications to iodine contrast or beta-blockers. INTERVENTION Initially, a noncontrast MDCT was performed to assess the extent of coronary artery calcification. Patients with an Agatston calcium score of less than 600 then underwent 16-row MDCT coronary angiography with iodine contrast-enhancement. Standard angiography was carried out in all patients 1-14 days after MDCT. OUTCOME MEASURES The main outcomes were segment-based and patient-based sensitivity and specificity for the detection of coronary artery stenosis (CAS) of more than 50% and more than 70% of luminal diameter. RESULTS Among the 238 patients enrolled in the study (mean age 60 years, 68% were male), 187 had a calcium score of less than 600 and underwent analysis. In total, 1,629 nonstented coronary artery segments with a diameter of more than 2 mm were identified. Stenosis of more than 50% was detected by standard coronary angiography in 89 segments in 59 of the 187 patients. In total, 1,157 (71%) of the 1,629 segments were successfully evaluated by MDCT; sensitivity and specificity for identifying stenosis of more than 50% were 89% (95% CI 82-95%) and 65% (95% CI 62-67%), respectively. The positive predictive value was 13% (95% CI 10-15%) and the negative predictive value was 99% (95% CI 98-100%). The sensitivity and specificity of MDCT for identifying stenosis of more than 70% were 94% (95% CI 87-100%) and 67% (95% CI 65-70%), respectively, with a positive predictive value of 6% (95% CI 4-6%) and a negative predictive value of 99% (95% CI 98-100%). CONCLUSION The authors concluded that while MDCT could have clinical application in selected patients with inconclusive stress-test results, it should not be adopted as a routine first-line diagnostic test in all patients with suspected CAD. C1 NIH, Clin Res Ctr, Bethesda, MD 20892 USA. Philips Res N Amer, Clin Sites Res Program, Briarcliff Manor, NY USA. RP Gharib, AM (reprint author), NIH, Clin Res Ctr, Room 3-5340,Bldg 10,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@nhlbi.nih.gov RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Herzka, Daniel/0000-0002-9400-7814 NR 5 TC 3 Z9 3 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1743-4297 J9 NAT CLIN PRACT CARD JI Nat. Clin. Pract. Cardiovasc. Med. PD FEB PY 2007 VL 4 IS 2 BP 74 EP 75 DI 10.1038/ncpcardio0777 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 129KY UT WOS:000243729600006 PM 17245400 ER PT J AU Yanovski, JA AF Yanovski, Jack A. TI How effective is sibutramine for the treatment of overweight adolescents? SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material DE adolescent; overweight; sibutramine; weight-loss ID OBESE ADOLESCENTS; TRIAL C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,Hatfield Clin Res Ctr, Room 1E-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999] NR 6 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD FEB PY 2007 VL 3 IS 2 BP 82 EP 83 DI 10.1038/ncpendmet0390 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 128UU UT WOS:000243685300004 PM 17237832 ER PT J AU Pacak, K Eisenhofer, G Ahlman, H Bornstein, SR Gimenez-Roqueplo, AP Grossman, AB Kimura, N Mannelli, M McNicol, AM Tischler, AS AF Pacak, Karel Eisenhofer, Graeme Ahlman, Hakan Bornstein, Stefan R. Gimenez-Roqueplo, Anne-Paule Grossman, Ashley B. Kimura, Noriko Mannelli, Massimo McNicol, Anne Marie Tischler, Arthur S. TI Pheochromocytoma: recommendations for clinical practice from the First International Symposium SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Review DE diagnosis; genetics; localization; paraganglioma; pheochromocytoma ID HIPPEL-LINDAU-DISEASE; ENDOCRINE NEOPLASIA TYPE-2A; TANDEM MASS-SPECTROMETRY; GERM-LINE MUTATIONS; MALIGNANT PHEOCHROMOCYTOMA; FAMILIAL PHEOCHROMOCYTOMA; METAIODOBENZYLGUANIDINE I-131-MIBG; HEREDITARY PHEOCHROMOCYTOMA; DETECTING PHEOCHROMOCYTOMA; SPORADIC PHEOCHROMOCYTOMAS AB The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity. Localization studies should only follow reasonable clinical evidence of a tumor. Preoperative pharmacologic blockade of circulatory responses to catecholamines is mandatory. Because approximately a quarter of tumors develop secondary to germ-line mutations in any one of five genes, mutation testing should be considered; however, it is not currently cost effective to test every gene in every patient. Consideration of tumor location, presence of multiple tumors, presence of metastases, and type of catecholamine produced is useful in deciding which genes to test. Inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution. C1 NICHD, NIH, Bethesda, MD USA. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden. Carl Gustav Carus Univ Hosp, Dept Med, Dresden, Germany. Univ Paris Descartes, Hosp Europeen Georges Pompidou, Assistance Publ Hop Paris, Paris, France. St Bartholomews Hosp Barts & London Sch Med, Dept Endocrinol, London, England. Tohoku Rosai Hosp, Sendai, Miyagi, Japan. Univ Florence, Dept Clin Pathophysiol, Florence, Italy. Univ Glasgow, Glasgow, Lanark, Scotland. Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Tischler, AS (reprint author), Tufts Univ New England Med Ctr, Dept Pathol, 750 Washington St, Boston, MA 02111 USA. EM atischler@tufts-nemc.org OI Mannelli, Massimo/0000-0002-8001-9857 NR 80 TC 310 Z9 336 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD FEB PY 2007 VL 3 IS 2 BP 92 EP 102 DI 10.1038/ncpendmet0396 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 128UU UT WOS:000243685300009 PM 17237836 ER PT J AU Mellins, ED Rider, LG AF Mellins, Elizabeth D. Rider, Lisa G. TI Clinical research networks: a step towards evidence-based practice in pediatric rheumatology SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Editorial Material C1 Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. RP Mellins, ED (reprint author), Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. OI Rider, Lisa/0000-0002-6912-2458 NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8382 J9 NAT CLIN PRACT RHEUM JI Nat. Clin. Pract. Rheumatol. PD FEB PY 2007 VL 3 IS 2 BP 59 EP 59 DI 10.1038/ncprheum0405 PG 1 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 132UA UT WOS:000243966500001 PM 17299440 ER PT J AU Srinivasan, R Linehan, WM AF Srinivasan, Ramaprasad Linehan, W. Marston TI Antiangiogenic therapy in renal cell carcinoma: from concept to reality SO NATURE CLINICAL PRACTICE UROLOGY LA English DT Editorial Material DE renal cancer; response; safety; sunitinib; vascular endothelial growth factor ID TRIAL C1 NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Ctr Canc Res, Urol Oncol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wml@mail.nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4270 J9 NAT CLIN PRACT UROL JI Nat. Clin. Pract. Urol. PD FEB PY 2007 VL 4 IS 2 BP 74 EP 75 DI 10.1038/ncpuro0705 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 133GZ UT WOS:000244002700006 PM 17287865 ER PT J AU Sudarshan, S Pinto, PA Neckers, L Linehan, WM AF Sudarshan, Sunil Pinto, Peter A. Neckers, Len Linehan, W. Marston TI Mechanisms of Disease: hereditary leiomyomatosis and renal cell cancer - a distinct form of hereditary kidney cancer SO NATURE CLINICAL PRACTICE UROLOGY LA English DT Review DE hereditary kidney cancer; hereditary leiomyomatosis and renal cell cancer; kidney cancer; renal cell carcinoma ID TUMOR-SUPPRESSOR GENE; HYPOXIA-INDUCIBLE GENES; FUMARATE-HYDRATASE; HIF-ALPHA; FH MUTATIONS; PARAGANGLIOMA; VHL; MITOCHONDRIAL; CARCINOMA; FAMILIES AB Renal cell carcinoma (RCC) represents a group of diseases linked by their primary site of origin, the kidney. Studies of families with a genetic predisposition to the development of kidney cancer have revealed that multiple genes are involved in the molecular pathogenesis of RCC. Germline mutations in a gene that encodes a Krebs cycle enzyme have been found to result in a distinct clinical entity referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is inherited in an autosomal-dominant fashion. Affected individuals in HLRCC families are at risk for the development of leiomyomas of the skin and uterus as well as renal cancers. HLRCC-associated kidney tumors are often biologically aggressive. Linkage analysis has identified germline alterations in the fumarate hydratase (FH) gene associated with HLRCC. While the mechanisms of molecular carcinogenesis are not entirely understood, several lines of evidence derived from clinical and basic research suggest that pseudohypoxia might drive cellular transformation. The role of FH mutations in sporadic tumors seems to be limited. Nevertheless, continued investigation of HLRCC should provide further insight into the mechanisms of kidney cancer development, and could potentially identify targets for new therapeutic approaches to RCC. C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, 10 Ctr Dr MSC 1107,Bldg 10 CRC,Room 1-5940, Bethesda, MD 20892 USA. EM linehanm@mail.nih.gov FU Intramural NIH HHS NR 37 TC 22 Z9 22 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4270 J9 NAT CLIN PRACT UROL JI Nat. Clin. Pract. Urol. PD FEB PY 2007 VL 4 IS 2 BP 104 EP 110 DI 10.1038/ncpuro0711 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 133GZ UT WOS:000244002700012 PM 17287871 ER PT J AU Xia, B Dorsman, JC Ameziane, N de Vries, Y Rooimans, MA Sheng, Q Pals, G Errami, A Gluckman, E Llera, J Wang, W Livingston, DM Joenje, H de Winter, JP AF Xia, Bing Dorsman, Josephine C. Ameziane, Najim de Vries, Yne Rooimans, Martin A. Sheng, Qing Pals, Gerard Errami, Abdellatif Gluckman, Eliane Llera, Julian Wang, Weidong Livingston, David M. Joenje, Hans de Winter, Johan P. TI Fanconi anemia is associated with a defect in the BRCA2 partner PALB2 SO NATURE GENETICS LA English DT Article AB The Fanconi anemia and BRCA networks are considered interconnected, as BRCA2 gene defects have been discovered in individuals with Fanconi anemia subtype D1. Here we show that a defect in the BRCA2- interacting protein PALB2 is associated with Fanconi anemia in an individual with a new subtype. PALB2- deficient cells showed hypersensitivity to cross- linking agents and lacked chromatin- bound BRCA2; these defects were corrected upon ectopic expression of PALB2 or by spontaneous reversion. C1 Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. MRC Holland BV, NL-1057 SN Amsterdam, Netherlands. Hop St Louis, Bone Marrow Transplant Unit, F-75475 Paris 10, France. Hosp Italiano Buenos Aires, Dept Pediat, Buenos Aires, DF, Argentina. NIA, Genet Lab, US Natl Inst Hlth, Baltimore, MD 21224 USA. RP de Winter, JP (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Van Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM David_Livingston@dfci.harvard.edu; j.dewinter@vumc.nl RI Pals, Gerard/A-5198-2011 FU Intramural NIH HHS NR 13 TC 256 Z9 260 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2007 VL 39 IS 2 BP 159 EP 161 DI 10.1038/ng1942 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 134DU UT WOS:000244063900011 PM 17200672 ER PT J AU Hackett, CJ Rotrosen, D Auchincloss, H Fauci, AS AF Hackett, Charles J. Rotrosen, Daniel Auchincloss, Hugh Fauci, Anthony S. TI Immunology research: challenges and opportunities in a time of budgetary constraint SO NATURE IMMUNOLOGY LA English DT Editorial Material ID TOLL-LIKE RECEPTORS; ANTIVIRAL RESPONSES; B-CELLS; BACTERIA; IMMUNITY; NAIVE AB There have been enormous advances in the field of immunology over the past 3 decades, and those advances have had a positive effect on many subspecialties of medicine. Opportunities for even more notable advances remain. However, present and projected budget constraints for the National Institutes of Health have created formidable challenges. This commentary addresses the opportunities and challenges for the field of immunology during a period of restricted budgets. C1 NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hackett, CJ (reprint author), NIAID, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM chackett@niaid.nih.gov OI Hackett, Charles/0000-0003-4586-9669 NR 28 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2007 VL 8 IS 2 BP 114 EP 117 DI 10.1038/ni0207-114 PG 4 WC Immunology SC Immunology GA 127PA UT WOS:000243597600003 PM 17242679 ER PT J AU Round, JL Humphries, LA Tomassian, T Mittelstadt, P Zhang, M Miceli, MC AF Round, June L. Humphries, Lisa A. Tomassian, Tamar Mittelstadt, Paul Zhang, Min Miceli, M. Carrie TI Scaffold protein Dlgh1 coordinates alternative p38 kinase activation, directing T cell receptor signals toward NFAT but not NF-kappa B transcription factors SO NATURE IMMUNOLOGY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; IMMUNE-RESPONSES; NUCLEAR FACTOR; IMMUNOLOGICAL SYNAPSE; LYMPHOCYTE-ACTIVATION; ACTIN POLYMERIZATION; PLASMA-MEMBRANE; GENE-EXPRESSION; MAGUK FAMILY; C-THETA AB Tyrosine kinases couple the T cell receptor (TCR) to discrete signaling cascades, each of which is capable of inducing a distinct functional outcome. Precisely how TCR signals are channeled toward specific targets remains unclear. TCR stimulation triggers 'alternative' activation of the mitogen-activated protein kinase p38, whereby the Lck and Zap70 tyrosine kinases directly activate p38. Here we report that alternatively activated p38 associated with the Dlgh1 MAGUK scaffold protein. 'Knockdown' of Dlgh1 expression blocked TCR-induced activation of p38 and the transcription factor NFAT but not of the mitogen-activated protein kinase Jnk or transcription factor NF-kappa B. A Dlgh1 mutant incapable of binding p38 failed to activate NFAT. Along with reports that the CARMA1 MAGUK scaffold protein coordinates activation of Jnk and NF-kappa B but not of p38 or NFAT, our findings identify MAGUK scaffold proteins as 'orchestrators' of TCR signal specificity. C1 Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90066 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90066 USA. NCI, Ctr Canc Res, Lab Immune Cell Biol, Bethesda, MD 20892 USA. RP Miceli, MC (reprint author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90066 USA. EM cmiceli@ucla.edu FU NCI NIH HHS [CA-16042]; NIAID NIH HHS [AI-28697, 2-T32-AI07323, AI07126-30]; NIGMS NIH HHS [T32 GM007185, GM07185]; PHS HHS [R01A1056155] NR 49 TC 68 Z9 70 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2007 VL 8 IS 2 BP 154 EP 161 DI 10.1038/ni1422 PG 8 WC Immunology SC Immunology GA 127PA UT WOS:000243597600013 PM 17187070 ER PT J AU Li, B Scarselli, M Knudsen, CD Kim, SK Jacobson, KA McMillin, SM Wess, J AF Li, Bo Scarselli, Marco Knudsen, Christopher D. Kim, Soo-Kyung Jacobson, Kenneth A. McMillin, Sara M. Wess, Juergen TI Rapid identification of functionally critical amino acids in a G protein-coupled receptor SO NATURE METHODS LA English DT Article ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; MUTANT M-3 RECEPTOR; RANDOM MUTAGENESIS; 7-TRANSMEMBRANE RECEPTORS; SACCHAROMYCES-CEREVISIAE; YEAST; ACTIVATION; LOCALIZATION; CONSTRUCTION; MUTATIONS AB G protein-coupled receptors (GPCRs) comprise one of the largest protein families found in nature. Here we describe a new experimental strategy that allows rapid identification of functionally critical amino acids in the rat M-3 muscarinic acetylcholine receptor (M3R), a prototypic class I GPCR. This approach involves low-frequency random mutagenesis of the entire M3R coding sequence, followed by the application of a new yeast genetic screen that allows the recovery of inactivating M3R single point mutations. The vast majority of recovered mutant M3Rs also showed substantial functional impairments in transfected mammalian (COS-7) cells. A subset of mutant receptors, however, behaved differently in yeast and mammalian cells, probably because of the specific features of the yeast expression system used. The screening strategy described here should be applicable to all GPCRs that can be expressed functionally in yeast. C1 NIDDKD, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Scarselli, Marco/0000-0001-5087-3182 FU Intramural NIH HHS NR 29 TC 36 Z9 36 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD FEB PY 2007 VL 4 IS 2 BP 169 EP 174 DI 10.1038/nmeth990 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 133FJ UT WOS:000243998100020 PM 17206152 ER PT J AU Isoda, M Hikosaka, O AF Isoda, Masaki Hikosaka, Okihide TI Switching from automatic to controlled action by monkey medial frontal cortex SO NATURE NEUROSCIENCE LA English DT Article ID PRESUPPLEMENTARY MOTOR AREA; SUPPLEMENTARY EYE FIELD; MEMORY-GUIDED SACCADES; NEURONAL-ACTIVITY; ELECTRICAL-STIMULATION; MACAQUE MONKEY; SUBTHALAMIC NUCLEUS; RESPONSE-CONFLICT; BASAL GANGLIA; PRE-SMA AB Human behavior is mostly composed of habitual actions that require little conscious control. Such actions may become invalid if the environment changes, at which point individuals need to switch behavior by overcoming habitual actions that are otherwise triggered automatically. It is unknown how the brain controls this type of behavioral switching. Here we show that the presupplementary motor area ( pre- SMA) in the medial frontal cortex has a function in switching from automatic to volitionally controlled action in rhesus macaque monkeys. We found that a group of pre- SMA neurons was selectively activated when subjects successfully switched to a controlled alternative action. Electrical stimulation in the pre- SMA replaced automatic incorrect responses with slower correct responses. A further test suggested that the pre- SMA enabled switching by first suppressing an automatic unwanted action and then boosting a controlled desired action. Our data suggest that the pre- SMA resolves response conflict so that the desired action can be selected. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Isoda, M (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM isodam@nei.nih.gov FU Intramural NIH HHS NR 49 TC 250 Z9 253 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2007 VL 10 IS 2 BP 240 EP 248 DI 10.1038/nn1830 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 135TB UT WOS:000244175200019 PM 17237780 ER PT J AU Dorsam, RT Gutkind, JS AF Dorsam, Robert T. Gutkind, J. Silvio TI G-protein-coupled receptors and cancer SO NATURE REVIEWS CANCER LA English DT Review ID CELL LUNG-CANCER; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BETA-CATENIN STABILIZATION; METASTASIS-SUPPRESSOR GENE; HETEROTRIMERIC G-PROTEINS; EPIDERMAL-GROWTH-FACTOR; BREAST-CANCER; PROSTATE-CANCER; COLORECTAL-CANCER; COLON-CANCER AB G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU Intramural NIH HHS NR 153 TC 553 Z9 569 U1 8 U2 89 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2007 VL 7 IS 2 BP 79 EP 94 DI 10.1038/nrc2069 PG 16 WC Oncology SC Oncology GA 130HH UT WOS:000243790200011 PM 17251915 ER PT J AU Kummar, S Kinders, R Rubinstein, L Parchment, RE Murgo, AJ Collins, J Pickeral, O Low, J Steinberg, SM Gutierrez, M Yang, S Helman, L Wiltrout, R Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Kinders, Robert Rubinstein, Larry Parchment, Ralph E. Murgo, Anthony J. Collins, Jerry Pickeral, Oxana Low, Jennifer Steinberg, Seth M. Gutierrez, Martin Yang, Sherry Helman, Lee Wiltrout, Robert Tomaszewski, Joseph E. Doroshow, James H. TI Compressing drug development timelines in oncology using phase '0' trials SO NATURE REVIEWS CANCER LA English DT Article ID CLINICAL-TRIALS; CANCER; INHIBITOR; THERAPY; DESIGN; AGENTS; TUMORS AB The optimal evaluation of molecularly targeted anticancer agents requires the integration of pharmacodynamic assays into early clinical investigations. Phase '0' trials conducted under the new Exploratory Investigational New Drug Guidance from the US Food and Drug Administration can provide a platform to establish the feasibility of assays for target modulation in human samples, evaluate biomarkers for drug effects and provide pharmacokinetic data. Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and might compress timelines for anticancer drug development. We expect that such trials will become a routine part of early-phase oncological drug development in the future. C1 NCI, Ctr Canc Res, SAIC Frederick, Frederick, MD 21701 USA. NCI, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Ctr Canc Res, SAIC Frederick, Frederick, MD 21701 USA. EM doroshoj@mail.nih.gov NR 21 TC 121 Z9 128 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD FEB PY 2007 VL 7 IS 2 BP 131 EP 139 DI 10.1038/nrc2066 PG 9 WC Oncology SC Oncology GA 130HH UT WOS:000243790200015 PM 17251919 ER PT J AU Guttmacher, AE Porteous, ME McInerney, JD AF Guttmacher, Alan E. Porteous, Mary E. McInerney, Joseph D. TI Educating health-care professionals about genetics and genomics SO NATURE REVIEWS GENETICS LA English DT Review ID BREAST-CANCER SUSCEPTIBILITY; KNOWLEDGE; SEQUENCE; PATTERNS; SERVICES AB To biomedical researchers, this is the 'genome era'. Advances in genetics and genomics such as the sequence of the human genome, the human haplotype map, open access databases, cheaper genotyping and chemical genomics have already transformed basic and translational biomedical research. However, for most clinicians, the genome era has not yet arrived. For genomics to have an effect on clinical practice that is comparable to its impact on research will require advances in the genomic literacy of health-care providers. Here we describe the knowledge, skills and attitudes that genomic medicine will require, and approaches to integrate them into the health-care community. C1 NHGRI, Bethesda, MD 20892 USA. Western Gen Hosp, SE Scotland Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. Natl Coalit Hlth Profess Educ Genet, Lutherville Timonium, MD 21093 USA. RP Guttmacher, AE (reprint author), NHGRI, Bldg 31,Room 4Bop, Bethesda, MD 20892 USA. EM guttmach@mail.nih.gov NR 27 TC 145 Z9 153 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD FEB PY 2007 VL 8 IS 2 BP 151 EP U6 DI 10.1038/nrg2007 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 126VU UT WOS:000243544400015 PM 17230201 ER PT J AU Mazzucchelli, R Durum, SK AF Mazzucchelli, Renata Durum, Scott K. TI Interleukin-7 receptor expression: intelligent design SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID T-CELL DEVELOPMENT; COMMON LYMPHOID PROGENITORS; THYMIC STROMAL LYMPHOPOIETIN; MOUSE BONE-MARROW; PRO-B CELLS; IL-7 RECEPTOR; ALPHA-CHAIN; DEFICIENT MICE; MEMORY CELLS; IN-VIVO AB Interleukin-7 (IL-7) is produced by stromal cells in lymphoid tissues and is required for the development of T cells and for their persistence in the periphery. Unlike many other cytokines that act on lymphocytes, IL-7 production by stromal cells is not substantially affected by extrinsic stimuli. So, the amount of available IL-7 protein is thought to be regulated by the rate that it is scavenged by T cells. As we review here, there is mounting evidence indicating that the amount of IL-7 receptor expressed on a cell not only determines how vigorously the cell responds to IL-7, but it can also determine how efficiently the cell consumes IL-7 and, therefore, affect the supply of this limiting resource in the niche. C1 NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res,NIH, Bldg 56,Room 31-71, Frederick, MD 21702 USA. EM durums@mail.nih.gov NR 116 TC 297 Z9 301 U1 1 U2 10 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 FEB PY 2007 VL 7 IS 2 BP 144 EP 154 DI 10.1038/nri2023 PG 11 WC Immunology SC Immunology GA 131AD UT WOS:000243839200013 PM 17259970 ER PT J AU Doyle, SM Shorter, J Zolkiewski, M Hoskins, JR Lindquist, S Wickner, S AF Doyle, Shannon M. Shorter, James Zolkiewski, Michal Hoskins, Joel R. Lindquist, Susan Wickner, Sue TI Asymmetric deceleration of ClpB or Hsp104 ATPase activity unleashes protein-remodeling activity SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID PLUS CHAPERONE CLPB; SACCHAROMYCES-CEREVISIAE HSP104; ESCHERICHIA-COLI; AGGREGATED PROTEINS; BINDING-SITES; SUBSTRATE RECOGNITION; THERMUS-THERMOPHILUS; MOLECULAR CHAPERONE; DISAGGREGATION; DNAK AB Two members of the AAA+ superfamily, ClpB and Hsp104, collaborate with Hsp70 and Hsp40 to rescue aggregated proteins. However, the mechanisms that elicit and underlie their protein-remodeling activities remain unclear. We report that for both Hsp104 and ClpB, mixtures of ATP and ATP-gamma S unexpectedly unleash activation, disaggregation and unfolding activities independent of cochaperones. Mutations reveal how remodeling activities are elicited by impaired hydrolysis at individual nucleotide-binding domains. However, for some substrates, mixtures of ATP and ATP-gamma S abolish remodeling, whereas for others, ATP binding without hydrolysis is sufficient. Remodeling of different substrates necessitates a diverse balance of polypeptide 'holding' (which requires ATP binding but not hydrolysis) and unfolding (which requires ATP hydrolysis). We suggest that this versatility in reaction mechanism enables ClpB and Hsp104 to reactivate the entire aggregated proteome after stress and enables Hsp104 to control prion inheritance. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Kansas State Univ, Dept Biochem, Manhattan, KS 66506 USA. RP Lindquist, S (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM lindquist_admin@wi.mit.edu; wickners@mail.nih.gov RI Shorter, James/E-8207-2011 FU Intramural NIH HHS; NIGMS NIH HHS [GM25874, GM58626, R01 GM025874, R01 GM058626, R37 GM025874] NR 53 TC 90 Z9 91 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD FEB PY 2007 VL 14 IS 2 BP 114 EP 122 DI 10.1038/nsmb1198 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 133RX UT WOS:000244031900009 PM 17259993 ER PT J AU Agarwal, SK Impey, S McWeeney, S Scacheri, PC Collins, FS Goodman, RH Spiegel, AM Marx, SJ AF Agarwal, Sunita K. Impey, Soren McWeeney, Shannon Scacheri, Peter C. Collins, Francis S. Goodman, Richard H. Spiegel, Allen M. Marx, Stephen J. TI Distribution of menin-occupied regions in chromatin specifies a broad role of menin in transcriptional regulation SO NEOPLASIA LA English DT Article DE MEN1; multiple endocrine neoplasia; SACO; chromatin immunoprecipitation; ChIP ID TUMOR-SUPPRESSOR MENIN; HISTONE METHYLTRANSFERASE COMPLEX; HOX GENE-EXPRESSION; TARGET GENES; HUMAN GENOME; FACTOR JUND; IDENTIFICATION; BINDING; PROTEIN; GROWTH AB Menin is the protein product of the MEN1 tumor-suppressor gene; one allele of MEN1 is inactivated in the germ line of patients with "multiple endocrine neoplasia type 1'' (MEN1) cancer syndrome. Menin interacts with several proteins involved in transcriptional regulation. RNA expression analyses have identified several menin-regulated genes that could represent proximal or distal interaction sites for menin. This report presents a substantial and unbiased sampling of menin-occupied chromatin regions using Serial Analysis of Chromatin Occupancy; this method combines chromatin immuno-precipitation with Serial Analysis of Gene Expression. Hundreds of menin-occupied genomic sites were identified in promoter regions (32% of menin-occupied loci), near the 3' end of genes (14%), or inside genes (21%), extending other data about menin recruitments to many sites of transcriptional activity. A large number of menin-occupied sites (33%) were located outside known gene regions. Additional annotation of the human genome could help in identifying genes at these loci, or these might be gene-free regions of the genome where menin occupancy could play some structural or regulatory role. Menin occupancy at many intragenic positions distant from the core promoter reveals an unexpected type of menin target region at many loci in the genome. These unbiased data also suggest that menin could play a broad role in transcriptional regulation. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Inst Canc, Portland, OR 97239 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NIDCD, NIH, Bethesda, MD 20892 USA. RP Agarwal, SK (reprint author), NIDDKD, NIH, Bldg 10,Room 9C-103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sunitaa@mail.nih.gov RI Agarwal, Sunita/D-1428-2016; OI Agarwal, Sunita/0000-0002-7557-3191; McWeeney, Shannon/0000-0001-8333-6607 FU Intramural NIH HHS; NIDDK NIH HHS [DK45423, R37 DK045423] NR 35 TC 32 Z9 33 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD FEB PY 2007 VL 9 IS 2 BP 101 EP 107 DI 10.1593/neo.06706 PG 7 WC Oncology SC Oncology GA 139XN UT WOS:000244466200002 PM 17356705 ER PT J AU Yaffe, K Barnes, D Lindquist, K Cauley, J Simonsick, EM Penninx, B Satterfield, S Harris, T Cummings, SR AF Yaffe, K. Barnes, D. Lindquist, K. Cauley, J. Simonsick, E. M. Penninx, B. Satterfield, S. Harris, T. Cummings, S. R. CA Hlth ABC Investigators TI Endogenous sex hormone levels and risk of cognitive decline in an older biracial cohort SO NEUROBIOLOGY OF AGING LA English DT Article DE cognition; dementia; sex hormones; estrogen ID CENTRAL-NERVOUS-SYSTEM; HEALTH INITIATIVE MEMORY; ESTROGEN-RECEPTOR-ALPHA; BETA-AMYLOID PEPTIDES; POSTMENOPAUSAL WOMEN; ALZHEIMERS-DISEASE; MESSENGER-RNA; ELDERLY-WOMEN; FREE TESTOSTERONE; MEN AB Background: Older women treated with conjugated estrogens may have an increased risk of dementia. but the effect of naturally occurring sex hormones on cognition is not certain. Methods: Bioavailable estradio and free testosterone level were obtained from 792 (55% men, 51% black) participants. We assessed cognition with the Modified Mini-Mental State Examination (3MS). Selective Reminding Test (SRT) and CLOX 1 at baseline and 2 years later. Results: Women in the lowest estradiol tertile were more likely than those in the highest fertile to decline (>= 1.0 S.D. of change) on 3MS (25% versus 9%, adjusted odds ratio [OR] = 3.9; 95% confidence interval [CI] = 1.6-9.6) and on SRT (28% versus 12%, adjusted OR [95% CI] = 3.3 [1.4-7.9]) but not CLOX 1. There was a borderline association between low estradiol tertile and decline on SRT in men (22% versus 14%, adjusted OR [95% CI] = 1.9 [0.0-3.9]). Testosterone level was not associated with decline in cognition in either men or women. Findings did not differ by race. Conclusions: Older women with low estradiol levels were more likely to experience decline in global cognitive function and verbal memory and a similar trend was observec for verbal memory in men. This supports, the hypothesis that endogenous sex hormones may play an important role in the maintenance of cognitive function in older adults. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Geriatr, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA 94121 USA. Univ Pittsburgh, Sch Med, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. NIA, Clin Res Branch, Baltimore, MD 21224 USA. NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, EMGO Inst, NL-1007 MB Amsterdam, Netherlands. Univ Tennessee, Dept Prevent Med, Memphis, TN 38163 USA. Calif Pacific Med Ctr, San Francisco, CA 94107 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Box 181,4150 Clement St, San Francisco, CA 94121 USA. EM Kristine.Yaffe@ucsf.edu RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-2103, N01-AG-2106, N01-AG-6-2101, R01 AG021918-03] NR 47 TC 66 Z9 71 U1 3 U2 4 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 FEB PY 2007 VL 28 IS 2 BP 171 EP 178 DI 10.1016/j.neurobiolaging.2006.10.004 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 128ZK UT WOS:000243698000001 PM 17097195 ER PT J AU Pardue, S Wang, S Miller, MM Morrison-Bogorad, M AF Pardue, S. Wang, S. Miller, M. M. Morrison-Bogorad, M. TI Elevated levels of inducible heat shock 70 proteins in human brain SO NEUROBIOLOGY OF AGING LA English DT Article DE aging; agonal state; hsp70; heat shock genes; human brain; postmortem interval ID HEAT-SHOCK PROTEINS; FOCAL CEREBRAL-ISCHEMIA; RAT-BRAIN; MESSENGER-RNA; CHAPERONE SUPPRESSION; MOLECULAR CHAPERONES; STRESS TOLERANCE; GENE-EXPRESSION; TRANSGENIC MICE; IN-VITRO AB Differential expression of heat shock genes can modulate protein folding and stress-related cell death. There have been no comparisons of their levels of expression in animals and humans. Levels of expression of heat shock 70 genes in human brain were compared to levels in non-stressed and heat-stressed brain of rat. Levels of hsp70 proteins in human brain were 43-fold higher than in non-stressed rat brain and 14-fold higher than highest induced levels in brains of heat-shocked rats. Levels of constitutively synthesized hsc70 proteins were approximately 1.5-fold higher in human than in rat. Higher levels of hsp70 proteins in human brain may serve to protect brain cells against stress-related death or dysfunction throughout the lifespan. Published by Elsevier Inc. C1 NIA, Neurosci & Neuropsychol Aging Program, Bethesda, MD 20892 USA. NIA, Sect Brain Physiol & Metab, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Dept Pathol, Newark, NJ 07103 USA. RP Morrison-Bogorad, M (reprint author), NIA, Neurosci & Neuropsychol Aging Program, Gateway Bldg,Suite 350, Bethesda, MD 20892 USA. EM morrisom@nia.nih.gov FU NIA NIH HHS [P50 AG08013, AG12297, P30 AG12300] NR 78 TC 9 Z9 9 U1 0 U2 1 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 FEB PY 2007 VL 28 IS 2 BP 314 EP 324 DI 10.1016/j.neurobiolaging.2005.12.001 PG 11 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 128ZK UT WOS:000243698000015 PM 16413087 ER PT J AU Hoepken, HH Gispert, S Morales, B Wingerter, O Del Turco, D Mulsch, A Nussbaum, RL Muller, K Drose, S Brandt, U Deller, T Wirth, B Kudin, AP Kunz, WS Auburger, G AF Hoepken, Hans-Hermann Gispert, Suzana Morales, Blas Wingerter, Oliver Del Turco, Domenico Muelsch, Alexander Nussbaum, Robert L. Mueller, Klaus Droese, Stefan Brandt, Ulrich Deller, Thomas Wirth, Brunhilde Kudin, Alexei P. Kunz, Wolfram S. Auburger, Georg TI Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6 SO NEUROBIOLOGY OF DISEASE LA English DT Article DE malondialdehyde; MnSOD; glutathione; mitochondria; oxidative stress; PINK1; PARK6; fibroblasts ID LEWY BODY DISEASE; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; COMPLEX-I; DOPAMINERGIC-NEURONS; LIPID-PEROXIDATION; ALPHA-SYNUCLEIN; CELL-DEATH; OXIDIZED GLUTATHIONE AB Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine-threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione-S-transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Frankfurt Klinikum, Neurol Clin, Sect Mol Neurogenet, D-60590 Frankfurt, Germany. Univ Hosp San Cecilio, Dept Neurol, Granada, Spain. Univ Frankfurt Klinikum, Inst Clin Neuroanat, Frankfurt, Germany. Univ Frankfurt Klinikum, Ctr Physiol, Frankfurt, Germany. Univ Frankfurt Klinikum, Pediat Clin, Frankfurt, Germany. Univ Frankfurt Klinikum, Ctr Biol Chem, Frankfurt, Germany. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Cologne, Inst Human Genet, Cologne, Germany. Univ Bonn, Dept Epileptol, Bonn, Germany. RP Auburger, G (reprint author), Univ Frankfurt Klinikum, Neurol Clin, Sect Mol Neurogenet, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM auburger@em.uni-frankfurt.de RI Drose, Stefan/E-4903-2010; Brandt, Ulrich/C-4406-2008 OI Drose, Stefan/0000-0002-9361-9034; Brandt, Ulrich/0000-0003-1869-6811 NR 68 TC 124 Z9 127 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 0969-9961 EI 1095-953X J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2007 VL 25 IS 2 BP 401 EP 411 DI 10.1016/j.nbd.2006.10.007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 132ZM UT WOS:000243981400019 PM 17141510 ER PT J AU Hernandez-Echeagaray, E Cepeda, C Ariano, MA Lobo, MK Sibley, DR Levine, MS AF Hernandez-Echeagaray, Elizabeth Cepeda, Carlos Ariano, Marjorie A. Lobo, Mary Kay Sibley, David R. Levine, Michael S. TI Dopamine reduction of GABA currents in striatal medium-sized spiny neurons is mediated principally by the D-1 receptor subtype SO NEUROCHEMICAL RESEARCH LA English DT Article DE dopamine receptors; GABA; knockout mice; neuromodulation ID DEPENDENT PROTEIN-KINASE; NEUROMODULATORY ACTIONS; SYNAPTIC-TRANSMISSION; NEOSTRIATAL NEURONS; RAT; MODULATION; BRAIN; D5; RESPONSES; SYSTEM AB Dopamine modulates voltage- and ligand-gated currents in striatal medium-sized neurons (MSNs) through the activation of D1- and D2-like family receptors. GABA(A) receptor-mediated currents are reduced by D1 receptor agonists, but the relative contribution of D-1 or D-5 receptors in this attenuation has been elusive due to the lack of selective pharmacological agents. Here we examined GABA(A) receptor-mediated currents and the effects of D1 agonists on MSNs from wildtype and D-1 or D-5 receptor knockout (KO) mice. Immunohistochemical and single-cell RT-PCR studies demonstrated a lack of compensatory effects after genetic deletion of D-1 or D-5 receptors. However, the expression of GABA(A) receptor alpha 1 subunits was reduced in D-5 KO mice. At the functional level, whole-cell patch clamp recordings in dissociated MSNs showed that GABA peak current amplitudes were smaller in cells from D-5 KO mice indicating that lack of this receptor subtype directly affected GABA(A)-mediated currents. In striatal slices, addition of a D1 agonist reduced GABA currents significantly more in D-5 KO compared to D-1 KO mice. We conclude that D-1 receptors are the main D1-like receptor subtype involved in the modulation of GABA currents and that D-5 receptors contribute to the normal expression of these currents in the striatum. C1 Univ Calif Los Angeles, David Geffen Sch Med, Mental Retardat Res Ctr, Los Angeles, CA 90024 USA. Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Neurosci, N Chicago, IL USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Levine, MS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Mental Retardat Res Ctr, Room 58-258,760 Westwood Plaza, Los Angeles, CA 90024 USA. EM mlevine@mednet.ucla.edu RI Lobo, Mary Kay/K-7734-2015 OI Lobo, Mary Kay/0000-0002-9419-2079 FU NINDS NIH HHS [NS33538] NR 43 TC 6 Z9 8 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD FEB PY 2007 VL 32 IS 2 BP 229 EP 240 DI 10.1007/s11064-006-9141-8 PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 134PI UT WOS:000244094900010 PM 17031565 ER PT J AU Volkow, ND Wang, GJ Newcorn, J Fowler, JS Telang, F Solanto, MV Logan, J Wong, C Ma, YM Swanson, JM Schulz, K Pradhan, K AF Volkow, Nora D. Wang, Gene-Jack Newcorn, Jeffrey Fowler, Joanna S. Telang, Frank Solanto, Mary V. Logan, Jean Wong, Christopher Ma, Yeming Swanson, James M. Schulz, Kurt Pradhan, Kith TI Brain dopamine transporter levels in treatment and drug naive adults with ADHD SO NEUROIMAGE LA English DT Article DE PET; saliency; caudate; hypothalamus; nucleus accumbens; noradrenergic; stimulants ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; BASAL GANGLIA; METHYLPHENIDATE TREATMENT; ORAL METHYLPHENIDATE; COCAINE BINDING; C-11 RACLOPRIDE; BLOOD-FLOW; IN-VIVO; CHILDREN AB Attention deficit hyperactivity disorder (ADHD) is the most frequent psychiatric disorder in children, yet data are sparse on its pathophysiology. Particularly relevant are the dopamine transporters since these are the main targets of stimulant medications used for ADHD treatment. Though some imaging studies have shown increases in dopamine transporters in ADHD others have not and their role in the neurobiology of ADHD remains unclear. Here we investigate dopamine transporters in ADHD subjects with control of potentially confounding factors (previous medication and/or drug histories, comorbidity) and their association with clinical symptoms. Positron emission tomography and [C-11]cocaine were used to measure dopamine transporters in 20 never medicated adults with ADHD and 25 controls. Dopamine transporters were lower in left caudate (13%, p < 0.05) and in left nucleus accumbens (p < 0.005) in ADHD subjects than in controls. In putamen dopamine transporters did not differ between groups but were associated with scores of inattention (Conners Adult Attention Rating Scale) both in ADHD subjects (p < 0.005) and in controls (p < 0.005). Thus, for a given transporter level the scores for inattention were on average five times greater in ADHD subjects than in controls. These results do not corroborate increases in dopamine transporters in ADHD subjects and show that in some they are reduced. It also provides evidence that dopamine transporter levels modulate attention but suggest that additional pathology (e.g., prefrontal or cingulostriatal pathways, noradrenergic neurotransmission) is necessary to account for the large differences in inattention observed between controls and ADHD subjects. (c) 2006 Published by Elsevier Inc. C1 NIDA, Bethesda, MD 20892 USA. NIAAA, Lab Neuroimaging, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. Mt Sinai Med Ctr, Dept Psychiat, New York, NY 10029 USA. Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. SUNY Stony Brook, Dept Appl Math, Stony Brook, NY 11794 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov OI Solanto, Mary/0000-0002-3153-9610; Newcorn, Jeffrey /0000-0001-8993-9337; Logan, Jean/0000-0002-6993-9994 FU Intramural NIH HHS; NIMH NIH HHS [MH66961-02] NR 67 TC 124 Z9 125 U1 5 U2 18 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 FEB 1 PY 2007 VL 34 IS 3 BP 1182 EP 1190 DI 10.1016/j.neuroimage.2006.10.014 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 129VR UT WOS:000243758700028 PM 17126039 ER PT J AU Goelman, G Pelled, G Dodd, S Koretsky, A AF Goelman, Gadi Pelled, Galit Dodd, Steve Koretsky, Alan TI Observation of two distinct spatial-temporal BOLD clusters during sensory stimulation in rats SO NEUROIMAGE LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; FUNCTIONAL CONNECTIVITY; BRAIN ACTIVATION; BLOOD-FLOW; BALLOON MODEL; MOTOR CORTEX; DATA SETS; FMRI DATA; MRI; OXYGENATION AB Neuronal activity evokes changes in local CBF and CBV, whose spatial differences are not fully known. We use the Radial Correlation Contrast (RCC) analysis method with high spatial resolution 100 x 100 x 1000 mu m(3) data collected with an 11.7 T magnet to differentiate two spatial-temporal BOLD clusters during sensory rat forepaw stimulation and hypothesize that each corresponds to either the CBF or the CBV processes. One cluster, obtained during the time segment of stimulation onset, is characterized by a high positive BOLD signal whereas the other, obtained during the simulation decline time segment, is characterized by a lower positive signal and strong post stimulus undershoot. The average volume of stimulation onset clusters is embedded in the stimulation decline clusters with the latter significantly larger and shifted towards deeper cortical layers. Comparison of amplitude-RCC and cross-correlation analyses performed on equivalent time segments (30 s, 40 images) revealed no differences in cluster size or location, demonstrating that temporal locality is more important than spatial locality in distinguishing between stimulation onset and stimulation decline clusters. We hypothesize that clusters characterized by stimulation onset are highly weighted by local changes in CBF whereas clusters characterized by stimulation decline are more CBV weighted. Moreover, the data suggest that the locations of the highest CBF changes are distinct from the locations of the highest CBV changes. While the former located within stimulation decline clusters and its weight is gradually reduced towards cluster's periphery (mainly ventrally), the highest changes in CBV occur in the cluster's periphery with only modest changes towards its center. (c) 2006 Elsevier Inc. All rights reserved. C1 Hadassah Hebrew Univ Med Ctr, Dept Med Biophys & Nucl Med, MRI MRS Lab Human Biol Res Ctr, IL-91120 Jerusalem, Israel. NINDS, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Goelman, G (reprint author), Hadassah Hebrew Univ Med Ctr, Dept Med Biophys & Nucl Med, MRI MRS Lab Human Biol Res Ctr, POB 1200, IL-91120 Jerusalem, Israel. EM gadig@hadassah.org.il RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08]; NIBIB NIH HHS [EB01015] NR 35 TC 2 Z9 2 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 1 PY 2007 VL 34 IS 3 BP 1220 EP 1226 DI 10.1016/j.neuroimage.2006.09.052 PG 7 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 129VR UT WOS:000243758700032 PM 17137795 ER PT J AU Mitchell, DGV Nakic, M Fridberg, D Kamel, N Pine, DS Blair, RJR AF Mitchell, D. G. V. Nakic, M. Fridberg, D. Kamel, N. Pine, D. S. Blair, R. J. R. TI The impact of processing load on emotion SO NEUROIMAGE LA English DT Article ID EVENT-RELATED FMRI; HUMAN AMYGDALA; PREFRONTAL CORTEX; COGNITIVE CONTROL; VISUAL-STIMULI; HUMAN BRAIN; ATTENTION; FACES; PERCEPTION; RESPONSES AB This event-related fMRI study examined the impact of processing load on the BOLD response to emotional expressions. Participants were presented with composite stimuli consisting of neutral and fearful faces upon which semi-transparent words were superimposed. This manipulation held stimulus-driven features constant across multiple levels of processing load. Participants made either (1) gender discriminations based on the face; (2) case judgments based on the words; or (3) syllable number judgments based on the words. A significant main effect for processing load was revealed in prefrontal cortex, parietal cortex, visual processing areas, and amygdala. Critically, enhanced activity in the amygdala and medial prefrontal cortex seen during gender discriminations was significantly reduced during the linguistic task conditions. A connectivity analysis conducted to investigate theories of cognitive modulation of emotion showed that activity in dorsolateral prefrontal cortex was inversely related to activity in the ventromedial prefrontal cortex. Together, the data suggest that the processing of task-irrelevant emotional information, like neutral information, is subject to the effects of processing load and is under top-down control. (c) 2006 Elsevier Inc. All rights reserved. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Western Ontario, Dept Psychiat, London, England. Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. RP Mitchell, DGV (reprint author), Univ Western Ontario, Univ Hosp, Dept Psychiat, 339 Windermere Rd, London, ON N6A 5A5, Canada. EM dmitch8@uwo.ca FU Intramural NIH HHS [Z99 MH999999] NR 58 TC 78 Z9 82 U1 2 U2 9 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 FEB 1 PY 2007 VL 34 IS 3 BP 1299 EP 1309 DI 10.1016/j.neuroimage.2006.10.012 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 129VR UT WOS:000243758700040 PM 17161627 ER PT J AU Korn, T Rao, M Magnus, T AF Korn, Thomas Rao, Mahendra Magnus, Tim TI Autoimmune modulation of astrocyte-mediated homeostasis SO NEUROMOLECULAR MEDICINE LA English DT Review DE astrocyte; autoimmunity; glutamate; lactate; homeostasis; multiple sclerosis; T cell ID NECROSIS-FACTOR-ALPHA; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE SYNTHASE; MAGNETIC-RESONANCE SPECTROSCOPY; SODIUM-BICARBONATE COTRANSPORT; GLUTAMATE TRANSPORTER GLAST; RAT HIPPOCAMPAL ASTROCYTES; 1-INFECTED T-LYMPHOCYTES; CALCIUM-BINDING PROTEIN; MULTIPLE-SCLEROSIS AB Astrocytes are principal mediators of homeostasis in the central nervous system (CNS). They supply neurons and oligodendrocytes with substrates for energy metabolism and clear the extracellular space of excess neurotransmitters. In neuroinflammation, astrocytes have classically been regarded as unimportant since their capacity to present antigen to T cells is limited and has been questioned in vivo. However, it is an evolving concept that autoimmunity in the CNS has a profound impact on astrocytes. In this review, we focus on the alterations in astrocyte functions that occur during an autoimmune attack of the CNS. C1 [Korn, Thomas] Harvard Univ, Brigham & Womens Hosp, Inst Med, Ctr Neurol Dis, Boston, MA 02115 USA. [Korn, Thomas; Magnus, Tim] Neurol Univ Klin, Homburg, Germany. [Rao, Mahendra; Magnus, Tim] NIA, Stem Cell Sect, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Korn, T (reprint author), Harvard Univ, Brigham & Womens Hosp, Inst Med, Ctr Neurol Dis, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM tkorn@rics.bwh.harvard.edu; magnust@grc.nia.nih.gov OI Korn, Thomas/0000-0002-3633-0955 FU Intramural NIH HHS NR 102 TC 7 Z9 7 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 EI 1559-1174 J9 NEUROMOL MED JI Neuromol. Med. PD FEB PY 2007 VL 9 IS 1 BP 1 EP 15 DI 10.1385/NMM:9:1:1 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 318OP UT WOS:000257101800001 PM 17114820 ER PT J AU Mattson, MP Cutler, RG Camandola, S AF Mattson, Mark P. Cutler, Roy G. Camandola, Simonetta TI Energy intake and amyotrophic lateral sclerosis SO NEUROMOLECULAR MEDICINE LA English DT Editorial Material DE caloric restriction; motor neurons; HSP-70; superoxide dismutase; oxidative stress; ALS ID CALORIC RESTRICTION; DIETARY RESTRICTION; MUTANT MICE; DISEASE; ALS; PROGRESSION; BIOSPHERE-2; MECHANISM; SURVIVAL; BENEFIT AB Roy Walford, a physician and scientist who pioneered research on the anti-aging effects of caloric restriction and subjected himself to a low-energy diet, recently died from amyotrophic lateral sclerosis (ALS). Information from his case, epidemiological findings, and recent controlled studies in mouse models of ALS suggest that low-energy diets might render motor neurons vulnerable to degeneration, whereas high-energy diets are ameliorative. This contrasts with the effects of low-energy diets on various neuronal populations in the brain that respond adaptively, activating pathways that promote plasticity and resistance to disease. One reason that motor neurons might be selectively vulnerable to low-energy diets is that they are unable to engage neuroprotective responses to energetic stress response involving the protein chaperones, such as, heat-shock protein-70. C1 [Mattson, Mark P.; Cutler, Roy G.; Camandola, Simonetta] 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. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 22 TC 56 Z9 56 U1 0 U2 7 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD FEB PY 2007 VL 9 IS 1 BP 17 EP 20 DI 10.1385/NMM:9:1:17 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 318OP UT WOS:000257101800002 PM 17114821 ER PT J AU Morgan, GA Guo, Q Chan, SL Gary, DS Osborne, BA Mattson, MP AF Morgan, Grant A. Guo, Qing Chan, Sic L. Gary, Devin S. Osborne, Barbara A. Mattson, Mark P. TI Defects of immune regulation in the presenilin-1 mutant knockin mouse SO NEUROMOLECULAR MEDICINE LA English DT Article DE calcium; lymphocyte; mitochondria; presenilin; Alzheimer's; apoptosis ID AMYLOID PRECURSOR PROTEIN; FAMILIAL ALZHEIMERS-DISEASE; HIPPOCAMPAL-NEURONS; MITOCHONDRIAL DYSFUNCTION; INCREASED VULNERABILITY; CALCIUM HOMEOSTASIS; INDUCED APOPTOSIS; OXIDATIVE STRESS; IN MICE; ACTIVATION AB Mutations in the presenilin-1 (PS1) gene are causally linked to early-onset Alzheimer's disease (AD). Studies of neurons suggest that PS1 mutations result in a gain-of-function, which perturbs calcium regulation and increases cell vulnerability to apoptosis. Alterations in immune cell function have also been demonstrated in AD, and a role for PS1 in immune regulation has been suggested recently. We now report that splenocytes from PS1-mutant (M146V) knockin mice exhibit increased caspase activity, abnormal calcium regulation and aberrant mitochondrial function. Isolated splenic T cells from PS1-mutant mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)-2-receptor expression necessary for a normal T-cell immune response. Thus, adverse effects of a mutation that causes AD on immune function that involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to apoptosis are demonstrated. These findings suggest that abnormalities in immune function might play major roles in the pathogenesis of AD. C1 [Morgan, Grant A.; Osborne, Barbara A.] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. [Guo, Qing] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK 73104 USA. [Chan, Sic L.; Gary, Devin S.; Mattson, Mark P.] NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21224 USA. RP Osborne, BA (reprint author), Univ Massachusetts, Dept Vet & Anim Sci, 311 Paige Lab, Amherst, MA 01003 USA. EM osborne@vasci.umass.edu RI Mattson, Mark/F-6038-2012 NR 42 TC 5 Z9 5 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1535-1084 J9 NEUROMOL MED JI Neuromol. Med. PD FEB PY 2007 VL 9 IS 1 BP 35 EP 45 DI 10.1385/NMM:9:1:35 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 318OP UT WOS:000257101800004 PM 17114823 ER PT J AU Shrimali, RK Weaver, JA Miller, GF Starost, MF Carlson, BA Novoselov, SV Kumaraswamy, E Gladyshev, VN Hatfield, DL AF Shrimali, Rajeev K. Weaver, James A. Miller, Georgina F. Starost, Matthew F. Carlson, Bradley A. Novoselov, Sergey V. Kumaraswamy, Easwari Gladyshev, Vadim N. Hatfield, Dolph L. TI Selenoprotein expression is essential in endothelial cell development and cardiac muscle function SO NEUROMUSCULAR DISORDERS LA English DT Article DE cardiovascular disease; conditional knockout; endothelial cells; heart muscle; selenocysteine; selenocysteine tRNA; selenoproteins ID SELENOCYSTEINE TRANSFER-RNA; TYPE-2 IODOTHYRONINE DEIODINASE; THIOREDOXIN REDUCTASE; TARGETED DISRUPTION; TRANSGENIC MICE; ADAPTIVE THERMOGENESIS; SELENIUM DEFICIENCY; OXIDATIVE DAMAGE; GENE TRSP; MOUSE AB LoxP-Cre technology was used to remove the selenocysteine tRNA gene, trsp, in either endothelial cells or myocytes of skeletal and heart muscle to elucidate the role of selenoproteins in cardiovascular disease. Loss of selenoprotein expression in endothelial cells was embryonic lethal. A 14.5-day-old embryo had numerous abnormalities including necrosis of the central nervous system, subcutaneous hemorrhage and erythrocyte immaturity. Loss of selenoprotein expression in myocytes manifested no apparent phenotype until about day 12 after birth. Affected mice had decreased mobility and an increased respiratory rate, which proceeded rapidly to death. Pathological analysis revealed that mice lacking trsp had moderate to severe myocarditis with inflammation extending into the mediastinitis. Thus, ablation of selenoprotein expression demonstrated an essential role of selenoproteins in endothelial cell development and in proper cardiac muscle function. The data suggest a direct connection between the loss of selenoprotein expression in these cell types and cardiovascular disease. (C) 2006 Elsevier B.V. All rights reserved. C1 NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NIH, Div Vet Resources, Off Res Serv, Div Intramural Res Serv, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005317-22, CA080946, R01 CA080946]; NIGMS NIH HHS [GM065204, R01 GM065204, R37 GM065204] NR 28 TC 23 Z9 23 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD FEB PY 2007 VL 17 IS 2 BP 135 EP 142 DI 10.1016/j.nmd.2006.10.006 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 148AG UT WOS:000245046300002 PM 17142041 ER PT J AU Singhal, SK Zhang, L Morales, M Oz, M AF Singhal, Sachin K. Zhang, Li Morales, Marisela Oz, Murat TI Antipsychotic clozapine inhibits the function of alpha(7)-nicotinic acetylcholine receptors SO NEUROPHARMACOLOGY LA English DT Article DE nicotinic receptors; clozapine; antipsychotic; Xenopus oocyte ID HIPPOCAMPAL CA1 REGION; LONG-TERM POTENTIATION; NICOTINIC RECEPTORS; XENOPUS-OOCYTES; 5-HT3 RECEPTOR; SCHIZOPHRENIA; RAT; SMOKING; DRUGS; NEURONS AB The effects of the antipsychotic clozapine on the function of the cloned alpha(7) subunit of the nicotinic acetylcholine (nACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Clozapine reversibly inhibited nicotine (10 mu M)-induced currents in a concentration-dependent manner (300 nM to 90 mu M), with an IC50 value of 3.2 +/- 0.4 mu M. The effect of clozapine was not dependent on the membrane potential. Clozapine did not affect the activity of endogenous Ca2+-dependent Cl- channels since the inhibition by clozapine was unaltered by the intracellularly injected Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Clozapine decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on alpha(7)-nACh receptors. In hippocampal slices, the whole-cell recordings from CA1 pyramidal neurons indicated that the increases in the frequency and amplitudes of the GABA-mediated spontaneous inhibitory postsynaptic currents induced by bath application of 2 mM choline, a specific agonist for a7-nACh receptors, were abolished after 10 min application of 5 mu M Clozapine. In conclusion, these results demonstrate that clozapine inhibits the function of alpha(7)-nACh receptors expressed in Xenopus oocytes and in hippocampal neurons. (c) 2006 Elsevier Ltd. All rights reserved. C1 Natl Inst Drug Abuse, NIH, DHHS,Intramural Res Program,Cellular Neurobiol Br, Electrophysiol Sect, Baltimore, MD 21224 USA. NIAAA, NIH, DHHS, Mol & Cellular Neurobiol Lab, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, NIH, DHHS, Intramural Res Program,Cellular Neurobiol Branch,, Baltimore, MD 21224 USA. RP Oz, M (reprint author), Natl Inst Drug Abuse, NIH, DHHS,Intramural Res Program,Cellular Neurobiol Br, Electrophysiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 NR 43 TC 27 Z9 27 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2007 VL 52 IS 2 BP 387 EP 394 DI 10.1016/j.neuropharm.2006.08.023 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 141RD UT WOS:000244595500016 PM 17161853 ER PT J AU Li, CY Carlier, PR Ren, H Kan, KKW Hui, KM Wang, H Li, WM Li, ZW Xiong, KM Clement, EC Xue, H Liu, XG Li, MT Pang, YP Han, YF AF Li, Chaoying Carlier, Paul R. Ren, Hong Kan, Kelvin K. W. Hui, Kwokmin Wang, Hong Li, Wenming Li, Zhiwang Xiong, Keming Clement, Ella Chow Xue, Hong Liu, Xiangou Li, Mingtao Pang, Yuanping Han, Yifan TI Alkylene tether-length dependent gamma-aminobutyric acid type A receptor competitive antagonism by tacrine dimers SO NEUROPHARMACOLOGY LA English DT Article DE GABA(A) receptor; acetylcholinesterase; tacrine; bis(7)-tacrine ID 3-ISOXAZOLOL GABA(A) ANTAGONISTS; INDUCED NEURONAL APOPTOSIS; ALZHEIMERS-DISEASE; ACETYLCHOLINESTERASE INHIBITOR; MUSCARINIC RECEPTORS; BIS(7)-TACRINE; POTENT; DESENSITIZATION; PHARMACOLOGY; BINDING AB Bis(7)-tacrine was previously demonstrated as an antagonist of gamma-aminobutyric acid type A (GABA(A)) receptors. In this study, the effects of a series of alkylene-linked tacrine dimers on GABAA receptors were examined. In radioligand binding assay, the analogues differed in binding affinity for GABAA receptors, and potency monotonically increased as the tether was shortened from nine to two methylenes. Bis(2)-tacrine, the shortest tacrine dimer, could displace [H-3]muscimol from rat brain membranes with an IC50 of 0.48 M, which was 11, 13 and 525 times more potent than the GABAA receptor antagonist (+)-bicucul line, bis(7)-tacrine and tacrine, respectively. In whole-cell patch-clamp recordings, these dimeric tacrine analogues competitively antagonized GABA-induced inward current with a rank order of potency of bis(2)-tacrine > bicuculline > bis(7)-tacrine > bis(9)-tacrine > tacrine, and the potency of bis(2)-tacrine was 11, 18 and 487 times higher than that of (+)bicuculline, bis(7)-tacrine and tacrine, respectively. Bis(2)-tacrine shifted the GABA concentration-response curve to the right in a parallel manner, and the inhibition was voltage-independent between -80 and +20 mV. It can be concluded that the shorter the alkylene linkage in tacrine dimers the stronger the binding affinity and higher the antagonistic effect on the GABAA receptor will be. (c) 2006 Elsevier Ltd. All rights reserved. C1 Hong Kong Univ Sci & Technol, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Virginia Tech, Dept Chem, Blacksburg, VA 24061 USA. Huazhong Univ Sci & Technol, Tongji Med Coll, Inst Neurobiol & Neuroinformat, Wuhan 430030, Peoples R China. Sun Yat Sen Univ, Dept Pharmacol, Guangzhou 510080, Peoples R China. Sun Yat Sen Univ, Dept Physiol, Guangzhou 510080, Peoples R China. May Clin, Coll Med, Comp Aided Mol Design Lab, Rochester, MN 55905 USA. RP Han, YF (reprint author), Hong Kong Univ Sci & Technol, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. EM bcyfhan@ust.hk OI Han, Yifan/0000-0002-5833-069X; Xue, Hong/0000-0002-8133-9828 NR 38 TC 6 Z9 9 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2007 VL 52 IS 2 BP 436 EP 443 DI 10.1016/j.neuropharm.2006.07.039 PG 8 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 141RD UT WOS:000244595500022 PM 17056074 ER PT J AU Smith, CPS Oh, JD Bibbiani, F Collins, MA Avila, I Chase, TN AF Smith, C. P. S. Oh, J. D. Bibbiani, F. Collins, M. A. Avila, I. Chase, T. N. TI Tamoxifen effect on L-DOPA induced response complications in parkinsonian rats and primates SO NEUROPHARMACOLOGY LA English DT Article DE tamoxifen; PKC isoforms; Parkinson's disease; 6-hydroxydopamine lesion; motor response alteration ID PROTEIN-KINASE-C; NIGROSTRIATAL DOPAMINERGIC SYSTEM; NMDA RECEPTOR SUBUNITS; BREAST-CANCER; MOTOR COMPLICATIONS; STRIATAL DOPAMINE; EPITHELIAL-CELLS; MESSENGER-RNA; ACTIVATION; ESTROGEN AB The contribution of striatal protein kinase C (PKC) isoform changes in levodopa (L-DOPA) induced motor response complications in parkinsonian rats was investigated and the ability of tamoxifen, an antiestrogen with a partial PKC antagonist property, to prevent these response alterations in 6-hydroxydopamine (6-OHDA) lesioned rats as well as in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) treated cynomologous monkeys was studied. Following treatment of adult male rats with L-DOPA twice daily for 3 weeks, protein levels of left (lesioned) and right (intact) striatal PKC isoforms were measured. Western blot analysis showed increased protein expression of both the novel PKC epsilon isoform and the atypical PKC lambda isoform ipsilateral to the lesion (174 +/- 17% for epsilon, 140 +/- 9% for lambda, of intact striaturn in 6-OHDA lesioned plus chronic L-DOPA treated animals) in acute L-DOPA treated rats. No enhancement was observed in PKC immunoreactivity for other isoforms. Tamoxifen (5.0 mg/kg p.o.) significantly attenuated the L-DOPA induced augmentation of protein expression of PKC epsilon and PKC lambda, but had no effect on immunoreactivity for other PKC isoforms. In chronic L-DOPA treated parkinsonian rats, tamoxifen prevented (5.0 mg/kg p.o.) as well as ameliorated (5.0 mg/kg p.o.) the characteristic shortening in duration of motor response to L-DOPA challenge. In MPTP lesioned primates, similar to the ameliorative effect seen in rats, tamoxifen (1 and 3 mg/kg p.o) reduced the appearance of L-DOPA induced dyskinesia by 61% and 55% respectively (p < 0.05). These results suggest that changes in specific striatal PKC isoforms contribute to the pathogenesis of L-DOPA induced motor complications and further that drugs able to selectively inhibit these signaling kinases might provide adjunctive benefit in the treatment of Parkinson's disease. Published by Elsevier Ltd. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Cent Michigan Univ, Dept Psychol, Mt Pleasant, MI 48859 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C-103, Bethesda, MD 20892 USA. EM tchase@hamiltonpharma.com FU Intramural NIH HHS NR 58 TC 9 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD FEB PY 2007 VL 52 IS 2 BP 515 EP 526 DI 10.1016/j.neuropharm.2006.08.018 PG 12 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 141RD UT WOS:000244595500031 PM 17116309 ER PT J AU Sampson, JH Brady, ML Petry, NA Croteau, D Friedman, AH Friedman, HS Wong, T Bigner, DD Pastan, I Puri, RK Pedain, C AF Sampson, John H. Brady, Martin L. Petry, Neil A. Croteau, David Friedman, Allan H. Friedman, Henry S. Wong, Terence Bigner, Darell D. Pastan, Ira Puri, Raj K. Pedain, Christoph TI Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning SO NEUROSURGERY LA English DT Article DE brain neoplasms; convection; drug delivery systems; glioblastoma; single-photon emission-computed tomography ID IL4-PSEUDOMONAS EXOTOXIN NBI-3001; BRAIN-TUMORS; PSEUDOMONAS EXOTOXIN; NEUROTROPHIC FACTOR; GLIAL NEOPLASMS; COMPUTED-TOMOGRAPHY; FUSION PROTEINS; DRUG-DELIVERY; INFUSION; MICROINFUSION AB OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with I-123-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of I-123-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of I-123-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery. C1 Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Therataxis LLC, Baltimore, MD USA. NeoPharm Inc, Lake Forest, IL USA. NCI, Mol Biol Lab, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Bethesda, MD USA. BrainLAB AG, Heimstetten, Germany. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Dept Surg, Div Neurosurg, Box 3050,Room 220,Sands Bldg, Durham, NC 27710 USA. EM john.sampson@duke.edu NR 56 TC 51 Z9 52 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD FEB PY 2007 VL 60 IS 2 SU S BP 89 EP 98 DI 10.1227/01.NEU.0000249256.09289.5F PG 10 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 136NE UT WOS:000244230600025 ER PT J AU Krasnova, IN Betts, ES Dada, A Jefferson, A Ladenheim, B Becker, KG Cadet, JL Hohmann, CF AF Krasnova, Irina N. Betts, Elizabeth S. Dada, Abiola Jefferson, Akilah Ladenheim, Bruce Becker, Kevin G. Cadet, Jean Lud Hohmann, Christine F. TI Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex SO NEUROTOXICITY RESEARCH LA English DT Article DE cerebral cortex; dopamine; gene expression; 6-hydroxydopamine; microarray; morphology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; RAT CEREBRAL-CORTEX; FUNCTION IN-VIVO; CORTICAL DEVELOPMENT; 6-HYDROXYDOPAMINE TREATMENT; SACCHAROMYCES-CEREVISIAE; BEHAVIORAL CONSEQUENCES; MOLECULAR-MECHANISMS; PREFRONTAL CORTEX AB The mesocorticolimbic dopamine (DA) system is implicated in mental health disorders affecting attention, impulse inhibition and other cognitive functions. It has also been involved in the regulation of cortical morphogenesis. The present study uses focal injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of BALB/c mice to examine morphological, behavioral and transcriptional responses to selective DA deficit in the fronto-parietal cortex. Mice that received injections of 6-OHDA on postnatal day I (PND1) showed reduction in DA levels in their cortices at PND7. Histological analysis at PND120 revealed increased fronto-cortical width, but decreased width of somatosensory parietal cortex. Open field object recognition suggested impaired response inhibition in adult mice after 6-OHDA treatment. Transcriptional analyses using 17K mouse microarrays showed that such lesions caused up-regulation of 100 genes in the cortex at PND7. Notably, among these genes are Sema3A which plays a repulsive role in axonal guidance, RhoD which inhibits dendritic growth and tubulin beta 5 microtubule subunit. In contrast, 127 genes were down-regulated, including CCT epsilon and CCT zeta that play roles in actin and tubulin folding. Thus, neonatal DA depletion affects transcripts involved in control of cytoskeletal formation and pathway finding, instrumental for normal differentiation and synaptogenesis. The observed gene expression changes are consistent with histological cortical and behavioral impairments in the adult mice treated with 6-OHDA on PND1. Our results point towards specific molecular targets that might be involved in disease process mediated by altered developmental DA regulation. C1 Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. NIDA, Mol Neuropsychiat Branch, US Dept HHS, NIH, Baltimore, MD 21251 USA. NIA, Gene Express & Genom Unit, US Dept HHS, NIH, Baltimore, MD 21251 USA. RP Hohmann, CF (reprint author), Morgan State Univ, Dept Biol, Baltimore, MD 21251 USA. EM chohmann@jewel.morgan.edu OI Becker, Kevin/0000-0002-6794-6656 FU Intramural NIH HHS; NCRR NIH HHS [1G12 RR 17581]; NICHD NIH HHS [P01 HD 24448]; NIGMS NIH HHS [S06 GM 051971-09] NR 80 TC 22 Z9 23 U1 0 U2 1 PU F P GRAHAM PUBLISHING CO PI MOUNTAIN HOME PA PO BOX 370, MOUNTAIN HOME, TN 37684 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD FEB PY 2007 VL 11 IS 2 BP 107 EP 130 PG 24 WC Neurosciences SC Neurosciences & Neurology GA 156GB UT WOS:000245635000004 PM 17449454 ER PT J AU Henley, DV Lipson, N Korach, KS Bloch, CA AF Henley, Derek V. Lipson, Natasha Korach, Kenneth S. Bloch, Clifford A. TI Brief report - Prepubertal gynecomastia linked to lavender and tea tree oils SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BREAST-CANCER-CELLS; ESTROGENIC ACTIVITY; ANDROGEN; RECEPTOR; EXPRESSION; ESTRADIOL; MDA-KB2 AB Most cases of male prepubertal gynecomastia are classified as idiopathic. We investigated possible causes of gynecomastia in three prepubertal boys who were otherwise healthy and had normal serum concentrations of endogenous steroids. In all three boys, gynecomastia. coincided with the topical application of products that contained lavender and tea tree oils. Gynecomastia resolved in each patient shortly after the use of products containing these oils was discontinued. Furthermore, studies in human cell lines indicated that the two oils had estrogenic and antiandrogenic activities. We conclude that repeated topical exposure to lavender and tea tree oils probably caused prepubertal gynecomastia in these boys. C1 NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. Pediat Endocrine Associates, Greenwood Village, CO USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Sect, Reprod & Dev Toxicol Lab, MD B3-02,POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov FU Intramural NIH HHS NR 18 TC 93 Z9 96 U1 0 U2 15 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 1 PY 2007 VL 356 IS 5 BP 479 EP 485 DI 10.1056/NEJMoa064725 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 131HW UT WOS:000243860700008 PM 17267908 ER PT J AU Fagan, P Shavers, V Lawrence, D Gibson, JT Ponder, P AF Fagan, Pebbles Shavers, Vickie Lawrence, Deirdre Gibson, James Todd Ponder, Paris TI Cigarette smoking and quitting behaviors among unemployed adults in the United States SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SOCIOECONOMIC INEQUALITIES; CANCER-MORTALITY; HEART-DISEASE; PRIMARY-CARE; FOLLOW-UP; HEALTH; MEN; EMPLOYMENT; CONSEQUENCES; WOMEN AB Little is known about factors associated with smoking among the unemployed. This study estimated the prevalence of smoking and examined sociodemographic factors associated with current, former, and successful quitting among unemployed adults aged 18-64. Cross-sectional data on 13,480 participants in the 1998-1999 and 2001-2002 Tobacco Use Supplements to the Current Population Surveys were analyzed. Multivariate logistic regression analyses were used to examine factors associated with study outcomes (current vs. never, former vs. current, successful quitter vs. other former smoker). Among the unemployed, 35% were current smokers and 13% were former smokers. Of the former smokers, 81% quit successfully for at least 12 months. Participants with family incomes of less than US$25,000 were more likely than those with incomes of $50,000 or more to currently smoke (OR=2.13, 95% CI=1.85-2.46). Service workers and blue-collar workers were less likely than white-collar workers to report former smoking. Participants unemployed for 6 months or more were twice as likely as those unemployed for less than 6 months to quit successfully (OR=2.05, 95% CI=1.07-3.95). Unemployed blue-collar workers had a greater odds ratio of successfully quitting than white-collar workers (OR=1.83, 95% CI=1.17-2.87). Smoking rates were high among the unemployed, and quitting behaviors varied by sociodemographic factors and length of unemployment. Studies are needed to examine the feasibility of cessation interventions for the unemployed. C1 NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Informat Management Syst, Silver Spring, MD USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Fagan, P (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4042, Bethesda, MD 20892 USA. EM faganp@mail.nih.gov NR 63 TC 29 Z9 29 U1 1 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2007 VL 9 IS 2 BP 241 EP 248 DI 10.1080/14622200601080331 PG 8 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 146IK UT WOS:000244927500009 PM 17365755 ER PT J AU Kiesewetter, DO Jagoda, EM Shimoji, K Ma, Y Eckelman, WC AF Kiesewetter, Dale O. Jagoda, Elaine M. Shimoji, Kazuaki Ma, Ying Eckelman, William C. TI Evaluation of [F-18]fluoroxanomeline {5-{4-[(6-[F-18]fluorohexyl)oxy]-1 2,5-thiadiazol-3-yl}-1-methyl-1,2,3,6-tetrahydropyridine} SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE Alzheimer's disease; muscarinic receptor; PET tracer; autoradiography ID MUSCARINIC ACETYLCHOLINE-RECEPTOR; CONSCIOUS MONKEY BRAIN; IN-VIVO SELECTIVITY; ALZHEIMERS-DISEASE; KNOCKOUT MICE; CHOLINERGIC RECEPTORS; PET LIGANDS; M2 SUBTYPE; AGONISTS; XANOMELINE AB Introduction: We set out to develop a muscarinic MI-selective agonist (based on the structure of the functionally MI-selective xanomeline) that could be radiolabeled with fluorine-18 for use as an imaging agent for positron emission tomography. Methods: The radiochemical synthesis was achieved, employing the arts of organic and radiochemical syntheses. Binding selectivity studies employed biodistribution studies, using autoradiography and/or tissue dissection, in wild-type or muscarinic receptor knockout mice. Results: [F-18]Fluoroxanomeline shows rather uniform uptake in all mouse brain regions and high specific binding, with a brain-to-blood ratio of 32 at 60 min postinjection. In addition, the specific binding is demonstrated by a 58% to 75% decrease in brain uptake upon coinjection with 5 nmol of unlabeled fluoroxanomeline or xanomeline. Brain uptake studies with [H-3]xanomeline in muscarinic knockout mice show decreased uptake in M1 (17-34%) and M2 (2-20%) knockout mice compared with control. However, statistical significance was observed in only a few regions. Comparison of [F-18]fluoroxanomeline in knockout mice showed no difference in M I or M4 knockout mice but a general decrease in M2 (2-24%) knockout mice. The decrease of [F-18]fluoroxanomeline uptake in M2 knockout mice reached statistical significance in brain stem, cerebellum, frontal cortex, hippocampus, inferior colliculus and superior colliculus. Conclusion: Although xanomeline displays highly selective MI agonist activity in functional assays, little selectivity for muscarinic subtype binding was observed for xanomeline or its fluorine-containing analogue, fluoroxanomeline. This emphasizes the lack of correlation between functional selectivity and binding selectivity. (c) 2007 Elsevier Inc. All rights reserved. C1 NIBIB, NIH, Positron Emiss Tomog Radiochem Grp, Bethesda, MD 20892 USA. NIH, Ctr Clin, Positron Emiss Tomog Dept, Bethesda, MD 20892 USA. Mol Tracer LLC, Bethesda, MD 20814 USA. RP Kiesewetter, DO (reprint author), NIBIB, NIH, Positron Emiss Tomog Radiochem Grp, 10-1C401, Bethesda, MD 20892 USA. EM dk7k@nih.gov FU Intramural NIH HHS NR 54 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD FEB PY 2007 VL 34 IS 2 BP 141 EP 152 DI 10.1016/j.nucmedbio.2006.11.002 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 142MW UT WOS:000244655000002 PM 17307122 ER PT J AU Shumway, DA Pavlova, OA Mukhin, AG AF Shumway, Dean A. Pavlova, Olga A. Mukhin, Alexey G. TI A simplified method for the measurement of nonmetabolized 2-[F-18]F-A-85380 in blood plasma using solid-phase extraction SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE positron emission tomography; 2-[F-18]F-A-85380; plasma; solid-phase extraction; nicotinic acetylcholine receptors ID NICOTINIC ACETYLCHOLINE-RECEPTORS; PARKINSON-DISEASE; DRUG DISCOVERY; PET; BRAIN; QUANTIFICATION; ALPHA4BETA2; NONSMOKERS; TARGETS; SMOKERS AB Quantification of alpha(4)beta(2)* nicotinic acetylcholine receptors using 2-[F-18]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[F-18]FA) and positron emission tomography (PET) imaging requires measurement of nonmetabolized radioligand in blood plasma, which was previously accomplished using high-performance liquid chromatography (HPLC). Here, we introduce a one-step solid-phase extraction (SPE) method for measuring the concentration of nonmetabolized 2-[18F]FA. This method allows many samples to be processed in a short period of time. SPE effectively separated 2-[F-18]FA from radioactive metabolites typically observed in blood plasma after administration of radioligand in humans. Measurements of the 2-[F-18]FA parent fraction in healthy human volunteers obtained using the SPE method were nearly identical to those obtained using HPLC (1.3 +/- 5% average underestimation of SPE), and reproducibility was good within and between runs (2% and 6% coefficient of variation, respectively). SPE recovery of 2-[18F]FA from blood plasma was not appreciably diminished (3 +/- 0.6%) by a larger volume of blood plasma loaded onto the cartridge, suggesting the possibility of increasing the plasma sample volume at later times in a PET study to improve measurement sensitivity. 2-[F-18]FA was stable in blood stored on ice over 8 h and in saline at low concentrations (< 2 MBq/ml) but not at high concentrations (ca. 130 MBq/ml). Using SPE, the elimination half-life and full body distribution volume of 2-[F-18]FA in healthy human volunteers were estimated as 4.2 +/- 0.8 h and 220 +/- 70 L, respectively. These results suggest that SPE is the method of choice for the determination of the plasma 2-[18F]FA concentration when measurement of individual metabolites is not required. (c) 2007 Elsevier Inc. All rights reserved. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Mukhin, AG (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. EM amukhin@intra.nida.nih.gov FU Intramural NIH HHS NR 22 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD FEB PY 2007 VL 34 IS 2 BP 221 EP 228 DI 10.1016/j.nucmedbio.2006.12.001 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 142MW UT WOS:000244655000010 PM 17307130 ER PT J AU Shultzaberger, RK Chen, ZH Lewis, KA Schneider, TD AF Shultzaberger, Ryan K. Chen, Zehua Lewis, Karen A. Schneider, Thomas D. TI Anatomy of Escherichia coli sigma(70) promoters SO NUCLEIC ACIDS RESEARCH LA English DT Review ID RNA-POLYMERASE HOLOENZYME; OPEN COMPLEX-FORMATION; DNA-BINDING SITES; TRANSCRIPTION INITIATION; INFORMATION ANALYSIS; SEQUENCE LOGOS; CONSENSUS SEQUENCES; STRUCTURAL BASIS; NONTEMPLATE STRAND; GENOME SEQUENCE AB Information theory was used to build a promoter model that accounts for the -10, the -35 and the uncertainty of the gap between them on a common scale. Helical face assignment indicated that base -7, rather than -11, of the -10 may be flipping to initiate transcription. We found that the sequence conservation of sigma(70) binding sites is 6.5 +/- 0.1 bits. Some promoters lack a -35 region, but have a 6.7 +/- 0.2 bit extended -10, almost the same information as the bipartite promoter. These results and similarities between the contacts in the extended -10 binding and the -35 suggest that the flexible bipartite sigma factor evolved from a simpler polymerase. Binding predicted by the bipartite model is enriched around 35 bases upstream of the translational start. This distance is the smallest 5' mRNA leader necessary for ribosome binding, suggesting that selective pressure minimizes transcript length. The promoter model was combined with models of the transcription factors Fur and Lrp to locate new promoters, to quantify promoter strengths, and to predict activation and repression. Finally, the DNA-bending proteins Fis, H-NS and IHF frequently have sites within one DNA persistence length from the -35, so bending allows distal activators to reach the polymerase. C1 NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD 21702 USA. RP Schneider, TD (reprint author), NCI, Ctr Canc Res, Nanobiol Program, POB B,Bldg 469,Room 144, Frederick, MD 21702 USA. EM toms@ncifcrf.gov RI Chen, Zehua/E-6356-2011; chen, zehua/H-1260-2011; OI Schneider, Thomas/0000-0002-9841-1531 NR 114 TC 96 Z9 98 U1 2 U2 17 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2007 VL 35 IS 3 BP 771 EP 788 DI 10.1093/nar/gkl956 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139KD UT WOS:000244429800013 PM 17189297 ER PT J AU Mendiratta, G Eriksson, PR Clark, DJ AF Mendiratta, Geetu Eriksson, Peter R. Clark, David J. TI Cooperative binding of the yeast Spt10p activator to the histone upstream activating sequences is mediated through an N-terminal dimerization domain SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CHROMATIN-STRUCTURE; ZINC-FINGER; SPT21 GENES; DNA-BINDING; CELL-CYCLE; TRANSCRIPTION; COMPLEX; PROTEIN; CONFORMATION AB The yeast Spt10p activator is a putative histone acetyltransferase (HAT) possessing a sequence-specific DNA-binding domain (DBD) which binds to the upstream activation sequences (UAS elements) in the histone gene promoters. Spt10p binds to a pair of histone UAS elements with extreme positive cooperativity. The molecular basis of this cooperativity was addressed. Spt10p (640 residues) is an elongated dimer, but the isolated DBD (residues 283-396) is a monomer and binds non-cooperatively to DNA. A Spt10p fragment comprising the N-terminal domain (NTD), HAT domain and DBD (residues 1-396) binds cooperatively and is a dimer, whereas an overlapping Spt10p fragment comprising the DBD and C-terminal domains (residues 283-640) binds non-cooperatively and is a monomer. These observations imply that cooperative binding requires dimerization. The isolated NTD (residues 1-98) is a dimer and is responsible for dimerization. We propose that cooperativity involves a conformational change in the Spt10p dimer which facilitates the simultaneous recognition of two UAS elements. In vivo, deletion of the NTD results in poor growth, but does not prevent the binding at the HTA1 promoter, suggesting that dimerization is biologically important. Residues 1-396 are sufficient for normal growth, indicating that the critical functions of Spt10p reside in the N-terminal domains. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Clark, DJ (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6A,Room 2A14,6 Ctr Dr, Bethesda, MD 20892 USA. EM clarkda@mail.nih.gov FU Intramural NIH HHS NR 31 TC 7 Z9 7 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2007 VL 35 IS 3 BP 812 EP 821 DI 10.1093/nar/gkl1079 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139KD UT WOS:000244429800016 PM 17202156 ER PT J AU Krasilnikova, MM Kireeva, ML Petrovic, V Knijnikova, N Kashlev, M Mirkin, SM AF Krasilnikova, Maria M. Kireeva, Maria L. Petrovic, Vladimir Knijnikova, Nelli Kashlev, Mikhail Mirkin, Sergei M. TI Effects of Friedreich's ataxia (GAA)(n)center dot(TTC)(n) repeats on RNA synthesis and stability SO NUCLEIC ACIDS RESEARCH LA English DT Article ID GAA TRIPLET-REPEAT; ESCHERICHIA-COLI-CELLS; DOT-TTC REPEATS; IN-VIVO; MESSENGER-RNA; STICKY DNA; FRATAXIN GENE; TRANSCRIPTION; EXPANSION; INSTABILITY AB Expansions of (GAA)(n) repeats within the first intron of the frataxin gene reduce its expression, resulting in a hereditary neurodegenerative disorder, Friedreich's ataxia. While it is generally believed that expanded (GAA)(n) repeats block transcription elongation, fine mechanisms responsible for gene repression are not fully understood. To follow the effects of (GAA)(n).(TTC)(n) repeats on gene expression, we have chosen E. coli as a convenient model system. (GAA)(n).(TTC)(n) repeats were cloned into bacterial plasmids in both orientations relative to a promoter, and their effects on transcription and RNA stability were evaluated both in vitro and in vivo. Expanded (GAA)(n) repeats in the sense strand for transcription caused a significant decrease in the mRNA levels in vitro and in vivo. This decrease was likely due to the tardiness of the RNA polymerase within expanded (GAA)(n) runs but was not accompanied by the enzyme's dissociation and premature transcription termination. Unexpectedly, positioning of normal- and carrier-size (TTC)(n) repeats into the sense strand for transcription led to the appearance of RNA transcripts that were truncated within those repetitive runs in vivo. We have determined that these RNA truncations are consistent with cleavage of the full-sized mRNAs at (UUC)(n) runs by the E. coli degradosome. C1 Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA. RP Mirkin, SM (reprint author), Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. EM sergei.mirkin@tufts.edu RI Mirkin, Sergei/A-7310-2010 NR 39 TC 32 Z9 32 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2007 VL 35 IS 4 BP 1075 EP 1084 DI 10.1093/nar/gkl1140 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 152HT UT WOS:000245353300013 PM 17264130 ER PT J AU Renaud, S Loukinov, D Abdullaev, Z Guilleret, I Bosman, FT Lobanenkov, V Benhattar, J AF Renaud, S. Loukinov, D. Abdullaev, Z. Guilleret, I. Bosman, F. T. Lobanenkov, V. Benhattar, J. TI Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CATALYTIC SUBUNIT HTERT; REVERSE-TRANSCRIPTASE; CANCER-CELLS; CPG ISLAND; PROMOTER SEQUENCES; CERVICAL-CANCER; RNA COMPONENT; MESSENGER-RNA; UP-REGULATION; EXPRESSION AB Expression of hTERT is the major limiting factor for telomerase activity. We previously showed that methylation of the hTERT promoter is necessary for its transcription and that CTCF can repress hTERT transcription by binding to the first exon. In this study, we used electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) to show that CTCF does not bind the methylated first exon of hTERT. Treatment of telomerase-positive cells with 5-azadC led to a strong demethylation of hTERT 5'-regulatory region, reactivation of CTCF binding and downregulation of hTERT. Although complete hTERT promoter methylation was associated with full transcriptional repression, detailed mapping showed that, in telomerase-positive cells, not all the CpG sites were methylated, especially in the promoter region. Using a methylation cassette assay, selective demethylation of 110 bp within the core promoter significantly increased hTERT transcriptional activity. This study underlines the dual role of DNA methylation in hTERT transcriptional regulation. In our model, hTERT methylation prevents binding of the CTCF repressor, but partial hypomethylation of the core promoter is necessary for hTERT expression. C1 CHU Vaudois, Inst Pathol, CH-1011 Lausanne, Switzerland. NIAID, Mol Pathol Sect, Lab Immunopathol, NIH, Rockville, MD 20892 USA. RP Benhattar, J (reprint author), CHU Vaudois, Inst Pathol, CH-1011 Lausanne, Switzerland. EM Jean.Benhattar@chuv.ch OI Lobanenkov, Victor/0000-0001-6665-3635 FU Intramural NIH HHS NR 45 TC 86 Z9 95 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB PY 2007 VL 35 IS 4 BP 1245 EP 1256 DI 10.1093/nar/gkl1125 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 152HT UT WOS:000245353300028 PM 17267411 ER PT J AU Davis, CD Ross, SA AF Davis, Cindy D. Ross, Sharon A. TI Dietary components impact histone modifications and cancer risk SO NUTRITION REVIEWS LA English DT Review DE cancer prevention; diet; epigenetics; histones ID TUMOR CELL-LINES; DIALLYL DISULFIDE; COLON-CANCER; RAT-LIVER; IN-VIVO; DEACETYLASE; ACETYLATION; CHROMATIN; SULFORAPHANE; EXPRESSION AB Epigenetics refers to the study of heritable changes in gene expression that occur without a change in the DNA sequence and constitute an important mechanism by which dietary components can selectively activate or inactivate gene expression. Alterations in histone acetylation and methylation are a common hallmark of human cancer. This review focuses on several histone-modifying enzymes that are associated with cancer development and their modification by bioactive food components. C1 NCI, Nutr Sci Res Grp, Div Canc Prevent, Rockville, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Div Canc Prevent, 6130 Execut Blvd,Suite 3159, Rockville, MD 20892 USA. EM davisci@mail.nih.gov NR 40 TC 42 Z9 46 U1 1 U2 3 PU INT LIFE SCIENCES INST NORTH AMERICA PI WASHINGTON PA ONE THOMAS CIRCLE, N W, 9TH FLOOR, WASHINGTON, DC 20005 USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD FEB PY 2007 VL 65 IS 2 BP 88 EP 94 DI 10.1301/nr.2007.feb.88-94 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 136NI UT WOS:000244231000004 PM 17345961 ER PT J AU Grobman, WA Gilbert, S Landon, MB Spong, CY Leveno, KJ Rouse, DJ Varner, MW Moawad, AH Caritis, SN Harper, M Wapner, RJ Sorokin, Y Miodovnik, M Carpenter, M O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Ramin, SM Mercer, BM AF Grobman, William A. Gilbert, Sharon Landon, Mark B. Spong, Catherine Y. Leveno, Kenneth J. Rouse, Dwight J. Varner, Michael W. Moawad, Atef H. Caritis, Steve N. Harper, Margaret Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem Carpenter, Marshall O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA Natl I Child Hlth Human TI Outcomes of induction of labor after one prior cesarean SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID UTERINE RUPTURE; VAGINAL BIRTH; DELIVERY; TRIAL; SECTION; WOMEN; RISK; MULTICENTER; SUCCESS AB OBJECTIVE: To compare pregnancy outcomes in women with one prior low-transverse cesarean delivery after induction of labor with pregnancy outcomes after spontaneous labor. METHODS: This study is an analysis of women with one prior low-transverse cesarean and a singleton gestation who underwent a trial of labor and who were enrolled in a 4-year prospective observational study. Pregnancy outcomes were evaluated according to whether a woman underwent spontaneous labor or labor induction. RESULTS: Among the 11,778 women studied, vaginal delivery was less likely after induction of labor both in women without and with a prior vaginal delivery (51% versus 65%, P<.001; and 83% versus 88%, P<.001). An increased risk of uterine rupture after labor induction was found only in women with no prior vaginal delivery (1.5% versus 0.8%, P=.02; and 0.6% versus 0.4%, P=.42). Blood transfusion, venous thromboembolism, and hysterectomy were also more common with induction among women without a prior vaginal delivery. No measure of perinatal morbidity was associated with labor induction. An unfavorable cervix at labor induction was not associated with any adverse outcomes except an increased risk of cesarean delivery. CONCLUSION: Induction of labor in the study population is associated with an increased risk of cesarean delivery in all women with an unfavorable cervix, a statistically significant, albeit clinically small, increase in maternal morbidity in women with no prior vaginal delivery, and no appreciable increase in perinatal morbidity. C1 Northwestern Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Texas San Antonio, SW Med Ctr, Dallas, TX 75216 USA. Univ Alabama Birmingham, Birmingham, AL 35487 USA. Univ Utah, Salt Lake City, UT 84112 USA. Univ Chicago, Chicago, IL 60637 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Wayne State Univ, Detroit, MI 48202 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Columbia Univ, New York, NY 10027 USA. Brown Univ, Providence, RI 02912 USA. Univ Miami, Miami, FL 33124 USA. Univ Tennessee, Memphis, TN 37996 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Texas San Antonio, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. RP Grobman, WA (reprint author), 333 E Superior St,Suite 410, Chicago, IL 60611 USA. EM w-grobman@northwestern.edu RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU NICHD NIH HHS [HD 36801, HD 21410, HD 21414, HD 27860, HD 27861, HD 27869, HD 27905, HD 27915, HD 27917, HD 34116, HD 34122, HD 34146, HD 34208, HD 34210, HD 40485, HD 40500, HD 40512, HD 40544, HD 40545, HD 40560] NR 22 TC 52 Z9 58 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2007 VL 109 IS 2 BP 262 EP 269 DI 10.1097/01.AOG.0000254169.49346.e9 PN 1 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171YK UT WOS:000246771100004 PM 17267822 ER PT J AU Gibson, CS MacLennan, AH Dekker, GA Goldwater, PN Dambrosia, JM Munroe, DJ Tsang, S Stewart, C Nelson, KB AF Gibson, Catherine S. MacLennan, Alastair H. Dekker, Gustaaf A. Goldwater, Paul N. Dambrosia, James M. Munroe, David J. Tsang, Shirley Stewart, Claudia Nelson, Karin B. TI Genetic polymorphisms and spontaneous preterm birth SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID BETA-2-ADRENERGIC RECEPTOR; THROMBOPHILIC POLYMORPHISMS; BETA(2)-ADRENERGIC RECEPTOR; CEREBRAL-PALSY; DELIVERY; RISK; LABOR; ASSOCIATION; CONTRACTILITY; THROMBIN AB OBJECTIVE: To examine whether selected genetic polymorphisms in the infant are associated with spontaneous preterm birth (less than 37 weeks) among children with or without later-diagnosed cerebral palsy. METHODS: Exploratory case-control study investigating the relationship of gestational age at delivery to 31 single nucleotide polymorphisms measured in newborn screening bloodspots. Among all 443 children with later-diagnosed cerebral palsy born to white women in South Australia in 1986-1999, 234 were born after spontaneous onset of labor, and 108 of these were preterm (gestational age less than 37 weeks). The comparison group was 549 infants born after spontaneous onset of labor, of whom 147 were preterm. Distributions of genotypic frequencies were examined in preterm compared with term infants with and without cerebral palsy. Genotyping was performed using a Taqman assay. RESULTS: In children without cerebral palsy, preterm birth after spontaneous onset of labor was more frequent in association with a variant of the 1;2 adrenergic receptor gene (ADRB2 Q27E, P=.003), inducible nitric oxide synthase (iNOS or NOS2A, P=.042), or thrombomodulin (G127A, P=.006). Among children with cerebral palsy, preterm birth was associated with polymorphisms in genes for enclothelial nitric oxide synthase (eNOS -922, P=.012), plasminogen activator inhibitor-2 (P=.015 and.019), and alpha adducin (ADD1, P=.047). CONCLUSION: We confirm previous observations that variants of the 13 adrenergic receptor and of nitric oxide synthase are associated with prematurity, and suggest that genetic variants of the placental antifibrinolytic plasminogen activator inhibitor-2, and thrombomodulin and alpha adducin may be contributors to risk of spontaneous preterm birth. C1 Univ Adelaide, Sch Paediat & Reprod Hlth, Adelaide, SA 5005, Australia. Womens & Childrens Hosp, Dept Microbiol & Infect Dis, Adelaide, SA, Australia. NINDS, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Mol Technol, Frederick, MD USA. NCI, Frederick, MD 21701 USA. RP Nelson, KB (reprint author), NIH, Bldg 31,Room 8A03, Bethesda, MD 20892 USA. EM knelson@helix.nih.gov FU NCI NIH HHS [N01 CO 12400] NR 40 TC 37 Z9 38 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2007 VL 109 IS 2 BP 384 EP 391 DI 10.1097/01.AOG.0000252712.62241.1a PN 1 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171YK UT WOS:000246771100022 PM 17267840 ER PT J AU Goldenberg, RL Andrews, WW Hoffman, I Fawzi, W Valentine, M Young, A Read, JS Brown, ER Mudenda, V Kafulafula, G Mwinga, K Taha, TE AF Goldenberg, Robert L. Andrews, William W. Hoffman, Irving Fawzi, Wafai Valentine, Megan Young, Alicia Read, Jennifer S. Brown, Elizabeth R. Mudenda, Victor Kafulafula, George Mwinga, Kasonde Taha, Taha E. TI Fetal fibronectin and adverse infant outcomes in a predominantly human immunodeficiency virus-infected African population - A randomized controlled trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID SPONTANEOUS PRETERM BIRTH; BACTERIAL VAGINOSIS; WEEKS GESTATION; PREDICTION; DELIVERY; CHORIOAMNIONITIS; ANTIBIOTICS; HPTN-024; RISK AB OBJECTIVE To evaluate the relationship between fetal fibronectin and preterm birth and maternal-to-child transmission of human immunodeficiency virus (HIV) in an African population of predominantly HIV-infected women. METHODS: During a trial of second trimester and intraparturn antibiotics compared with placebo to prevent chorioamnionitis and reduce preterm birth and mother-to-child transmission of HIV, vaginal fluid was collected before antibiotics (20-24 weeks) and after treatment at 28 weeks and assayed for fetal fibronectin. Pregnancy outcomes of 2,353 women delivering liveborn singleton infants are presented. RESULTS: Positive fetal fibronectin assays (50 ng/mL or more) were detected in 4.2% and 4.9% of samples at 20-24 weeks and 28 weeks. Positive fetal fibronectin assays at 28 weeks but not at 20-24 weeks were associated with lower mean birthweight (199 g, P<.001); lower mean gestational age (2 weeks, P<.001); six-fold higher rate of preterm birth less than 32 weeks (10.8% compared with 1.9%, odds ratio 6.3, 95% confidence interval 3.2-12.3) and a two-fold higher rate of preterm birth less than 37 weeks (38.7 compared with 22.0%, odds ratio 2.3, 95% confidence interval 1.5-3.3). Also, at 28 weeks, as the fetal fibronectin values increased, each of the outcomes worsened, and every test of trend was significant. An association between elevated fetal fibronectin levels and mother-to-child transmission of HIV was present at 20 to 24 weeks but not at 28 weeks. Antibiotic treatment at 20 to 24 weeks was not associated with fetal fibronectin levels at 28 weeks. CONCLUSION: In a population of predominantly HIV-infected African women, fetal fibronectin concentrations at 28 but not at 20-24 weeks were associated with increased risk of preterm birth. The associations were stronger for early preterm birth and when fetal fibronectin levels were higher. High levels of fetal fibronectin were positively associated with mother-to-child transmission of HIV at 20 -24 but not at 28 weeks. Antibiotic treatment did not influence fetal fibronectin levels. C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Univ N Carolina, Ctr Infect Dis, Chapel Hill, NC USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. Family Hlth Int, Res Triangle Pk, NC USA. SCHARP FHCRC, Seattle, WA USA. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Teaching Hosp, Dept Pathol, Lusaka, Zambia. Univ Malawi, Coll Med, Dept Obstet & Gynecol, Blantyre, Malawi. Univ Teaching Hosp, Dept Pediat & Child Hlth, Lusaka, Zambia. Johns Hopkins Univ, Bloomberg Shc Publ Hlth, Baltimore, MD USA. RP Goldenberg, RL (reprint author), Univ Alabama, Dept Obstet & Gynecol, 1500 6th Ave S,CRWH 379, Birmingham, AL 35233 USA. EM rlg@uab.edu RI Brown, Elizabeth/A-8984-2008 FU NIAID NIH HHS [N01 AI 35173, U01 AI 48005, N01 AI 45200, U01 AI 048006, N01 AI 35173-117/412, U01 AI 47972] NR 22 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2007 VL 109 IS 2 BP 392 EP 401 DI 10.1097/01.AOG.0000247628.68415.00 PN 1 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171YK UT WOS:000246771100023 PM 17267841 ER PT J AU Smith, L AF Smith, Lawrence TI Pregnancy loss rates after midtrimester amniocentesis SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Smith, L (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD FEB PY 2007 VL 109 IS 2 BP 452 EP 452 DI 10.1097/01.AOG.0000244693.92097.3b PN 1 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 171YK UT WOS:000246771100036 PM 17267853 ER PT J AU Raafat, A Zoltan-Jones, A Strizzi, L Bargo, S Kimura, K Salomon, D Callahan, R AF Raafat, A. Zoltan-Jones, A. Strizzi, L. Bargo, S. Kimura, K. Salomon, D. Callahan, R. TI Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis SO ONCOGENE LA English DT Article DE Kit; PDGFR-alpha; Notch4/Int3; Gleevec; phosphorylation; siRNA ID GASTROINTESTINAL STROMAL TUMORS; TRUNCATED INT3 GENE; C-KIT; GROWTH-FACTOR; NEOPLASTIC TRANSFORMATION; ENDOTHELIAL-CELLS; BREAST-CANCER; MOUSE MODEL; STEM-CELLS; MAMMARY AB Transgenic mice overexpressing Notch4 intracellular domain (Int3) under the control of the whey acidic protein (WAP) or mouse mammary tumor virus-long terminal repeat promoters, develop mammary tumors. Microarray analysis of these tumors revealed high levels of c-Kit expression. Gleevec is a tyrosine kinase inhibitor that targets c-Kit, platelet-derived growth factor receptors (PDGFRs) and c-Abl. This led us to speculate that tyrosine kinase receptor activity might be a driving force in the development of Int3 mammary tumors. WAP-Int3 tumor-bearing mice were treated with continuous release of Gleevec using subcutaneously implanted Alzet pumps. Phoshorylation of c-Kit, PDGFRs and c-Abl is inhibited in Int3 transgenic mammary tumors by Gleevec. Inhibition of these enzymes is associated with a decrease in cell proliferation and angiogenesis, and an induction of apoptosis. To examine the signaling mechanisms underlying Notch4/Int3 tumorigenesis, we employed small interfering RNA (siRNA) to knock down c-Kit, PDGFRs and c-Abl alone or in combination and observed the effects on soft agar growth of HC11 cells overexpressing Int3. Only siRNA constructs for c-Kit and/or PDGFR-alpha were able to inhibit HC11-Int3colony formation in soft agar. Our data demonstrate an inhibitory effect of Gleevec on Int3-induced transformation of HC11 cells and mammary tumors and indicate an oncogenic role for c-Kit and PDGFR-alpha tyrosine kinases in the context of Int3 signaling. C1 NCI, Mammary Biol & Tumorigenesis Lab, Oncogenet Sect, NIH, Bethesda, MD 20892 USA. RP Callahan, R (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Oncogenet Sect, NIH, 37 Convent Dr,Bldg 37,Rm 1118A, Bethesda, MD 20892 USA. EM rc54d@nih.gov NR 46 TC 13 Z9 14 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB PY 2007 VL 26 IS 5 BP 662 EP 672 DI 10.1038/sj.onc.1209823 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 131WM UT WOS:000243902200004 PM 16878155 ER PT J AU Trimble, EL Christian, MC AF Trimble, Edward L. Christian, Michaele C. TI Intraperitoneal therapy for ovarian cancer reconsidered - The Hess/Alberts article reviewed SO ONCOLOGY-NEW YORK LA English DT Review C1 [Christian, Michaele C.] NCI, Diag Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Christian, Michaele C.] NCI, Div Canc Treatment, Bethesda, MD 20892 USA. [Trimble, Edward L.] NCI, Surg Sect, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), NCI, Diag Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD FEB PY 2007 VL 21 IS 2 BP 232 EP + PG 2 WC Oncology SC Oncology GA 270RB UT WOS:000253736800011 ER PT J AU Yang, SX Hewitt, SM Steinberg, SM Liewehr, DJ Swain, SM AF Yang, Sherry X. Hewitt, Stephen M. Steinberg, Seth M. Liewehr, David J. Swain, Sandra M. TI Expression levels of eIF4E, VEGF, and cyclin D1, and correlation of e1F4E with VEGF and cyclin D1 in multi-tumor tissue microarray SO ONCOLOGY REPORTS LA English DT Article DE cyclin D1; eukaryotic initiation factor 4E; tissue microarray; vascular endothelial growth factor ID INITIATION-FACTOR 4E; ENDOTHELIAL GROWTH-FACTOR; TRANSLATION INITIATION; BREAST-CANCER; MESSENGER-RNA; MICROVESSEL DENSITY; CELL-LINES; STAGE-I; CARCINOMA; PROTEIN AB The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), is a rate-limiting factor of cap-dependent translation initiation. When elevated, eIF4E greatly facilitates translation of a selected spectrum of mRNAs coding for proteins critical to angiogenesis and growth such as vascular endothelial growth factor (VEGF) and cyclin D1. Expression levels of eIF4E, VEGF, and cyclin D1 were examined in multi-tumor tissue microarray by immunohistochemistry and analyzed quantitatively. eIF4E, VEGF and cyclin D1 protein were elevated in tumors of the breast (62, 78, or 40%), colon (72, 77, or 12%), glioblastoma multiforme (48, 68, or 52%), lymphoma (66, 74, or 38%), melanoma (59, 73, or 58%), NSCLC (81, 82, or 29%), ovary (50, 39, or 13%), and prostate (78, 97, or 21%), respectively. eIF4E levels were strongly correlated with VEGF and cyclin D1 in melanoma (Spearman's r=0.97 and 0.77; all P < 0.0001); moderately in tumors of the breast (r=0.55 and 0.41; all P < 0.0005), colon (0.63 and 0.56; all P < 0.0001), lung (0.53 and 0.53; all P < 0.005), lymphoma (0.50 and 0.61; all P < 0.0005), prostate (0.46 and 0.54; all P < 0.005), or ovary (0.56 and 0.46; all P < 0.005); and weakly in tumors of glioblastoma multiforme (r=0.20 and 0.31; all P > 0.15). The significant association of eIF4E with VEGF and cyclin D1 in multiple tumors supports a role for eIF4E in translational regulation of proteins related to angiogenesis and growth. C1 NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. NCI, Lab Pathol, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yang, SX (reprint author), 37 Convent Dr,Bldg 37-Rm 1048A, Bethesda, MD 20892 USA. EM yangxia@mail.nih.gov NR 34 TC 30 Z9 40 U1 0 U2 4 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD FEB PY 2007 VL 17 IS 2 BP 281 EP 287 PG 7 WC Oncology SC Oncology GA 127UI UT WOS:000243611400002 PM 17203162 ER PT J AU He, MG Huang, WY Zheng, YF Huang, L Ellwein, LB AF He, Mingguang Huang, Wenyong Zheng, Yingfeng Huang, Li Ellwein, Leon B. TI Refractive error and visual impairment in school children in rural southern China SO OPHTHALMOLOGY LA English DT Article ID SHUNYI DISTRICT; AGE-CHILDREN; MYOPIA; POPULATION; WORK; SCHOOLCHILDREN; TAIWAN AB Purpose: To assess the prevalence of refractive error and visual impairment in schoolchildren in a rural area of southern China. Design: Prospective cross-sectional survey. Participants: Two thousand four hundred children from junior high schools in Yangxi County. Methods: Random selection of classes from the 3 junior high school grade levels was used to identify the study sample. Children from 36 classes in 13 schools were examined in April 2005. The examination included visual acuity (VA) testing; ocular motility evaluation; cycloplegic autorefraction; and examination of the external eye, anterior segment, media, and fundus. Main Outcome Measures: Distance VA and cycloplegic refraction. Results: Among 2515 enumerated children, 2454 (97.6%) were examined. The study population consisted of the 2400 children between 13 and 17 years old. Prevalences of uncorrected, presenting, and best-corrected VA <= 20/40 in the better eye were 27.0%, 16.6%, and 0.46%, respectively. Sixty percent of those who could achieve acuity >= 20/32 in at least one eye with best correction were without the necessary spectacles. Refractive error was the cause in 97.1% of eyes with reduced vision; amblyopia, 0.81%; other causes, 0.67%; and unexplained causes, 1.4%. Myopia (spherical equivalent, -0.50 diopters [D] or more in either eye) affected 36.8% of 13-year-olds, increasing to 53.9% of 17-year-olds. Myopia was associated with higher grade level, female gender, schooling in the county urban center, and higher parental education. Hyperopia (+2.00 D or more) affected approximately 1.0% in all age groups. Astigmatism ( >= 0.75 D) was present in 25.3% of all children. Conclusions: Reduced vision because of uncorrected myopia is a public health problem among school-age children in rural China. Effective VA screening strategies are needed to eliminate this easily treated cause of visual impairment. C1 NEI, NIH, Bethesda, MD 20892 USA. Sun Yat Sen Univ, Key Lab Ophthalmol, Guangzhou, Peoples R China. Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou, Peoples R China. Helen Keller Int, New York, NY USA. Guangming Eye Hosp, Yangjiang, Peoples R China. RP Ellwein, LB (reprint author), NEI, NIH, 31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM ellweinl@nei.nih.gov OI He, Mingguang/0000-0002-6912-2810 FU NEI NIH HHS [N01-EY-2103] NR 29 TC 139 Z9 156 U1 7 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2007 VL 114 IS 2 BP 374 EP 382 DI 10.1016/j.ophtha.2006.08.020 PG 9 WC Ophthalmology SC Ophthalmology GA 131CC UT WOS:000243844600028 PM 17123622 ER PT J AU Tallent, CR Twine, CE Risbood, P Seltzman, HH AF Tallent, C. R. Twine, C. E., Jr. Risbood, P. Seltzman, H. H. TI An improved preparation of 2,2,4,4-tetramethyl-6-aminothiochroman, a key intermediate to urea and thiourea heteroarotinoids for anticancer studies SO ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL LA English DT Article C1 RTI Int, Res Triangle Pk, NC 27709 USA. NCI, Drug Synth & Chem Branch, Bethesda, MD 20892 USA. RP Seltzman, HH (reprint author), RTI Int, Res Triangle Pk, NC 27709 USA. EM hhs@rti.org NR 6 TC 3 Z9 3 U1 0 U2 0 PU ORGANIC PREP PROCEDURES INC PI NEWTON HIGHLANDS PA PO BOX 9, NEWTON HIGHLANDS, MA 02161 USA SN 0030-4948 J9 ORG PREP PROCED INT JI Org. Prep. Proced. Int. PD FEB PY 2007 VL 39 IS 1 BP 96 EP 101 PG 6 WC Chemistry, Organic SC Chemistry GA 135KT UT WOS:000244153200008 ER PT J AU Mansky, P Arai, A Stratton, P Bernstein, D Long, L Reynolds, J Chen, D Steinberg, SM Lavende, N Hoffman, K Nathan, PC Parks, R Augustine, E Chaudhry, U Derdak, J Wiener, L Gerber, L Mackall, C AF Mansky, Patrick Arai, Andrew Stratton, Pamela Bernstein, Donna Long, Lauren Reynolds, James Chen, Donna Steinberg, Seth M. Lavende, Neil Hoffman, Karen Nathan, Paul C. Parks, Rebecca Augustine, Elizabeth Chaudhry, Usha Derdak, Joanne Wiener, Lori Gerber, Lynn Mackall, Crystal TI Treatment late effects in long-term survivors of pediatric sarcoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE cancer survivors; cardiac; infertility; late effects; musculoskeletal; renal; stress; treatment ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHILDHOOD-CANCER SURVIVORS; STRESS ECHOCARDIOGRAPHY; DOXORUBICIN THERAPY; METABOLIC SYNDROME; EWINGS-SARCOMA; RISK-FACTORS; RADIOTHERAPY; NEOPLASMS AB Purpose. To assess health and musculoskeletal function in survivors of pediatric sarcomas. Patients and Methods. Thirty-two individuals treated for Ewing sarcoma family of tumors (ESFT), rhabdomyosarcoma (RMS), or non-rhabdomyosarcoma soft tissue sarcomas (NR-STS) with multi-modality therapy were enrolled on this cross-sectional study. Median age at the time of therapy was 15.4 years (range 7.1-34.2), median age at the time of analysis was 37.4 years (17.5-55.4), and median duration of time elapsed from completion of therapy was 17.3 years (2.9-32.6). Participants underwent assessments of musculoskeletal functioning, cardiac function, metabolic and lipid analyses, renal and gonadal function, and psychological evaluation. Results. This cohort of sarcoma survivors shows expected locoregional limitations in function of the area affected by sarcoma, and impaired global musculoskeletal functioning as evidenced by limited endurance and limited overall activity levels. The cohort also demonstrated substantial rates of cardiac dysfunction, elevated body fat index, hyperlipidemia, chronic psychological distress, and infertility in men (76%) and premature menopause (49%) in women. Conclusion. Sarcoma Survivors demonstrate diminished locoregional and global musculoskeletal functioning which likely limit occupational opportunities and socioeconomic health. in addition, the combination of diminished cardiac reserve, limited activity levels, and lipid dysregulation in sarcoma survivors suggests that this population is at increased risk for cardiovascular disease, even many years following completion of sarcoma therapy. Sarcoma survivors may benefit from life long follow-Lip for cardiovascular disease and from occupational counseling upon completion of therapy. C1 NIH, Div Intramural Res, Natl Ctr Complementary & Alternat Med, DHHS, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. Ctr Clin, Dept Nucl Med, Bethesda, MD USA. Ctr Clin, Dept Rehabil Med, Bethesda, MD USA. NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, NIH, DHHS, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. RP Mansky, P (reprint author), NIH, Div Intramural Res, Natl Ctr Complementary & Alternat Med, DHHS, 10 Ctr Dr,Bldg 10,CRC,Room 4-1730,MSC 1302, Bethesda, MD 20892 USA. EM manskyp@mail.nih.gov FU Intramural NIH HHS NR 28 TC 35 Z9 37 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD FEB PY 2007 VL 48 IS 2 BP 192 EP 199 DI 10.1002/pbc.20871 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 117LX UT WOS:000242875800013 PM 16642490 ER PT J AU Paulson, JA Arnesen, SJ AF Paulson, Jerome A. Arnesen, Stacey J. TI The use of the Internet for children's health and the environment SO PEDIATRIC CLINICS OF NORTH AMERICA LA English DT Article AB The Internet can provide a wealth of information related to the effects of environmental exposures on children's health. This article provides guidance on searching the Internet for pertinent information and discusses how to evaluate such information. It also provides an extensive list of environmental-health-related websites hosted by governmental and nongovernmental agencies, and other organizations. C1 Mid Atlantic Ctr Childrens Hlth & Environm, Washington, DC 20052 USA. George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. Natl Lib Med, Specialized Informat Serv, Bethesda, MD 20892 USA. RP Paulson, JA (reprint author), Mid Atlantic Ctr Childrens Hlth & Environm, 2300 M St NW 203, Washington, DC 20052 USA. EM jpaulson@cnmc.org NR 8 TC 4 Z9 4 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0031-3955 J9 PEDIATR CLIN N AM JI Pediatr. Clin. N. Am. PD FEB PY 2007 VL 54 IS 1 BP 135 EP + DI 10.1016/j.pcl.2006.11.011 PG 21 WC Pediatrics SC Pediatrics GA 146PY UT WOS:000244947900010 PM 17306688 ER PT J AU Hill, SC Namde, M Dwyer, A Poznanski, A Canna, S Goldbach-Mansky, R AF Hill, Suvimol Chirathivat Namde, Madjimbaye Dwyer, Andrew Poznanski, Andrew Canna, Scott Goldbach-Mansky, Raphaela TI Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA) SO PEDIATRIC RADIOLOGY LA English DT Article DE NOMID/CINCA; knee; arthropathy; CIAS1; neonate ID AUTOINFLAMMATORY DISEASES; ARTICULAR SYNDROME; INTERLEUKIN-1; PATHOGENESIS; MUTATIONS; ANAKINRA; GROWTH; CELLS; CIAS1; ASC AB Background Neonatal onset multisystem inflammatory disease (NOMID), an autoinflammatory disease, is characterized by fever, chronic urticarial rash, CNS manifestations, and arthropathy. Approximately 50% of patients with NOMID have de novo missense mutations in CIAS1, which is associated with modulation of the IL-1b and apoptotic pathways. Approximately 60% of NOMID patients have prominent arthropathy, most commonly involving the knees, the cause of which remains poorly understood. Objective To more fully describe the findings of NOMID arthropathy on MRI and radiography and to provide a better understanding of the origin of the bony lesions. Materials and methods We imaged 20 patients with NOMID to further investigate NOMID-associated bony lesions. Results Bony abnormalities were seen in the knees of 11/20 patients. The knee findings included enlarged, deformed femora and patellae in all and tibiae in the majority, without evidence of synovitis. Some patients had other joint involvement. Most had short stature and valgus or varus knee deformities. No association was noted between bony abnormalities and CIAS1 mutations. The abnormalities appeared to be the result of a mass-producing process. The resulting heterogeneously calcified masses appeared to originate in the physis and deformed the adjacent metaphysis and epiphysis. Conclusion These findings suggest that the arthropathy of NOMID is the result of abnormal endochondral bone growth. Further investigation is needed to determine whether this deformity is triggered by inflammation early in development or by CIAS1 mutations causing abnormal chondrocyte apoptosis. C1 Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Northwestern Univ, Childrens Mem Hosp, Dept Radiol, Chicago, IL 60614 USA. RP Hill, SC (reprint author), Warren G Magnuson Clin Ctr, NIH, 10 Ctr Dr,Rm N242, Bethesda, MD 20892 USA. EM shill@nih.gov OI Canna, Scott/0000-0003-3837-5337 NR 22 TC 47 Z9 48 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD FEB PY 2007 VL 37 IS 2 BP 145 EP 152 DI 10.1007/s00247-006-0358-0 PG 8 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 125TU UT WOS:000243466500004 PM 17136361 ER PT J AU Persaud-Sawin, DA Mousallem, T Wang, C Zucker, A Kominami, E Boustany, RMN AF Persaud-Sawin, Dixie-Ann Mousallem, Talal Wang, Christine Zucker, Adam Kominami, Eiki Boustany, Rose-Mary N. TI Neuronal ceroid lipofuscinosis: A common pathway? SO PEDIATRIC RESEARCH LA English DT Article ID LATE INFANTILE; CLN3; PROTEINS; APOPTOSIS; DISEASE AB The neuronal ceroid lipofuscinoses are pediatric neurodegenerative diseases with common clinical features. Of the nine clinical variants (CLN1-CLN9), six have been genetically identified. Most variants manifest cell death and dysregulated sphingolipid metabolism, suggesting the proteins defective in these disorders may interact along one pathway. NCL patient-derived cell lines exhibit cell growth and apoptotic defects that reverse following transfection with the wild-type gene. The membrane-bound proteins CLN3, CLN6, and CLN8 complement each other, as do CLN1 and CLN2 proteins, with respect to growth and apoptosis. The CLN2 protein also corrects growth and apoptosis in CLN3-, CLN6-, and CLN8-deficient cell lines. Neither CLN1-deficient nor CLN2-deficient growth defects are corrected by CLN3, CLN6, and CLN8 proteins. CLN2, CLN3, CLN6, and CLN8 proteins co-immunoprecipitate and co-localize to early and/or recycling endosomes and lipid rafts. Additionally, CLN2p and CLN1p co-immunoprecipitate. The work presented supports interactions between NCL proteins occurring at multiple points along one pathway. C1 Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. NIEHS, Lab Neurobiol Neurotoxicol, NIH, Res Triangle Pk, NC 27709 USA. Juntendo Univ, Sch Med, Dept Biochem, Tokyo 1138421, Japan. Amer Univ Beirut, Med Ctr, Abu Haidar Neurosci Inst, Beirut 11072020, Lebanon. RP Boustany, RMN (reprint author), Duke Univ, Med Ctr, Dept Pediat, Res Dr,MSRB 281B, Durham, NC 27710 USA. EM boust001@mc.duke.edu RI Kominami, Eiki/D-3802-2009 NR 22 TC 29 Z9 29 U1 0 U2 1 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD FEB PY 2007 VL 61 IS 2 BP 146 EP 152 DI 10.1203/pdr.0b013e31802d8a4a PG 7 WC Pediatrics SC Pediatrics GA 129FT UT WOS:000243714700004 PM 17237713 ER PT J AU Sun, SS Grave, GD Siervogel, RM Pickoff, AA Arslanian, SS Daniels, SR AF Sun, Shumei S. Grave, Gilman D. Siervogel, Roger M. Pickoff, Arthur A. Arslanian, Silva S. Daniels, Stephen R. TI Systolic blood pressure in childhood predicts hypertension and metabolic syndrome later in life SO PEDIATRICS LA English DT Article DE childhood blood pressure; adult hypertension; metabolic syndrome ID BODY-MASS INDEX; ADULT OVERWEIGHT; NATIONAL-HEALTH; YOUNG ADULTHOOD; SERIAL CHANGES; RISK-FACTORS; FOLLOW-UP; CHILDREN; ADOLESCENCE; PREVALENCE AB OBJECTIVE. The goal was to link hypertension and the metabolic syndrome in adulthood directly to blood pressures measured decades earlier for the same individuals as children and to establish criterion values for blood pressure that predict hypertension and the metabolic syndrome later in life. METHODS. We analyzed serial data for 240 men and 253 women in the Fels Longitudinal Study. We derived age- and gender- specific childhood blood pressures that predict hypertension and the metabolic syndrome in adulthood, and we validated these criterion values in a larger sample. RESULTS. Blood pressure diverged between adults with and without the metabolic syndrome beginning at age 5 for boys and age 8 for girls. The odds ratios for developing hypertension at >= 30 years of age ranged from 1.1 for 14- to 18-year-old boys to 3.8 for 5- to 7-year-old boys and from 2.7 for 8- to 13-year-old girls to 4.5 for 5- to 7-year-old girls, if their blood pressure exceeded criterion values at a single examination in childhood. The corresponding odds ratios for the metabolic syndrome, with or without hypertension, ranged from 1.2 for 14- to 18-year-old boys to 2.6 for 8- to 13-year-old boys and from 1.5 for 14- to 18-year-old girls to 3.1 for 5- to 7-year-old girls. The relative risk of adult hypertension ranged from 1.5 to 3.8 for boys and from 1.5 to 4.7 for girls, and that of the metabolic syndrome ranged from 1.1 to 1.8 for boys and from 1.2 to 5.6 for girls. These relative risks varied directly with the number of examinations at which systolic blood pressure exceeded criterion values. CONCLUSION. Children with systolic blood pressures above the criterion values established in this longitudinal study are at increased risk of hypertension and the metabolic syndrome later in life. C1 Wright State Univ, Boonshoft Sch Med, Dept Community Hlth, Lifespan Hlth Res Ctr, Dayton, OH 45420 USA. Wright State Univ, Boonshoft Sch Med, Dept Pediat, Dayton, OH 45420 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. Univ Colorado, Sch Med, Dept Pediat, Denver, CO 80202 USA. RP Sun, SS (reprint author), Wright State Univ, Boonshoft Sch Med, Dept Community Hlth, Lifespan Hlth Res Ctr, 3171 Res Blvd, Dayton, OH 45420 USA. EM shumei.sun@wright.edu FU NHLBI NIH HHS [HL 072838]; NICHD NIH HHS [HD 12252, R01 HD012252, R01 HD060913]; NIDDK NIH HHS [DK 071485] NR 26 TC 124 Z9 134 U1 0 U2 6 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2007 VL 119 IS 2 BP 237 EP 246 DI 10.1542/peds.2006-2543 PG 10 WC Pediatrics SC Pediatrics GA 132KP UT WOS:000243942000002 PM 17272612 ER PT J AU Alexander, D van Dyck, PC AF Alexander, Duane van Dyck, Peter C. TI Neonatal screening: Old dogma or sound principle? In reply. SO PEDIATRICS LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. Hlth Resources & Serv Adm, Rockville, MD 20857 USA. RP Alexander, D (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2007 VL 119 IS 2 BP 407 EP 407 DI 10.1542/peds.2006-3178 PG 1 WC Pediatrics SC Pediatrics GA 132KP UT WOS:000243942000022 ER PT J AU Bada, HS Das, A Bauer, CR Shankaran, S Lester, B LaGasse, L Hammond, J Wright, LL Higgins, R AF Bada, Henrietta S. Das, Abhik Bauer, Charles R. Shankaran, Seetha Lester, Barry LaGasse, Linda Hammond, Jane Wright, Linda L. Higgins, Rosemary TI Impact of prenatal cocaine exposure on child behavior problems through school age SO PEDIATRICS LA English DT Article DE child behavior; prenatal exposure; cocaine; tobacco; alcohol ID MATERNAL LIFE-STYLE; DEFICIT HYPERACTIVITY DISORDER; ENVIRONMENTAL TOBACCO-SMOKE; IN-UTERO; SUBSTANCE EXPOSURE; DRUG EXPOSURE; AGGRESSIVE-BEHAVIOR; ANTISOCIAL-BEHAVIOR; COMMUNITY VIOLENCE; MENTAL-HEALTH AB OBJECTIVE. We examined the trajectory of childhood behavior problems after prenatal cocaine exposure. METHODS. The Maternal Lifestyle Study, a longitudinal cohort study, enrolled children between 1993 and 1995 at 4 centers. Prenatal cocaine exposure was determined from mothers who admitted use and/or meconium results. Exposed children were matched with a group of nonexposed children within site and by gestational age, gender, race, and ethnicity. The study began at the 1-month corrected age with a total of 1388 children enrolled. A total of 1056 were assessed for internalizing, externalizing, and total behavior problems at ages 3, 5, and 7 years using the Child Behavior Checklist. Longitudinal hierarchical linear models were used to determine the effect of prenatal cocaine exposure on behavior problem trajectories while controlling for other prenatal exposures; time-varying covariates, including ongoing caregiver use of legal and illegal substances; demographic factors; family violence; and caregiver psychological distress. RESULTS. High prenatal cocaine exposure was associated with the trajectory of internalizing, externalizing, and total behavior problems; these effects were independent of and less than the significant combined effect of prenatal and postnatal tobacco and alcohol exposures. Caregiver depression and family violence had independent negative influence on all behavior outcomes. CONCLUSIONS. Prenatal cocaine exposure has a negative impact on the trajectories of childhood behavior outcomes. When they co-occur with prenatal cocaine exposure, prenatal and postnatal tobacco and alcohol exposures have added negative effects on behavior outcomes. C1 Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Pediat, Lexington, KY 40536 USA. Res Triangle Inst Int, Res Triangle Pk, NC USA. Univ Miami, Sch Med, Dept Pediat, Miami, FL 33152 USA. Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. NICHHD, Bethesda, MD 20892 USA. RP Bada, HS (reprint author), Univ Kentucky, Albert B Chandler Med Ctr, Coll Med, Dept Pediat, 800 Rose St,Room MS 477, Lexington, KY 40536 USA. EM hbada2@uky.edu FU NICHD NIH HHS [N01-HD-2-3159, U01 HD 36790, U10 HD 21385, U10 HD 21397, U10 HD 21415, U10 HD 27904, U10 HD021385]; NIDA NIH HHS [U10 DA024119] NR 93 TC 66 Z9 67 U1 2 U2 12 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2007 VL 119 IS 2 BP E348 EP E359 DI 10.1542/peds.2006-1404 PG 12 WC Pediatrics SC Pediatrics GA 132KP UT WOS:000243942000054 PM 17272597 ER PT J AU Comeau, AM Accurso, FJ White, TB Campbell, PW Hoffman, G Parad, RB Wilfond, BS Rosenfeld, M Sontag, MK Massie, J Farrell, PM O'Sullivan, BP AF Comeau, Anne Marie Accurso, Frank J. White, Terry B. Campbell, Preston W., III Hoffman, Gary Parad, Richard B. Wilfond, Benjamin S. Rosenfeld, Margaret Sontag, Marci K. Massie, John Farrell, Philip M. O'Sullivan, Brian P. TI Guidelines for implementation of cystic fibrosis newborn screening programs: Cystic Fibrosis Foundation workshop report SO PEDIATRICS LA English DT Article DE newborn screening; cystic fibrosis; genotype; sweat test; guidelines ID SWEAT CHLORIDE CONCENTRATIONS; IMMUNOREACTIVE TRYPSINOGEN; EARLY-DIAGNOSIS; CONSENSUS STATEMENT; UNITED-STATES; LUNG-DISEASE; MUTATION; OUTCOMES; INFANTS; CHILDREN AB Newborn screening for cystic fibrosis offers the opportunity for early intervention and improved outcomes. This summary, resulting from a workshop sponsored by the Cystic Fibrosis Foundation to facilitate implementation of widespread high quality cystic fibrosis newborn screening, outlines the steps necessary for success based on the experience of existing programs. Planning should begin with a workgroup composed of those who will be responsible for the success of the local program, typically including the state newborn screening program director and cystic fibrosis care center directors. The workgroup must develop a screening algorithm based on program resources and goals including mechanisms available for sample collection, regional demographics, the spectrum of cystic fibrosis disease to be detected, and acceptable failure rates of the screen. The workgroup must also ensure that all necessary guidelines and resources for screening, diagnosis, and care be in place prior to cystic fibrosis newborn screening implementation. These include educational materials for parents and primary care providers; systems for screening and for providing diagnostic testing and counseling for screen-positive infants and their families; and protocols for care of this unique population. This summary explores the benefits and risks of various screening algorithms, including complex situations that can occur involving unclear diagnostic results, and provides guidelines and sample materials for state newborn screening programs to develop and implement high quality screening for cystic fibrosis. C1 Cyst Fibrosis Fdn, Bethesda, MD 20814 USA. Univ Massachusetts, Sch Med, New England Newborn Screening Program, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Pediat, Worcester, MA 01605 USA. Univ Colorado, Hlth Sci Ctr, Dept Pediat, Mike McMorris Cyst Fibrosis Res & Treatment Ctr, Denver, CO 80202 USA. Childrens Hosp, Denver, CO 80218 USA. Univ Wisconsin, State Lab Hyg, Madison, WI USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. Brigham & Womens Hosp, Dept Newborn Med, Boston, MA 02115 USA. Childrens Hosp, Dept Newborn Med, Boston, MA 02115 USA. NHGRI, Behav Res Branch, Bethesda, MD USA. NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med, Denver, CO 80202 USA. Royal Childrens Hosp, Dept Resp Med, Melbourne, Vic, Australia. Univ Massachusetts, Med Ctr, Dept Pediat, Worcester, MA 01605 USA. RP White, TB (reprint author), Cyst Fibrosis Fdn, 6931 Arlington Rd, Bethesda, MD 20814 USA. EM tlbjww@att.net RI Parad, Richard/E-8559-2010 FU NIDDK NIH HHS [DK61886-01] NR 98 TC 61 Z9 63 U1 1 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2007 VL 119 IS 2 BP E495 EP E518 DI 10.1542/peds.2006-1993 PG 24 WC Pediatrics SC Pediatrics GA 132KP UT WOS:000243942000071 PM 17272609 ER PT J AU Thorsell, A AF Thorsell, Annika TI Neuropeptide Y (NPY) in alcohol intake and dependence SO PEPTIDES LA English DT Article; Proceedings Paper CT 8th International NPY Meeting CY APR 22-26, 2006 CL St Petersburg, FL DE alcohol intake; post-dependent state; rat; Y2 receptor ID ETHANOL-CONSUMPTION; WISTAR RATS; ELECTROCONVULSIVE STIMULATION; PARAVENTRICULAR NUCLEUS; RESTRAINT STRESS; TRANSGENIC RATS; INCREASES; EXPOSURE; BRAIN; RECEPTORS AB Neuropeptide Y has a role in alcohol intake and dependence. NPY's effect on alcohol intake appears to be in part dependent on the individual's history of alcohol dependence. In models of high intake such as alcohol-preferring, selectively bred rat lines (e.g., the P-line and the HAD line), as well as in ethanol-vapor-exposed subjects, NPY modulates alcohol intake while leaving it unaffected during baseline conditions. The primary receptor subtype mediating NPY's effect on ethanol intake remains in question. The Y2-antagonist BIIE0246 significantly suppresses ethanol intake in an operant paradigm with a sensitization to the effect of BIIE0246 in vapor-exposed subjects. We propose the NPY system to be one of the most interesting target systems for the development of treatments for alcohol abuse and dependence. (c) 2007 Published by Elsevier Inc. C1 NIAAA, Lab Clin Translat Studies, NIH, Bethesda, MD 20892 USA. RP Thorsell, A (reprint author), NIAAA, Lab Clin Translat Studies, NIH, Bldg 10 CRC Room 1-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM annika.thorsell@mail.nih.gov OI Thorsell, Annika/0000-0003-3535-3845 NR 39 TC 31 Z9 31 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD FEB PY 2007 VL 28 IS 2 SI SI BP 480 EP 483 DI 10.1016/j.peptides.2006.11.017 PG 4 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 140XJ UT WOS:000244539800041 PM 17239487 ER PT J AU Srivastava, S Wagner, PD AF Srivastava, Sudbir Wagner, Paul D. TI Risk-based and diagnostics-linked personalized medicine for cancer SO PERSONALIZED MEDICINE LA English DT Review DE biomarkers; cancer; oncogenes; ratoxifene; risk assessment; tamoxifen; tumor suppressor genes ID CELL LUNG-CANCER; STAR P-2 TRIAL; BREAST-CANCER; PREVENTION TRIAL; PROSTATE-CANCER; TYROSINE KINASE; BRCA2 MUTATION; INHIBITOR; TAMOXIFEN; PHARMACOGENETICS AB Personalized medicine is gaining momentum in healthcare by allowing physicians to determine an individual's predisposition to different diseases and to better diagnose and treat those diseases. Personalized medicine is frequently described as the right drug for the right patient at the right time; that is, a physician will prescribe treatment based on the individual characteristics of each patient such that the patient is likely to respond to a particular treatment with minimal adverse events. The heterogeneity of cancer makes the implementation of personalized medicine a necessity. C1 [Srivastava, Sudbir; Wagner, Paul D.] NCI, Canc Biomarkers Res Grp, Div Canc Prevent, NIH, Rockville, MD 20892 USA. RP Srivastava, S (reprint author), NCI, Canc Biomarkers Res Grp, Div Canc Prevent, NIH, 6130 Execut Blvd,Suite 3142, Rockville, MD 20892 USA. EM ssla@nih.gov NR 50 TC 0 Z9 0 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1741-0541 J9 PERS MED JI Pers. Med. PD FEB PY 2007 VL 4 IS 1 BP 33 EP 43 DI 10.2217/17410541.4.1.33 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 271IC UT WOS:000253781100009 ER PT J AU Lee, CR Bottone, FG Krahn, JM Li, LP Mohrenweiser, HW Cook, ME Petrovich, RM Bell, DA Eling, TE Zeldin, DC AF Lee, Craig R. Bottone, Frank G., Jr. Krahn, Joseph M. Li, Leping Mohrenweiser, Harvey W. Cook, Molly E. Petrovich, Robert M. Bell, Douglas A. Eling, Thomas E. Zeldin, Darryl C. TI Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1) SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE COX-1; cyclooxygenase-1; polymorphism; PTGS1 ID ENDOPEROXIDE-H SYNTHASE-1; SELECTIVE-INHIBITION; ARACHIDONIC-ACID; ACTIVE-SITE; PROSTAGLANDIN; GENE AB Objective Cyclooxygenase-1 (COX-1, PTGS1) catalyzes the conversion of arachidonic acid to prostaglandin H2, which is subsequently metabolized to various biologically active prostaglandins. We sought to identify and characterize the functional relevance of genetic polymorphisms in PTGS1. Methods Sequence variations in human PTGS1 were identified by resequencing 92 healthy individuals (24 African, 24 Asian, 24 European/Caucasian, and 20 anonymous). Using site-directed mutagenesis and a baculovirus/insect cell expression system, recombinant wild-type COX-1 and the R8W, P17L, R53H, R78W, K185T, G230S, L237M, and V481I variant proteins were expressed. COX-1 metabolic activity was evaluated in vitro using an oxygen consumption assay under basal conditions and in the presence of indomethacin. Results Forty-five variants were identified, including seven nonsynonymous polymorphisms encoding amino acid substitutions in the COX-1 protein. The R53H (35 +/- 5%), R78W (36 +/- 4%), K185T (59 +/- 6%), G230S (57 +/- 4%), and L237M (51 +/- 3%) variant proteins had significantly lower metabolic activity relative to wild-type (100 +/- 7%), while no significant differences were observed with the R8W (104 +/- 10%), P17L (113 +/- 7%), and V481I (121 +/- 10%) variants. Inhibition studies with indomethacin demonstrated that the P17L and G230S variants had significantly lower IC50 values compared to wild-type, suggesting these variants significantly increase COX-1 sensitivity to indomethacin inhibition. Consistent with the metabolic activity data, protein modeling suggested the G230S variant may disrupt the active conformation of COX-1. Conclusions Our findings demonstrate that several genetic variants in human COX-1 significantly alter basal COX-1-mediated arachidonic acid metabolism and indomethacin-mediated inhibition of COX-1 activity in vitro. Future studies characterizing the functional impact of these variants in vivo are warranted. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Div Pharmacol & Expt Therapeut, Chapel Hill, NC 27515 USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. Oregon Hlth Sci Univ, Ctr Res Occupat Toxicol, Portland, OR 97201 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Lee, Craig/0000-0003-3595-5301 FU Intramural NIH HHS [Z01 ES025043-08]; NIEHS NIH HHS [ES012856, F32 ES012856-02, F32 ES012856-01, F32 ES012856, F32 ES012856-03] NR 38 TC 31 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD FEB PY 2007 VL 17 IS 2 BP 145 EP 160 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 139WR UT WOS:000244463900006 PM 17301694 ER PT J AU Davis, CD AF Davis, Cindy D. TI Nutrigenomics and the prevention of colon cancer SO PHARMACOGENOMICS LA English DT Editorial Material ID GENE-EXPRESSION PROFILES; COLORECTAL-CANCER; DNA METHYLATION; FOLATE; CARCINOGENESIS; PROTEIN; CELLS; TUMORIGENESIS; POLYMORPHISMS; PROTEOMICS C1 NCI, Nutr Sci Res Grp, NIH, Bethesda, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, NIH, 6130 Execut Blvd,MSC 7328, Bethesda, MD 20892 USA. EM davisci@mail.nih.gov NR 25 TC 5 Z9 5 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD FEB PY 2007 VL 8 IS 2 BP 121 EP 124 DI 10.2217/146224168.8.2.121 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 139WU UT WOS:000244464200002 PM 17286532 ER PT J AU Hasko, G Pacher, P Deitch, EA Vizi, ES AF Hasko, Gyorgy Pacher, Pal Deitch, Edwin A. Vizi, E. Sylvester TI Shaping of monocyte and macrophage function by adenosine receptors SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE infection; autoimmunity; asthma; sepsis; arthritis; colitis ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA RELEASE; TISSUE FACTOR EXPRESSION; NITRIC-OXIDE PRODUCTION; FACTOR-KAPPA-B; TRIGGERED RESPIRATORY BURST; BLOOD MONONUCLEAR-CELLS; MARROW-DERIVED CELLS; TNF-ALPHA; A(2A) RECEPTOR AB Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A(1), A(2A), A(2B) and A(3)) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-alpha, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases. (c) 2006 Published by Elsevier Inc. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. Inst Expt Med, Dept Pharmacol, Budapest, Hungary. NIAAA, Sect Oxidat Stress, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Intramural NIH HHS [Z01 AA000375-02]; NIGMS NIH HHS [R01 GM066189, R01 GM066189-01, R01 GM066189-02, R01 GM66189] NR 126 TC 112 Z9 115 U1 3 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2007 VL 113 IS 2 BP 264 EP 275 DI 10.1016/j.pharmthera.2006.08.003 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 139CA UT WOS:000244408500003 PM 17056121 ER PT J AU Engel, S Gershengorn, MC AF Engel, Stanislav Gershengorn, Marvin C. TI Thyrotropin-releasing hormone and its receptors - A hypothesis for binding and receptor activation SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE GPCR activation; TRH receptor; structure-activity relationships; active conformation; ligand binding; agonist ID PROTEIN-COUPLED RECEPTORS; BETA-ADRENERGIC-RECEPTOR; LIGAND-BINDING; TRH RECEPTOR; CONFORMATIONAL STATES; EXTRACELLULAR LOOPS; SEQUENTIAL BINDING; REFINED MODEL; ANALOGS; RHODOPSIN AB THyrotropin-releasing hormone (TRH), a tripeptide, exerts its biological effects through stimulation of cell-surface receptors, TRH-R, belonging to the superfamily of G protein-coupled receptors (GPCR). Because of the intermediate size of TRH, it is smaller than polypeptide ligands that interact at GPCR ectodomains and larger than biogenic amines, which interact within GPCR transmembrane domains (TMD), the TRH/TRH-R complex probably shares properties of these 2 extremes, representing a unique system to study GPCR/ligand interactions. In this review, we summarize the current knowledge of the structure-activity relationships in the TRH/TRH-R system. Based on experimental data and the structural information acquired from computer simulations, we formulate a working hypothesis to describe the molecular events underlying the processes of TRH binding and TRH-R activation. This hypothesis represents a starting point for understanding the biology of the TRH/TRH-R system on a molecular level and provides a basis for potential design of new potent and selective modulators of TRH-R's activity. (c) 2006 Elsevier Inc. All rights reserved. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 50,Room 4133, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov RI Engel, Stanislav/G-2799-2013 FU Intramural NIH HHS [Z01 DK011006-04] NR 41 TC 19 Z9 21 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2007 VL 113 IS 2 BP 410 EP 419 DI 10.1016/j.pharmthera.2006.09.004 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 139CA UT WOS:000244408500012 PM 17123625 ER PT J AU Paolocci, N Jackson, MI Lopez, BE Miranda, K Tocchetti, CG Wink, DA Hobbs, AJ Fukuto, JM AF Paolocci, Nazareno Jackson, Matthew I. Lopez, Brenda E. Miranda, Katrina Tocchetti, Carlo G. Wink, David A. Hobbs, Adrian. J. Fukuto, Jon M. TI The pharmacology of nitroxyl (HNO) and its therapeutic potential: Not just the janus face of NO SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE nitroxyl; nitric oxide; calcitonin gene-related peptide; thiols; ischemia-reperfusion; vasorelaxation; Angeli's salt; heart failure; platelets; myocardium; inotropy; thrombosis ID GENE-RELATED PEPTIDE; NITRIC-OXIDE NO; LOW-DENSITY-LIPOPROTEIN; ISCHEMIA-REPERFUSION INJURY; OXIDIZED LIPID DERIVATIVES; DETERRENT AGENT CYANAMIDE; NEUTRAL AQUEOUS-SOLUTION; ANGELIS SALT; ALDEHYDE DEHYDROGENASE; NITROSYL HYDRIDE AB Nitroxyl (HNO), the I-electron reduced and protonated congener of nitric oxide (NO), has received recent attention as a potential pharmacological agent for the treatment of heart failure and as a preconditioning agent for the mitigation of ischemia-reperfusion injury. Interest in the pharmacology and biology of HNO has prompted examination, or in some instances reexamination, of many of its chemical properties. Such studies have provided insight into the chemical basis for the biological effects of HNO, although the biochemical mechanisms for many of these effects remain to be established. In this review, a brief description of the biologically relevant chemistry of HNO is given, followed by a more detailed discussion of the pharmacology and potential toxicology of HNO. (c) 2006 Elsevier Inc. All rights reserved. C1 Johns Hopkins Med Inst, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. Univ Calif Los Angeles, Sch Publ Hlth, Interdepartmental Program Mol Toxicol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Pharmacol, Hlth Sci Ctr, Los Angeles, CA 90095 USA. Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. Univ Coll, Wolfson Inst Biomed Res, London WC1E 6AE, England. RP Paolocci, N (reprint author), Johns Hopkins Med Inst, Div Cardiol, Dept Med, Baltimore, MD 21287 USA. EM npaolocc@jhmi.edu; jfukuto@mednet.ucla.edu RI Miranda, Katrina/B-7823-2009; OI tocchetti, carlo gabriele/0000-0001-5983-688X; Paolocci, Nazareno/0000-0001-7011-997X FU Wellcome Trust [067422] NR 158 TC 132 Z9 133 U1 1 U2 22 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD FEB PY 2007 VL 113 IS 2 BP 442 EP 458 DI 10.1016/j.pharmthera.2006.11.002 PG 17 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 139CA UT WOS:000244408500015 PM 17222913 ER PT J AU Miller, SA Coelho, SC Zmudzka, BZ Beer, JZ AF Miller, Sharon A. Coelho, Sergio C. Zmudzka, Barbara Z. Beer, Janusz Z. TI Criticism of FDA pilot study unfounded (response to R. M. Sayre and J. C. Dowdy) SO PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE LA English DT Letter ID BED C1 US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Miller, SA (reprint author), US FDA, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. NR 8 TC 2 Z9 2 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0905-4383 J9 PHOTODERMATOL PHOTO JI Photodermatol. Photoimmunol. Photomed. PD FEB PY 2007 VL 23 IS 1 BP 59 EP 60 DI 10.1111/j.1600-0781.2007.00272.x PG 2 WC Dermatology SC Dermatology GA 129US UT WOS:000243756200015 ER PT J AU Hohmannn-Marriott, M Dorward, L Aronova, M Zang, G AF Hohmannn-Marriott, M. Dorward, L. Aronova, M. Zang, G. TI The three-dimensional chloroplast structure of Ostreococcus tauri SO PHOTOSYNTHESIS RESEARCH LA English DT Meeting Abstract C1 NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0166-8595 J9 PHOTOSYNTH RES JI Photosynth. Res. PD FEB-MAR PY 2007 VL 91 IS 2-3 MA PS75 BP 212 EP 212 PG 1 WC Plant Sciences SC Plant Sciences GA 191RZ UT WOS:000248151000310 ER PT J AU Mulkidjanian, A Koonin, E Makarova, K Haselkorn, R Galperin, M AF Mulkidjanian, A. Koonin, E. Makarova, K. Haselkorn, R. Galperin, M. TI The cyanobacterial genome core and the origin of photosynthesis SO PHOTOSYNTHESIS RESEARCH LA English DT Meeting Abstract C1 Univ Osnabruck, D-4500 Osnabruck, Germany. NIH, Bethesda, MD USA. Natl Lib Med, NCBI, NIH, Bethesda, MD 20894 USA. Univ Chicago, Chicago, IL 60637 USA. RI Mulkidjanian, Armen/J-8086-2013 OI Mulkidjanian, Armen/0000-0001-5844-3064 NR 0 TC 1 Z9 1 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0166-8595 J9 PHOTOSYNTH RES JI Photosynth. Res. PD FEB-MAR PY 2007 VL 91 IS 2-3 MA PS182 BP 269 EP 269 PG 1 WC Plant Sciences SC Plant Sciences GA 191RZ UT WOS:000248151000517 ER PT J AU Tomic, S Babic, SD Vuletic, T Krca, S Ivankovic, D Griparic, L Podgornik, R AF Tomic, S. Babic, S. Dolanski Vuletic, T. Krca, S. Ivankovic, D. Griparic, L. Podgornik, R. TI Dielectric relaxation of DNA aqueous solutions SO PHYSICAL REVIEW E LA English DT Article ID CHARGED LINEAR MACROMOLECULES; POLYELECTROLYTE SOLUTIONS; BIOLOGICAL-SYSTEMS; PERSISTENCE LENGTH; OSMOTIC-PRESSURE; DOUBLE-LAYER; NATIVE DNA; DYNAMICS; DENATURATION; BEHAVIOR AB We report on a detailed characterization of complex dielectric response of Na-DNA aqueous solutions by means of low-frequency dielectric spectroscopy (40 Hz-110 MHz). Results reveal two broad relaxation modes of strength 20 =,65 years. Depressive symptoms were assessed using the CES-D scale; cortisol levels were determined in 24-h urine samples. Metabolic syndrome was defined as three or more of the following: abdominal obesity, high triglycerides, tow HDL cholesterol, high blood pressure, and high fasting glucose. Results: Clinically relevant depressed mood (CES-D >= 20) was present in 20.6% of the sample, and 24.5% had the metabolic syndrome. After adjustment for sociodemographics and health indicators, depression score (per SD increase: OR = 1.20, 95% Cl = 1.02-1.41) and urinary cortisot level (per SD increase: OR = 1.23, 95% Cl = 1.01-1.51) were significantly associated with presence of metabolic syndrome. There was, however, a significant interaction (p = 0.003) between depressed mood and urinary cortisot in the probability of having metabolic syndrome. The odds of metabolic syndrome in persons with both depressed mood and urinary cortisot excretion in the highest tertile was 1.84 (95% Cl = 1.02-3.34) compared to persons with neither condition. Discussion: This study suggests a synergistic relationship between depression, cortisol and metabolic syndrome. Hypercortisolemic depression may constitute a specific risk group for the metabolic syndrome. (c) 2006 Elsevier Ltd. All rights reserved. C1 Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, NL-1081 HJ Amsterdam, Netherlands. Vrije Univ Amsterdam, Med Ctr, EMGO Inst, NL-1081 HJ Amsterdam, Netherlands. NIA, Clin Res Branch, Baltimore, MD 21224 USA. ASF, Florence, Italy. Tuscany Hlth Reg Agcy, Florence, Italy. NIA, Dept Epidemiol, Bethesda, MD 20892 USA. Univ Hosp Geneva, Dept Rehabil & Geriatr, Geneva, Switzerland. RP Vogelzangs, N (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Oldenaller 1, NL-1081 HJ Amsterdam, Netherlands. EM nicolev@ggzba.nl RI Giannelli, Sandra/E-8637-2011; Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NHLBI NIH HHS [R01 HL072972, R01 HL72972-01]; PHS HHS [IRTA 2300 320 7] NR 44 TC 133 Z9 137 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD FEB PY 2007 VL 32 IS 2 BP 151 EP 159 DI 10.1016/j.psyneuen.2006.11.009 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 147FE UT WOS:000244988000008 PM 17224244 ER PT J AU Kant, AK Graubard, BI AF Kant, Ashima K. Graubard, Barry I. TI Secular trends in the association of socio-economic position with self-reported dietary attributes and biomarkers in the US population: National Health and Nutrition Examination Survey (NHANES) 1971-1975 to NHANES 1999-2002 SO PUBLIC HEALTH NUTRITION LA English DT Article; Proceedings Paper CT Experimental Biology 2005 Meeting/35th International Congress of Physiological Sciences CY MAR 31-APR 06, 2005 CL San Diego, CA SP Amer Assoc Anatomists, Amer Assoc Immunologists, Amer Physiol Soc, Amer Soc Biochem & Mol Biol, Amer Soc Investigat Pathol, Amer Soc Nutr Sci, Amer Soc Pharmacol & Expt Therapeut, Int Union Physiol Sci DE body mass index; biomarkers; education and diet; income and diet; health disparities; NHANES; secular trends; socio-economic status ID FACTOR INTERVENTION TRIAL; FOOD-CONSUMPTION SURVEY; UNITED-STATES; ENERGY DENSITY; SOCIAL-CLASS; NUTRIENT DENSITY; MORTALITY RISK; ALL-CAUSE; ADULTS; DIFFERENTIALS AB Objective: Recent reports suggest persistence of health disparities related to socioeconomic position (SEP). To understand if diet may be a contributor to these trends, we examined secular trends in the association of diet and indicators of SEP from 1971-1975 to 1999-2002. Design: We used data from the National Health and Nutrition Examination Surveys (NHANES) I (1971-1975), II (1976-1980), III (1988-1994) and 1999-2002 to examine the independent associations of poverty income ratio (PIR) and education with diet and biomarkers of diet and disease in 25-74-year-olds (n = 36 600). We used logistic and linear regression methods to adjust for multiple covariates and survey design to examine these associations. Results: A large PIR differential in the likelihood of reporting a fruit or all five food groups and vitamin C intake, and an education differential in likelihood of obesity and carbohydrate intake, was noted in 1971-1975 but narrowed in 1999-2002 (P < 0.007). The positive association of education with intake of a fruit, vegetable or all five food groups, vitamins A and C, calcium and potassium intake remained unchanged across surveys (P < 0.001). Similarly, the positive association of PIR with the amount of foods and intakes of energy and potassium remained unchanged over three decades (P < 0.001). The education and the PIR differential in energy density, and the PIR differential in the likelihood of obesity, persisted over the period of the four surveys (P < 0.001). Conclusions: Persistence of unfavourable dietary and biomarker profiles in Americans with low income and education suggests continued need for improvement in the quality of diets of these high-risk groups. C1 CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E, Flushing, NY 11367 USA. EM ashima.kant@qc.cuny.edu FU Intramural NIH HHS; NCI NIH HHS [CA108274] NR 55 TC 83 Z9 83 U1 0 U2 9 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD FEB PY 2007 VL 10 IS 2 BP 158 EP 167 DI 10.1017/S1368980007246749 PG 10 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 147NX UT WOS:000245010800010 PM 17261225 ER PT J AU Thiebaut, ACM Kipnis, V AF Thiebaut, Anne C. M. Kipnis, Victor TI Dietary fat underreporting and risk estimation SO PUBLIC HEALTH NUTRITION LA English DT Letter ID MEASUREMENT ERROR; BREAST-CANCER; RELATIVE RISK; VALIDATION C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Thiebaut, ACM (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S3033, Bethesda, MD 20892 USA. EM thiebauta@mail.nih.gov NR 11 TC 1 Z9 1 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD FEB PY 2007 VL 10 IS 2 BP 212 EP 213 DI 10.1017/S1368980007339049 PG 2 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 147NX UT WOS:000245010800017 PM 17261232 ER PT J AU Datta, K Weinfeld, M Neumann, RD Winters, TA AF Datta, Kamal Weinfeld, Michael Neumann, Ronald D. Winters, Thomas A. TI Determination and analysis of site-specific I-125 decay-induced DNA double-strand break end-group structures SO RADIATION RESEARCH LA English DT Article ID DEPENDENT PROTEIN-KINASE; HUMAN CELL-EXTRACTS; IONIZING-RADIATION; SYNTHETIC OLIGODEOXYNUCLEOTIDE; MAMMALIAN-CELLS; DEOXYRIBONUCLEIC-ACID; 3'-PHOSPHOGLYCOLATE TERMINI; FRAGMENT DISTRIBUTION; AQUEOUS-SOLUTION; IN-VITRO AB End groups contribute to the structural complexity of radiation-induced DNA double-strand breaks (DSBs). As such, end-group structures may affect a cell's ability to repair DSBs. The 3'-end groups of strand breaks caused by gamma radiation, or oxidative processes, under oxygenated aqueous conditions have been shown to be distributed primarily between 3'-phosphoglycolate and 3'-phosphate, with 5'-phosphate ends in both cases. In this study, end groups of the high-LET-like DSBs caused by 1251 decay were investigated. Site-specific DNA double-strand breaks were produced in plasmid pTC27 in the presence or absence of 2 M DMSO by I-125-labeled triplex-forming oligonucleotide targeting. End-group structure was assessed enzymatically as a function of the DSB end to serve as a substrate for ligation and various forms of end labeling. Using this approach, we have demonstrated 3'-hydroxyl (3'-OH) and 3'-phosphate (3'-P) end groups and 5'-ends (>= 42%) terminated by phosphate. A P-32 postlabeling assay failed to detect 3'-phosphoglycolate in a restriction fragment terminated by the I'll-induced DNA double-strand break, and this is likely due to restricted oxygen diffusion during irradiation as a frozen aqueous solution. Even so, end-group structure and relative distribution varied as a function of the free radical scavenging capacity of the irradiation buffer. (c) 2007 by Radiation Research Society. C1 NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Cross Canc Inst, Dept Expt Oncol, Edmonton, AB T6G 1Z2, Canada. RP Winters, TA (reprint author), NIH, Dept Nucl Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C401,9000 Rockville Pl, Bethesda, MD 20892 USA. EM twinters@mail.cc.nih.gov FU Intramural NIH HHS NR 64 TC 8 Z9 10 U1 0 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2007 VL 167 IS 2 BP 152 EP 166 DI 10.1667/RR0629.1 PG 15 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 129ZQ UT WOS:000243769000003 PM 17390723 ER PT J AU Adiga, SK Toyoshima, M Shimura, T Takeda, J Uematsu, N Niwa, O AF Adiga, Satish Kumar Toyoshima, Megumi Shimura, Tsutomu Takeda, Jun Uematsu, Norio Niwa, Ohtsura TI Delayed and stage specific phosphorylation of H2AX during preimplantation development of gamma-irradiated mouse embryos SO REPRODUCTION LA English DT Article ID DOUBLE-STRAND BREAKS; CELL-CYCLE CHECKPOINTS; DNA-DAMAGE RESPONSE; HISTONE H2AX; CHROMOSOME INACTIVATION; GENE-EXPRESSION; GENOME; REPAIR; SPERM; PHASE AB Within minutes of the induction of DNA double-strand breaks in somatic cells, histone H2AX becomes phosphorylated in the serine 139 residue at the damage site. The phosphorylated H2AX, designated as gamma-1-12AX, is visible as nuclear foci in the irradiated cells which are thought to serve as a platform for the assembly of proteins involved in checkpoint response and DNA repair. It is known that early stage mammalian embryos are highly sensitive to radiation but the mechanism of radiosensitivity is not well understood. Thus, we investigated the damage response of the preimplantation stage development by analyzing focus formation of gamma-H2AX in mouse embryos gamma-irradiated in utero. Our analysis revealed that although H2AX is present in early preimplantation embryos, its phosphorylation after 3 Gy gamma-irradiation is hindered up to the two cell stage of development. When left in utero for another 24-64 h, however, these irradiated embryos showed delayed phosphorylation of H2AX. In contrast, phosphorylation of H2AX was readily induced by radiation in post-compaction stage embryos. it is possible that phosphorylation of H2AX is inefficient in early stage embryos. It is also possible that the phosphorylated H2AX exists in the dispersed chromatin structure of early stage embryonic pronuclei, so that it cannot readily be detected by conventional immunostaining method. In either case, this phenomenon is likely to correlate with the lack of cell cycle arrest, apoptosis and high radiosensitivity of these developmental stages. C1 Kasturba Med Coll & Hosp, Dept Obstet & Gynecol, Div Reprod Med, Manipal 576104, India. Kyoto Univ, Ctr Radiat Biol, Dept Late Effect Studies, Sakyo Ku, Kyoto 6068501, Japan. NCI, NIH, Bethesda, MD 20892 USA. RP Niwa, O (reprint author), Kasturba Med Coll & Hosp, Dept Obstet & Gynecol, Div Reprod Med, Manipal 576104, India. EM oniwa@house.rbc.kyoto-u.ac.jp NR 38 TC 26 Z9 28 U1 0 U2 4 PU BIO SCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD FEB PY 2007 VL 133 IS 2 BP 415 EP 422 DI 10.1530/REP-06-0048 PG 8 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 142WD UT WOS:000244680500007 PM 17307909 ER PT J AU Segars, JH AF Segars, James H. TI Invited comment: "Identification of a Sensitive Period for Developmental Programming That Increases Risk for Uterine Leiomyoma in Eker Rats" SO REPRODUCTIVE SCIENCES LA English DT Editorial Material ID DIETHYLSTILBESTROL DES EXPOSURE C1 NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), NICHHD, Reprod Biol & Med Branch, NIH, Bldg 10,CRC,1E-3140,9000 Rockville Pike, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Intramural NIH HHS NR 9 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD FEB PY 2007 VL 14 IS 2 BP 99 EP 100 DI 10.1177/1933719107300290 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 328FR UT WOS:000257784300001 PM 17636221 ER PT J AU Gooden, KM Schroeder, JC North, KE Gammon, MD Hartmann, KE Taylor, J Baird, DD AF Gooden, Kyna M. Schroeder, Jane C. North, Kari E. Gammon, Marille D. Hartmann, Katherine E. Taylor, Jack Baird, Donna D. TI Val153Met polymorphism of catechol-O-methyltransferase and prevalence of uterine leiomyomata SO REPRODUCTIVE SCIENCES LA English DT Article DE uterine fibroids; uterine neoplasms; catechol-O-methyltransferase gene; leiomyomata; genetic predisposition to disease; genetics; polymorphism; females ID ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER RISK; 2-METHOXYESTRADIOL; WOMEN; ANGIOGENESIS; APOPTOSIS; FIBROIDS; AGE AB The catechol-O-methyltransferase (COMT) gene encodes enzymes that inactivate catechol estrogens and may have a protective role in estrogen-induced tumorigenesis, such as uterine leiomyoma (fibroids). Val158Met is a common single-nucleotide polymorphism of the COMT gene (Ex4-12 G>A; rs4680) that results in a lower activity enzyme, increasing susceptibility to tumorigenesis. The purpose of this study was to evaluate the relation between the COMT Val158Met polymorphism and uterine fibroids, Participants were 972 premenopausal African American (n = 576) and white (n = 396) women from a cross-sectional sample of women in the National Institute of Environmental Health Science's Uterine Fibroid Study. Blood was collected from participants for DNA, and telephone interviews and questionnaires were completed to gather demographic and reproductive history. Prevalence ratios and 95% confidence intervals were estimated using race-specific log-risk regression models. Effect measure modification by age, body mass index, oral contraceptive use, full-term births, smoking, and alcohol use were also evaluated. Distributions of genotypes and fibroid prevalence varied by race. No associations between fibroids and Val158Met were observed among African American or white participants. This study suggests that variation in this polymorphism alone does not affect fibroid prevalence. Additional research is needed to examine other variations and haplotypes within the COMT gene. C1 [Gooden, Kyna M.; Schroeder, Jane C.; North, Kari E.; Gammon, Marille D.; Hartmann, Katherine E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Gammon, Marille D.] Univ N Carolina, Ctr Environm Hlth & Susceptibil, Chapel Hill, NC USA. [Hartmann, Katherine E.] Univ N Carolina, Ctr Womens Hlth Res, Chapel Hill, NC USA. [Taylor, Jack; Baird, Donna D.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Gooden, KM (reprint author), 124 Canadian Court, Durham, NC 27713 USA. EM kyna@unc.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS NR 22 TC 13 Z9 14 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD FEB PY 2007 VL 14 IS 2 BP 117 EP 120 DI 10.1177/1933719106298687 PG 4 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 328FR UT WOS:000257784300003 PM 17636223 ER PT J AU Cook, JD Davis, BJ Goewey, JA Berry, TD Walker, CL AF Cook, Jennifer DeAnn Davis, Barbara J. Goewey, Julia Alicia Berry, Tia D. Walker, Cheryl Lyn TI Identification of a sensitive period for developmental programming that increases risk for uterine leiomyoma in Eker rats SO REPRODUCTIVE SCIENCES LA English DT Article DE developmental programming; xenoestrogens; tumor suppressor gene; Eker rat; tuberous sclerosis complex 2; uterine leiomyoma ID DIETHYLSTILBESTROL DES; IMMUNOCYTOCHEMICAL ANALYSIS; MYOMETRIAL DEVELOPMENT; EXPOSURE; MICE; GENE; ADENOCARCINOMA; DEMETHYLATION; UTERUS; GROWTH AB Epidemiological and experimental animal studies have shown that exposure to xenoestrogens during reproductive tract development reprograms target tissues, leading to increased disease risk later in adult life. To understand what defines the critical risk period for this effect, termed developmental programming, the authors assess the sensitivity of the female reproductive tract to developmental programming during various stages of neonatal development. Eker rats, which are predisposed to develop uterine leiomyoma because of a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene, Were exposed to the xenoestrogen diethylstilbestrol (DES) on either postnatal days 3 to 5, 10 to 12, or 17 to 19, 3 important periods of reproductive tract development and differentiation. Developmental programming was observed in both carrier (Tsc-2(Ek/+)) and wild-type (Tsc-2(+/+)) rats exposed to DES at days 3 to 5 and days 10 to 12 but not in rats exposed at days 17 to 19. Developmental programming resulted in increased tumor suppressor gene penetrance in Tsc-2(Ek/+) females relative to vehicle controls. In contrast, DES exposure at days 17 to 19 did not significantly increase the incidence of uterine leiomyoma in carrier females, indicating that the window of susceptibility had closed by this time. Gene expression analysis to determine what defined the susceptible (days 3-5 and days 10-12) versus resistant (days 17-19) periods revealed that in adult myometrium, expression of the estrogen-responsive genes calbindin D9K and progesterone receptor had been reprogrammed in females exposed to DES at days 3 to 5 and days 10 to 12 but not in those exposed at days 17 to 19. Reprogramming in response to DES exposure resulted in a hyperresponsiveness to ovarian hormones and could be prevented by ovariectomy prior to sexual maturity. Furthermore, in the neonatal uterus, DES was equally effective at inducing transcription of estrogen-responsive genes during both sensitive and resistant periods, indicating that resistance to developmental programming was not due to an inability of the estrogen receptor to transactivate gene expression. Interestingly, the resistant period coincided with the time at which reproductive tract tissues are exposed to endogenous estrogen, suggesting that target tissues are most vulnerable to developmental programming during the period in which they would normally be maintained in an estrogen-naive state. C1 [Cook, Jennifer DeAnn; Goewey, Julia Alicia; Berry, Tia D.; Walker, Cheryl Lyn] Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. [Cook, Jennifer DeAnn] Univ Texas Houston Hlth Sci Ctr, Grad Sch Biomed Sci, Houston, TX USA. [Davis, Barbara J.] NIEHS, Lab Womens Hlth, Res Triangle Pk, NC 27709 USA. RP Walker, CL (reprint author), Univ Texas MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. EM chwalker@manderson.org NR 25 TC 26 Z9 26 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD FEB PY 2007 VL 14 IS 2 BP 121 EP 136 DI 10.1177/1933719106298401 PG 16 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 328FR UT WOS:000257784300004 PM 17636224 ER PT J AU Dahr, SS Cusick, M Rodriguez-Coleman, H Srivastava, SK Thompson, DJ Linehan, WM Ferris, FL Chew, EY AF Dahr, Sam S. Cusick, Michael Rodriguez-Coleman, Hanna Srivastava, Sunil K. Thompson, Darby J. Linehan, W. Marston Ferris, Frederick L., III Chew, Emily Y. TI Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced Von Hippel-Lindau disease of the retina SO RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY APR 24-29, 2004 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol ID RECEPTOR INHIBITOR SU5416; MACULAR DEGENERATION; CLINICAL-FEATURES; HEMANGIOBLASTOMAS; ANGIOMATOSIS; PROMISES; PATIENT; GENE AB Objective: This pilot study was designed to provide preliminary data concerning the safety and efficacy of pegylated anti-vascular endothelial growth factor (VEGF) therapy, pegaptanib, for patients with juxtapapillary or large peripheral angiomas secondary to von Hippel-Lindau (VHL) disease. Methods: This study was an open label, nonrandomized, prospective, pilot study of intravitreal injections of pegaptanib (3 mg/100 mu L), given every 6 weeks for minimum of 6 injections. Five patients with severe ocular VHL lesions were enrolled in the study. The primary outcome of this study was a change of >= 15 letters (3 lines) in best-corrected visual acuity by 1 year. Secondary outcomes included changes in macular -thickness, as determined by optical coherence tomography, and changes in fluorescein leakage. Results: Two of five patients completed the course of treatment and 1 year of follow-up. These two patients had progressive decrease in retinal hard exudate and reduction in central retinal thickness measured by optical coherence tomography. One of these two patients had improvement in visual acuity of 3 lines. No significant change in fluorescein leakage or tumor size was detected in either patient. Lesions in the other three patients continued to progress despite treatment, and these patients did not complete the entire treatment course. One patient developed a tractional retinal detachment. Additional serious adverse events included transient postinjection hypotony in two eyes. Conclusions: Intravitreal injections of anti-VEGF therapy (pegaptanib) may decrease retinal thickening minimally and reduce retinal hard exudates in some patients with advanced VHL angiomas. This finding may be related to a reduction in vasopermeability, because there was no apparent effect of treatment on the size of the primary retinal angiomas in this small pilot study. C1 NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, NIH, Bldg 10,CRC,Room 3-2531,10 Ctr Dr,MSC-1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999, ZIE EY000487-01] NR 29 TC 22 Z9 24 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0275-004X J9 RETINA-J RET VIT DIS JI Retin.-J. Retin. Vitr. Dis. PD FEB PY 2007 VL 27 IS 2 BP 150 EP 158 DI 10.1097/IAE.0b013e318030a290 PG 9 WC Ophthalmology SC Ophthalmology GA 175BD UT WOS:000246986100003 PM 17290195 ER PT J AU Machold, KP Stamm, TA Nell, VPK Pflugbeil, S Aletaha, D Steiner, G Uffmann, M Smolen, JS AF Machold, K. P. Stamm, T. A. Nell, V. P. K. Pflugbeil, S. Aletaha, D. Steiner, G. Uffmann, M. Smolen, J. S. TI Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease SO RHEUMATOLOGY LA English DT Article DE very early rheumatoid arthritis; determinants of radiographic progression; disease control ID DIFFERENT TREATMENT STRATEGIES; RADIOLOGICAL PROGRESSION; INFLAMMATORY ARTHRITIS; COMBINATION THERAPY; PLUS METHOTREXATE; DELAYED TREATMENT; CONTROLLED-TRIAL; SHARED EPITOPE; ACTIVITY SCORE; CRITERIA AB Objectives. Despite early recognition and disease modifying anti-rheumatic drug ( DMARD) treatment, a sizable proportion of early rheumatoid arthritis (RA) patients show radiological progression. This study was performed to determine the frequency of erosive arthritis and the pace of radiological progression in an inception cohort of patients with very early RA (<= 3 months after onset of symptoms). Methods. In order to determine possible prognostic factors for development of erosive disease, we linked the clinical features of these patients to radiological progression in a regression model. About 55 patients with RA and follow-up of at least 3 yrs were analysed. All had complete series of clinical, serological and radiographic assessments. Radiographs were scored according to the Larsen method. Results. Erosive disease developed in 63.6% of the patients over 3 yrs, with the majority (74.3%) appearing already in the first and 97.2% by the end of the second year. Among all variables available, rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) first presentation were the most predictive for both development of erosions and the degree of radiological progression. None of the clinical variables at the onset was useful to discriminate between erosive and non-erosive patients. In the final regression model, however, cumulative clinical activity substantially contributed to explaining radiological progression. Conclusion. Despite early treatment, substantial damage occurred in some patients and was associated with presence of strong 'constitutive' predictors such as anti-CCP and RF as well as presence of high long-term clinical disease activity as indicated by C-reactive protein (CRP), swollen joint counts and the absence of a good clinical response (assessed by the failure to achieve lasting low disease activity). C1 Med Univ Vienna, Dept Rheumatol, Vienna, Austria. Hietzing Municipal Hosp, Dept Med 2, Vienna, Austria. NIAMS, Mark O Hatfield Clin Res Ctr, NIH, Bethesda, MD USA. Med Univ Vienna, Dept Radiol, Vienna, Austria. RP Machold, KP (reprint author), Med Univ Vienna, Dept Rheumatol, Vienna, Austria. EM Klaus.machold@meduniwien.ac.at NR 40 TC 143 Z9 156 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD FEB PY 2007 VL 46 IS 2 BP 342 EP 349 DI 10.1093/rheumatology/kel237 PG 8 WC Rheumatology SC Rheumatology GA 130OY UT WOS:000243810100028 PM 16899498 ER PT J AU Nugent, TF Herman, DH Ordonez, A Greenstein, D Hayashi, KM Lenane, M Clasen, L Jung, D Toga, AW Giedd, JN Rapoport, JL Thompson, PM Gogtay, N AF Nugent, Tom F., III Herman, David H. Ordonez, Anna Greenstein, Deanna Hayashi, Kiralee M. Lenane, Marge Clasen, Liv Jung, David Toga, Arthur W. Giedd, Jay N. Rapoport, Judith L. Thompson, Paul M. Gogtay, Nitin TI Dynamic mapping of hippocampal development in childhood onset schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE childhood onset schizophrenia; MRI; mapping; hippocampus; longitudinal ID MILD COGNITIVE IMPAIRMENT; CAUDATE NUCLEI VOLUMES; MEDIAL TEMPORAL-LOBE; GRAY-MATTER LOSS; BRAIN-DEVELOPMENT; 1ST-EPISODE SCHIZOPHRENIA; AMYGDALA VOLUMES; BIPOLAR DISORDER; FIRST-EPISODE; AGES 4-18 AB Prior cross-sectional anatomic brain imaging studies of the hippocampus in schizophrenia have generally shown loss in total hippocampal volume although the progressive course of these changes remains unknown. We report the first prospective sub-regional maps of hippocampal development in childhood onset schizophrenia (COS), reconstructed from serial brain MRI scans of 29 children with COS scanned every 2 years (87 scans) and compared to 31 controls matched for age, sex, and scan interval (94 scans). As expected, the COS subjects showed significant bilateral deficits (9-10%) in total hippocarnpal volume which remained consistent between age 9 and 26. However sub-regional maps showed heterogeneous changes with loss of hippocampal volume in both anterior as well as posterior ends while the body of the hippocampus gained in volume suggesting that hippocampal subunits are differentially affected in schizophrenia. Published by Elsevier B.V. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Lab Neuroimaging, Los Angeles, CA 90024 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, Bldg 10 Rm 3N 202, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov 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 FU NIMH NIH HHS [R25 MH060482] NR 68 TC 40 Z9 40 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB PY 2007 VL 90 IS 1-3 BP 62 EP 70 DI 10.1016/j.schres.2006.10.014 PG 9 WC Psychiatry SC Psychiatry GA 149NF UT WOS:000245152900006 PM 17161938 ER PT J AU Chen, CH Chen, BH Wang, BY Huang, C Zhao, J Dai, Y Kan, HD AF Chen, Changhong Chen, Bingheng Wang, Bingyan Huang, Cheng Zhao, Jing Dai, Yi Kan, Haidong TI Low-carbon energy policy and ambient air pollution in Shanghai, China: A health-based economic assessment SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE low-carbon development; air pollution; public health; economic evaluation ID RESPIRATORY HEALTH; ASTHMATIC-CHILDREN; TIME-SERIES; MORTALITY; ASSOCIATION; EXPOSURE; ADULTS AB Energy and related health issues are of growing concern worldwide today. To investigate the potential public health and economic impact of ambient air pollution under various low-carbon energy scenarios in Shanghai, we estimated the exposure level of Shanghai residents to air pollution under various planned scenarios, and assessed the public health impact using concentration-response functions derived from available epidemiologic studies. We then estimated the corresponding economic values of the health effects based on unit values for each health outcome. Our results show that ambient air pollution in relation to low-carbon energy scenarios could have a significant impact on the future health status of Shanghai residents, both in physical and monetary terms. Compared with the base case scenario, implementation of various low-carbon energy scenarios could prevent 2804-8249 and 9870-23,100 PM10-related avoidable deaths (mid-value) in 2010 and 2020, respectively. It could also decrease incidence of several relevant diseases. The corresponding economic benefits could reach 507.31-1492.33 and 2642.45-6192.11 million U.S. dollars (mid-value) in 2010 and 2020, respectively. These findings illustrate that a low-carbon energy policy will not only decrease the emission of greenhouse gases, but also play an active role in the reduction of air pollutant emissions, improvement of air quality, and promotion of public health. Our estimates can provide useful information to local decision-makers for further cost-benefit analysis. (c) 2006 Elsevier B.V All rights reserved. C1 Fudan Univ, Dept Environm Hlth, Sch Publ Hlth, Shanghai 200032, Peoples R China. Shanghai Acad Environm Sci, Shanghai 200233, Peoples R China. E China Univ Sci & Technol, Shanghai 200237, Peoples R China. RP Kan, HD (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM haidongkan@gmail.com NR 33 TC 24 Z9 28 U1 5 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 1 PY 2007 VL 373 IS 1 BP 13 EP 21 DI 10.1016/j.scitotenv.2006.11.030 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA 137XK UT WOS:000244326100002 PM 17207519 ER PT J AU Savinkov, A Semioshkina, N Howard, BJ Voigt, G AF Savinkov, A. Semioshkina, N. Howard, B. J. Voigt, G. TI Radiostrontium uptake by plants from different soil types in Kazakhstan SO SCIENCE OF THE TOTAL ENVIRONMENT LA English DT Article DE Sr-90; transfer to plant; semipalatinsk test site; radionuclides ID SEMIPALATINSK TEST-SITE; LONG-TERM; SR-90; CS-137; STRONTIUM; RADIOCESIUM; FALLOUT; CESIUM; COUNTERMEASURES; AVAILABILITY AB The transfer of Sr-90 to a range of different plant species grown on a range of different soil types in Kazakhstan, including three from the Semipalatinsk Test Site (STS), has been measured in a lysimeter experiment. Sr-90 uptake by Stipa spp was significantly higher than for other vegetation species. The uptake of Sr-90 from chemozem was significantly lower than that from the other soil types which is consistent with other literature. There was a significant negative relationship between Sr-90 uptake and calcium, humus and CEC concentration in the soil for Agropyrum spp, Artemisia spp but not for Stipa spp or Bromus spp. The transfer to vegetation from soil has been quantified using the aggregated transfer coefficients for each species. Tag values range from 0.6 to 11.9 m(2) kg(-1) X 10(-3) over all measurements. The transfer of Sr-90 to plants from the Kazakh soils was low compared to previously reported data and to that given from literature reviews. (c) 2006 Elsevier B.V All rights reserved. C1 GSF, Inst Strahlenschutz, D-85764 Neuherberg, Germany. SRAI, Natl Biotechnol Ctr, Minist Sci & Higher Educ Republ Kazakhstan, Gvardeiski 480544, Kazakhstan. Lancaster Environm Ctr, Ctr Ecol & Jydrol, Lancaster LA1 8PP, England. IAEA, Agcy Labs, A-1400 Vienna, Austria. RP Semioshkina, N (reprint author), GSF, Inst Strahlenschutz, Ingolstaedter Land Str 1, D-85764 Neuherberg, Germany. EM Chebotar@srai.kz; semi@gsf.de; bjho@ceh.ac.uk; g.voigt@iaea.org RI Howard, Brenda/I-8279-2012; OI Howard, Brenda/0000-0002-9698-9524; Semioshkina, Natalia/0000-0002-8954-5597 NR 42 TC 3 Z9 5 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0048-9697 J9 SCI TOTAL ENVIRON JI Sci. Total Environ. PD FEB 1 PY 2007 VL 373 IS 1 BP 324 EP 333 DI 10.1016/j.scitotenv.2006.11.001 PG 10 WC Environmental Sciences SC Environmental Sciences & Ecology GA 137XK UT WOS:000244326100029 PM 17187845 ER PT J AU Huppi, K Volfovsky, N Mackiewicz, M Runfola, T Jones, TL Martin, SE Stephens, R Caplen, NJ AF Huppi, Konrad Volfovsky, Natalia Mackiewicz, Mark Runfola, Timothy Jones, Tamara L. Martin, Scott E. Stephens, Robert Caplen, Natasha J. TI MicroRNAs and genomic instability SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE microRNAs; genomic instability; mouse genome; integration sites ID CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL LYMPHOMAS; MESSENGER-RNA; BURKITT-LYMPHOMA; GENE-EXPRESSION; LET-7 MICRORNA; NUCLEAR EXPORT; BXH2 MICE; CANCER; COMPLEX AB A new species of non-coding RNA, microRNAs (miRNAs) has been identified that may regulate the expression of as many as one third to one half of all protein encoding genes. MicroRNAs are found throughout mammalian genomes, but an association between the location of these miRNAs and regions of genomic instability (or fragile sites) in humans has been suggested [1]. In this review we discuss the possible role of altered miRNA expression on human cancer and conduct an analysis correlating the physical location of murine miRNAs with sites of genetic alteration in mouse models of cancer. Published by Elsevier Ltd. C1 NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI, Adv Biomed Comp Ctr, NIH, Frederick, MD USA. RP Huppi, K (reprint author), NCI, Gene Silencing Sect, Genet Branch, Ctr Canc Res,NIH, Bldg 37,Room 6128,37 Convent Dr, Bethesda, MD 20892 USA. EM huppi@helix.nih.gov RI Caplen, Natasha/H-2768-2016 OI Caplen, Natasha/0000-0002-0001-9460 FU Intramural NIH HHS [Z01 BC010612-02] NR 82 TC 57 Z9 64 U1 1 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2007 VL 17 IS 1 BP 65 EP 73 DI 10.1016/j.semcancer.2006.10.004 PG 9 WC Oncology SC Oncology GA 132VT UT WOS:000243971600007 PM 17113784 ER PT J AU Meaburn, KJ Misteli, T Soutoglou, E AF Meaburn, Karen J. Misteli, Tom Soutoglou, Evi TI Spatial genome organization in the formation of chromosomal translocations SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE chromosome territory; translocation; nuclear architecture; spatial organization; contact-first ID DOUBLE-STRAND BREAKS; ORDER CHROMATIN ARRANGEMENTS; HUMAN ACROCENTRIC CHROMOSOMES; BETA-GLOBIN LOCUS; ART. NO. 44; NUCLEAR ARCHITECTURE; INTERPHASE NUCLEI; GENE-DENSITY; CELL-NUCLEI; X-CHROMOSOME AB Chromosomal translocations and genomic instability are universal hallmarks of tumor cells. While the molecular mechanisms leading to the formation of translocations are rapidly being elucidated, a cell biological understanding of how chromosomes undergo translocations in the context of the cell nucleus in vivo is largely lacking. The recent realization that genomes are non-randomly arranged within the nuclear space has profound consequences for mechanisms of chromosome translocations. We review here the emerging principles of spatial genome organization and discuss the implications of non-random spatial genome organization for the genesis and specificity of cancerous chromosomal translocations. Published by Elsevier Ltd. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM meaburnk@mail.nih.gov; mistelit@mail.nih.gov; soutogle@mail.nih.gov OI Meaburn, Karen/0000-0002-1327-5957 FU NCI NIH HHS [Z01 BC010309-07] NR 130 TC 102 Z9 105 U1 1 U2 11 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2007 VL 17 IS 1 BP 80 EP 90 DI 10.1016/j.semcancer.2006.10.008 PG 11 WC Oncology SC Oncology GA 132VT UT WOS:000243971600009 PM 17137790 ER PT J AU Basser, PJ Pajevic, S AF Basser, Peter J. Pajevic, Sinisa TI Spectral decomposition of a 4th-order covariance tensor: Applications to diffusion tensor MRI SO SIGNAL PROCESSING LA English DT Article DE PCA; covariance; tensor; HOS; multi-linear algebra; DTI; DT-MRI; Karhunen-Loeve; anisotropy ID ANISOTROPIC ELASTIC-MATERIALS; BLIND SEPARATION; INDEPENDENT COMPONENTS; NOISE; REPRESENTATION; VARIABLES; SCHEMES; BRAIN AB We propose a novel spectral decomposition of a 4th-order covariance tensor, Sigma. Just as the variability of vector (i.e., a 1st-order tensor)-valued random variable is characterized by a covariance matrix (i.e., a 2nd-order tensor), S, the variability of a 2nd-order tensor-valued random variable, D, is characterized by a 4th-order covariance tensor, Sigma. Accordingly, just as the spectral decomposition of S is a linear combination of its eigenvalues and the outer product of its corresponding (1st-order tensors) eigenvectors, the spectral decomposition of Sigma is a linear combination of its eigenvalues and the outer product of its corresponding 2nd-order eigentensors. Analogously, these eigenvalues and 2nd-order eigentensors can be used as features with which to represent and visualize variability in tensor-valued data. Here we suggest a framework to visualize the angular structure of Sigma, and then use it to assess and characterize the variability of synthetic diffusion tensor magnetic resonance imaging (DTI) data. The spectral decomposition suggests a hierarchy of symmetries with which to classify the statistical anisotropy inherent in tensor data. We also present maximum likelihood estimates of the sample mean and covariance tensors associated with D, and derive formulae for the expected value of the mean and variance of the projection of D along a particular direction (i.e., the apparent diffusion coefficient or ADC). These findings would be difficult, if not impossible, to glean if we treated 2nd-order tensor random variables as vector-valued random variables, which is conventionally done in multi-variate statistical analysis. (c) 2006 Elsevier B.V. All rights reserved. C1 NICHD, Sect Tissue Biophys & Biomimet, LIMB, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, CIT, Bethesda, MD 20892 USA. RP Basser, PJ (reprint author), NICHD, Sect Tissue Biophys & Biomimet, LIMB, NIH, Bldg 13,Rm 3W16,13 S Dr, Bethesda, MD 20892 USA. EM pjbasser@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 57 TC 37 Z9 37 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-1684 J9 SIGNAL PROCESS JI Signal Process. PD FEB PY 2007 VL 87 IS 2 BP 220 EP 236 DI 10.1016/j.sigpro.2006.02.050 PG 17 WC Engineering, Electrical & Electronic SC Engineering GA 112GQ UT WOS:000242514200002 ER PT J AU Dror, DM Koren, R Ost, A Binnendijk, E Vellakkal, S Danis, M AF Dror, David Mark Koren, Ruth Ost, Alexander Binnendijk, Erika Vellakkal, Sukumar Danis, Marion TI Health insurance benefit packages prioritized by low-income clients in India: Three criteria to estimate effectiveness of choice SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE India; benefit package design; low-income population; rationing choices; access to healthcare; health insurance ID CARE; PREFERENCES; EXERCISE AB We applied a decision tool for rationing choices, with a predetermined budget of about US$11 per household per year, to identify priorities of poor people regarding health insurance benefits in India in late 2005. A total of 302 individuals, organized in 24 groups, participated from a number of villages and neighborhoods of towns in Karnataka and Maharashtra. Many individuals were illiterate, innumerate and without insurance experience. Involving clients in insurance package design is based on an implied assumption that people can make judicious rationing decisions. Judiciousness was assessed by examining the association between the frequency of choosing a package and its perceived effectiveness. Perceived effectiveness was evaluated by comparing respondents' choices to the costs registered in 2049 illness episodes among a comparable cohort, using three criteria: 'reimbursement' (reimbursement regardless of the absolute level of expenditure), 'fairness' (higher reimbursement rate for higher expenses) and 'catastrophic coverage' (insurance for catastrophic exposure). The most frequently chosen packages scored highly on all three criteria; thus, rationing choices were confirmed as judicious. Fully 88.4% of the respondents selected at least three of the following benefits: outpatient, inpatient, drugs and tests, with a clear preference to cover high aggregate costs regardless of their probability. The results show that involving prospective clients in benefit package design can be done without compromising the judiciousness of rationing choices, even with people who have low education, low-income and no previous experience in similar exercises. (c) 2006 Published by Elsevier Ltd. C1 Erasmus Univ, Inst Hlth Policy & Management, CH-1207 Geneva, Switzerland. Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. Univ Cologne, Cologne, Germany. Erasmus Univ, Inst Hlth Policy & Management, Rotterdam, Netherlands. Inst Social & Econ Change, Bangalore, Karnataka, India. NIH, Bethesda, MD 20892 USA. RP Dror, DM (reprint author), Erasmus Univ, Inst Hlth Policy & Management, Rte Frontenex 39B, CH-1207 Geneva, Switzerland. EM daviddror@socialre.org; rkoren@post.tau.ac.il; alexander.ost@gmx.de; erikabinnendijk@gmail.com; sukumar109@rediffmail.com; mdanis@nih.gov RI Dror, David /I-6021-2013; OI Dror, David /0000-0002-8757-4239; Vellakkal, Sukumar/0000-0003-2635-1944 NR 31 TC 16 Z9 16 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD FEB PY 2007 VL 64 IS 4 BP 884 EP 896 DI 10.1016/j.socscimed.2006.10.032 PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 136PR UT WOS:000244237100014 PM 17141931 ER PT J AU Shin, SJ Xue, HP Mattson, MP Rao, MS AF Shin, Soojung Xue, Haipeng Mattson, Mark P. Rao, Mahendra S. TI Stage-dependent Olig2 expression in motor neurons and oligodendrocytes differentiated from embryonic stem cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID SPINAL-CORD; DIRECTED DIFFERENTIATION; NEURAL PRECURSORS; PROGENITOR CELLS; GENE-EXPRESSION; ES CELLS; PROTEIN; SPECIFICATION; REQUIREMENT; ASTROCYTE AB Although embryonic stem (ES) cells are capable of forming any cell type in the body, the mechanisms that control cell type-specific differentiation are largely unknown. In the present study, we examined the process of differentiation to motor neurons and oligodendrocytes from mouse (Olig2-GFP) ES cells. Mouse ES cells undergo a sequential process of differentiation over a 3-week period to generate motor neurons and oligodendrocytes. At day 7 of differentiation, Olig2-expressing cells are biased to a neuronal lineage. However, further differentiation (day 32) resulted in the majority of Olig2-expressing cells exhibiting an oligodendrocyte phenotype as well as a reduced ability to make motor neurons. Exposure of human ES cells to Sonic hedgehog (Shh) likewise resulted in enhanced motor neuron differentiation. Our results establish the requirements for directing ES cells to become motor neurons and oligodendrocytes and show that ES cell-derived Olig2+ cells can give rise to both motor neurons and oligodendrocytes, depending on the time at which differentiation is initiated. C1 NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. Invitrogen Corp, Corp Res Lab, Carlsbad, CA 92008 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Rao, MS (reprint author), 1610 Faraday Ave, Carlsbad, CA 92008 USA. EM vzeq2tcr@verizon.net RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 34 TC 11 Z9 12 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD FEB PY 2007 VL 16 IS 1 BP 131 EP 141 DI 10.1089/scd.2006.0023 PG 11 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 144GC UT WOS:000244783500013 PM 17348811 ER PT J AU Furuya, F Ying, H Zhao, L Cheng, SY AF Furuya, Fumihiko Ying, Hao Zhao, Li Cheng, Sheue-yann TI Novel functions of thyroid hormone receptor mutants: Beyond nucleus-initiated transcription SO STEROIDS LA English DT Article; Proceedings Paper CT FASEB Summer Research Conference on Mechanisms of Action of Steroid Hormones CY JUL 29-AUG 03, 2006 CL Tucson, AZ SP FASEB DE phosphatidylinositol 3-kinase; pituitary tumor transforming gene; steroid hormone receptor coactivator-3; nongenomic actions; thyroid hormone receptor mutants; thyroid cancer ID TUMOR-TRANSFORMING GENE; KNOCK-IN MOUSE; BETA-RECEPTOR; PHOSPHOINOSITIDE 3-KINASE; GENERALIZED RESISTANCE; LIGAND-BINDING; PROTEIN-KINASE; CO-REPRESSOR; EXPRESSION; PHOSPHORYLATION AB Study of molecular actions of thyroid hormone receptor beta (TR beta) mutants in vivo has been facilitated by creation of a mouse model (TR beta PV mouse) that harbors a knockin mutant of T beta (denoted PV). PV, which was identified in a patient with resistance to thyroid hormone, has lost T3 binding activity and transcription capacity. The striking phenotype of thyroid cancer exhibited by TR beta(PV/PV) mice has allowed the elucidation of novel oncogenic activity of a TR beta mutant (PV) [PAS1] beyond nucleus-initiated transcription. PV was found to physically interact with the regulatory p85 alpha subunit of phosphatidylinositol 3-kinase (PI3K) in both the nuclear and cytoplasmic compartments. This protein-protein interaction activates the PI3K signaling by increasing phosphorylation of AKT, mammalian target of rapamycin (mTOR), and p70(S6K). PV, via interaction with p85 alpha, also activates the PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathway in the extra-nuclear compartment. The PV-mediated PI3K activation results in increased cell proliferation, motility migration, and metastasis. In addition to affecting these membrane-initiated signaling events, PV affects the stability of the pituitary tumor-transforming gene (PTTG) product. PTTG (also known as securin), a critical mitotic checkpoint protein, is physically associated with TR beta or PV in vivo. Concomitant with T3-induced degradation of TR beta, PTTG is degraded by the proteasome machinery, but no such degradation occurs when PTTG is associated with PV The degradation of PTTG/TR beta is activated by the direct interaction of the T3-bound TR beta with the steroid receptor coactivator-3 (SRC-3) that recruits a proteasome activator (PA28 gamma). PV that does not bind T3 cannot interact directly with SRC-3/PA28 gamma to activate proteasome degradation, and the absence of degradation results in an aberrant accumulation of PTTG. The PV-induced failure of timely degradation of PTTG results in mitotic abnormalities. PV, via novel protein-protein interaction and transcription regulation, acts to antagonize the functions of wild-type TRs and contributes to the oncogenic functions of this mutation. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Rom 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural NIH HHS [ZIA BC011191-01] NR 61 TC 17 Z9 20 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD FEB PY 2007 VL 72 IS 2 BP 171 EP 179 DI 10.1016/j.steroids.2006.11.005 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 150ZH UT WOS:000245257600011 PM 17169389 ER PT J AU Fisher, M Hanley, DF Howard, G Jauch, EC Warach, S AF Fisher, Marc Hanley, Daniel F. Howard, George Jauch, Edward C. Warach, Steven CA STAIR Grp TI Recommendations from the STAIR V meeting on acute stroke trials, technology and outcomes SO STROKE LA English DT Editorial Material DE ischemia; telemedicine; therapy; stroke trials ID ACUTE ISCHEMIC-STROKE; INDUSTRY-ROUND-TABLE; THERAPIES; THROMBOLYSIS; TELEMEDICINE; STANDARDS; FUTURE C1 Univ Massachusetts, Mem Healthcare, Worcester, MA 01605 USA. Johns Hopkins, Baltimore, MD USA. Univ Alabama, Birmingham, AL USA. NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. RP Fisher, M (reprint author), Univ Massachusetts, Mem Healthcare, 119 Belmont St, Worcester, MA 01605 USA. EM fisherm@ummhc.org OI Jauch, Edward/0000-0002-3533-4364 NR 22 TC 57 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 245 EP 248 DI 10.1161/01.STR.0000255951.37434.aa PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600013 PM 17204668 ER PT J AU Foroud, T Koller, D Lal, D Woo, D Sauerbeck, L Hornung, R Wiebers, D Connolly, ES Anderson, C Rouleau, G Deka, R Meissner, I Bailey-Wilson, J Huston, J Brown, RD Broderick, JP AF Foroud, Tatiana Koller, Daniel Lal, Dongbing Woo, Daniel Sauerbeck, Laura Hornung, Richard Wiebers, David Connolly, E. Sander Anderson, Craig Rouleau, Guy Deka, Ranjan Meissner, Irene Bailey-Wilson, Joan Huston, John, III Brown, Robert D., Jr. Broderick, Joseph P. CA FIA Investigators TI Genome-wide SNP linkage screen for intracranial aneurysm susceptibility genes SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Indiana Univ, Indianapolis, IN 46204 USA. Univ Cincinnati, Cincinnati, OH USA. Mayo Clin, Rochester, MN USA. Columbia Univ, New York, NY USA. Univ Sydney, Sydney, NSW 2006, Australia. Univ Montreal, Montreal, PQ, Canada. NHGRI, Baltimore, MD 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 455 EP 456 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600069 ER PT J AU Kidwell, CS Latour, LL Hsia, AW Merino, JG Burgess, RE Copenhaver, BR Castle, A Warach, S AF Kidwell, Chelsea S. Latour, Lawrence L. Hsia, Amie W. Merino, Jose G. Burgess, Richard E. Copenhaver, Brittany R. Castle, Amanda Warach, Steven TI Demonstration of blood-brain barrier disruption in humans with primary intracerebral hemorrhage SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Georgetown Univ, Washington, DC USA. NINDS, Bethesda, MD 20892 USA. Washington Hosp Ctr, Washington, DC 20010 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 464 EP 464 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600107 ER PT J AU Merino, JG Latour, LL An, L Hsia, AW Kang, DW Warach, S AF Merino, Jose G. Latour, Lawrence L. An, Li Hsia, Amie W. Kang, Dong-Wha Warach, Steven TI Reperfusion half-life: A novel pharmacodynamic measure of thrombolytic activity SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NINDS, Bethesda, MD 20892 USA. Washington Hosp Ctr, Washington, DC 20010 USA. Asan Med Ctr, Seoul, South Korea. 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 464 EP 464 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600105 ER PT J AU Howard, G Safford, MM Meschia, JF Moy, CS Howard, VJ Gomez, CR Crowther, M AF Howard, George Safford, Monika M. Meschia, James F. Moy, Claudia S. Howard, Virginia J. Gomez, Camilo R. Crowther, Martha CA REGARDS Investigators TI Stroke symptoms in individuals reporting no prior stroke or TIA are associated with a decrease in indices of mental and physical functioning SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Univ Alabama, Birmingham, AL USA. Mayo Clin, Jacksonville, FL 32224 USA. NINDS, Bethesda, MD 20892 USA. Alabama Neurol Inst, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 482 EP 482 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600183 ER PT J AU Elkins, JS Longstreth, WT Manolio, TA Newman, AB Bhadelia, RA Johnston, SC AF Elkins, Jacob S. Longstreth, W. T., Jr. Manolio, Teri A. Newman, Anne B. Bhadelia, Rafeeque A. Johnston, S. Claiborne TI MRI-defined brain infarct is associated with greater cognitive decline in hypertensives despite similar lesion size and location SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Washington, Seattle, WA 98195 USA. NHLBI, Washington, DC USA. Univ Pittsburgh, Pittsburgh, PA USA. Tufts Univ New England Med Ctr, Boston, MA USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 484 EP 484 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600192 ER PT J AU Fifi, JT Butman, JA Warach, S Luby, M Saver, JL Kidwell, CS AF Fifi, Johanna T. Butman, John A. Warach, Steven Luby, Marie Saver, Jeffrey L. Kidwell, Chelsea S. CA HEME Investigators TI Standard gradient echo (GRE) is far superior to other susceptibility-weighted MR sequences for identifying intracranial hemorrhage SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NINDS, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Georgetown Univ, Washington, DC USA. RI Butman, John/A-2694-2008 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 486 EP 486 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600201 ER PT J AU Burgess, RE Warach, S Schaewe, T Copenhaver, BR Alger, J Vespa, P Martin, N Saver, JL Kidwell, CS AF Burgess, Richard E. Warach, Steven Schaewe, Tim Copenhaver, Brittany R. Alger, Jeffry Vespa, Paul Martin, Neil Saver, Jeffrey L. Kidwell, Chelsea S. TI Development and validation of a simple conversion model for comparison of intracerebral hemorrhage volumes measured on CT and gradient echo MRI SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NINDS, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Georgetown Univ, Washington, DC 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 489 EP 489 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600212 ER PT J AU Miracle, A Gaudinski, MR Henning, EC Luby, M Latour, LL Warach, S AF Miracle, Aaron Gaudinski, Martin R. Henning, Erica C. Luby, Marie Latour, Lawrence L. Warach, Steven TI Ischemic lesion volume on FLAIR MRI does not differ between 30 and 90 days SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NINDS, Bethesda, MD 20892 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 490 EP 490 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600218 ER PT J AU Debrey, SM Janket, SJ Wright, VL Yu, H Baird, AE AF Debrey, Sarah M. Janket, Sok-Ja Wright, Violet L. Yu, Hua Baird, Alison E. TI Contrast-enhanced magnetic resonance angiography in the diagnosis of severe carotid artery stenosis and occlusion: A meta-analysis and systematic review SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Boston Univ, Goldman Sch Dent Med, Boston, MA 02215 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 497 EP 498 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600251 ER PT J AU Saver, JL Starkman, S Eckstein, M Hamilton, S Kidwell, CS Stratton, S Conwit, R Liebeskind, D Sung, G AF Saver, Jeffrey L. Starkman, Sidney Eckstein, Marc Hamilton, Scott Kidwell, Chelsea S. Stratton, Samuel Conwit, Robin Liebeskind, David Sung, Gene CA FAST-MAG Trial Investigators TI Hyperacute prehospital stroke trial patients: Insights from the first 180 patients enrolled in the FAST-MAG phase 3 trial SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Univ Calif Los Angeles, Geffen Sch Med, Los Angeles, CA USA. Univ So Calif, LAFD EMS Agcy, Los Angeles, CA USA. Stanford Sch Med, Palo Alto, CA USA. Los Angeles EMS Agcy, Los Angeles, CA USA. NIH, NINDS, Bethesda, MD 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 499 EP 499 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600260 ER PT J AU Paik, NJ Celnik, PA Vandermeeren, YJ Cohen, LG AF Paik, Nam-Jong Celnik, Pablo A. Vandermeeren, Yves J. Cohen, Leonardo G. TI Effects of combined peripheral nerve stimulation and noninvasive cortical stimulation on motor learning in chronic stroke SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NIH, Nat Inst Neurol Disorders & Stroke, Human Human Cort Physiol Sect, Bethesda, MD 20892 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 518 EP 518 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600345 ER PT J AU Seshadri, S Massaro, J Manning, WJ Au, R Petrea, RE Beiser, AS Gona, P Jefferson, AL Benjamin, EJ Vasan, RS D'Agostino, RB O'Donnell, CJ DeCarli, C Wolf, PA AF Seshadri, Sudha Massaro, Joseph Manning, Warren J. Au, Rhoda Petrea, Rodica E. Beiser, Alexa S. Gona, Philimon Jefferson, Angela L. Benjamin, Emelia J. Vasan, Ramachandran S. D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. DeCarli, Charles Wolf, Philip A. TI Association of aortic plaque measures with indices of brain aging on volumetric brain MRI in the Framingham Offspring study SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Boston Univ, Sch Med, Boston, MA 02215 USA. Beth Israel Med Ctr, Harvard Med Sch, Boston, MA USA. Boston Univ, Sch Med & Publ Hlth, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Univ Calif San Diego, San Diego, CA 92103 USA. RI DeCarli, Charles/B-5541-2009 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 527 EP 527 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600389 ER PT J AU Ulmer, H Brant, LJ Kelleher, CC Concin, H Klenk, J Rapp, K Weiland, SK Ruttmann, E AF Ulmer, Hanno Brant, Larry J. Kelleher, Cecily C. Concin, Hans Klenk, Jochen Rapp, Kilian Weiland, Stephan K. Ruttmann, Elfriede TI Gamma-glutamyltransferase predicts mortality from both ischemic and hemorraghic stroke in a cohort of 170,244 men and women SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Innsbruck Med Univ, Innsbruck, Austria. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Coll Dublin, Sch Publ Hlth & Populat Sci, Dublin 2, Ireland. Agcy Prevent & Social Med, Bregenz, Austria. Univ Ulm, D-89069 Ulm, Germany. RI Ruttmann, Elfriede/D-6501-2011; vhmpp, aks/F-9756-2012; Ulmer, Hanno/C-3488-2011 OI Ulmer, Hanno/0000-0001-5911-1002 NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 529 EP 529 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600396 ER PT J AU Hsia, AW Warach, S Fifi, JT Burgess, RE Merino, JG Castle, A Taylor, A Copenhaver, BR Kidwell, CS AF Hsia, Amie W. Warach, Steven Fifi, Johanna T. Burgess, Richard E. Merino, Jose G. Castle, Amanda Taylor, Alexis Copenhaver, Brittany R. Kidwell, Chelsea S. TI Hypertension, but not diabetes mellitus, is associated with cerebral microbleeds in patients with acute ischemic stroke SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Washington Hosp Ctr, Washington, DC 20010 USA. Natl Inst Neurol Dis & Stroke, Bethesda, MD USA. Georgetown Univ, Washington, DC 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 530 EP 530 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600402 ER PT J AU Henning, EC Rabinak, CA Panapitiya, NC Ruetzler, CA Hu, TC Latour, LL Hallenbeck, JM Warach, S AF Henning, Erica C. Rabinak, Christina A. Panapitiya, Narendra C. Ruetzler, Christl A. Hu, Tom C. Latour, Lawrence L. Hallenbeck, John M. Warach, Steven TI MRI and immunohistochemical visualization of macrophage activity following transient MCAO in spontaneously hypertensive rats SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 NINDS, Bethesda, MD 20892 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 550 EP 551 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600498 ER PT J AU Nyquist, P Hopkins, J Zhang, J Degraba, TJ AF Nyquist, Paul Hopkins, Johns Zhang, Jianhua Degraba, Thomas J. TI The -927 C single nucleotide polymorphism (SNP) has increased transcriptional activity in vitro and is a binding site for PARP-1 and ARNT SO STROKE LA English DT Meeting Abstract CT 32nd International Stroke Conference CY FEB 07-08, 2007 CL San Francisco, CA C1 Johns Hopkins, Baltimore, MD USA. Natl Inst Hlth, Bethesda, MD USA. Natl Naval Med Ctr, Bethesda, MD 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 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 568 EP 568 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600584 ER PT J AU Baird, AE AF Baird, Alison E. TI Blood Genomics in human stroke SO STROKE LA English DT Article; Proceedings Paper CT 25th Princeton Conference on Cerebrovascular Disease CY MAY 19-20, 2006 CL Portland, OR SP AstraZeneca, Bayers, Cardinal Hlth, Johnson & Johnson, Legacy Hlth Syst, Merck, Neurobiol Technol, Novo Nordisk, Oregon Hlth & Sci, Univ Neurol, Pfizer Inc, Portland Dev Commiss, Renovious, Virogen & Wyeth DE diagnostic methods; genetics; inflammation; stroke ID GENE-EXPRESSION PROFILES; ISCHEMIC-STROKE; MULTIPLE-SCLEROSIS; CONFERS RISK; DISEASE; BRAIN; RESPONSES; HYPOXIA; PROTEIN; CELL AB Advances in microarray technology and the sequencing of the human genome are opening up new possibilities for applying genomic information in clinical medicine, using information about structural polymorphisms in DNA and changes in gene expression as measured by mRNA. Gene expression profiling studies in cancer samples have led to the identification of clinical signatures that are already being applied in some centers. In stroke, it may be possible to use peripheral blood as a source of mRNA to study gene expression. After stroke, there is a selective recruitment and migration of white blood cells to the ischemic focus in the brain. This appears to involve all white cell types and is believed to impact significantly on tissue and clinical outcome through the exacerbation of ischemic injury, particularly after reperfusion, on the one hand, and conversely contributing to tissue remodeling and repair days to weeks after stroke. The first results from clinical studies in ischemic stroke suggest that a gene expression signature can be demonstrated from peripheral white blood cells and that this represents at least a partial adaptation to the altered cerebral microenvironment. Further studies are indicated to see whether these methods may lead to new management approaches for stroke. (Stroke. 2007;38[part 2]: 694-698.) C1 NINDS, Struct Neurosci Unit, NIH, Bethesda, MD 20892 USA. RP Baird, AE (reprint author), NINDS, Struct Neurosci Unit, NIH, 10 Ctr Dr,MSC 1294, Bethesda, MD 20892 USA. EM bairda@ninds.nih.gov FU Intramural NIH HHS NR 35 TC 24 Z9 27 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 694 EP 698 DI 10.1161/STR.0000250431.99687.7b PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600810 PM 17261718 ER PT J AU Nelson, KB AF Nelson, Karin B. TI Perinatal ischemic stroke SO STROKE LA English DT Article; Proceedings Paper CT 25th Princeton Conference on Cerebrovascular Disease CY MAY 19-20, 2006 CL Portland, OR SP AStraZeneca, Bayers, Cardinal Hlth, Johnson & Johnson, Legacy Hlth Syst, Merck, Neurobiol Technol, Novo Nordisk, Oregon Hlth & Sci, Univ Neurol, Pfizer Inc, Portland Dev Commiss, Renovious, Virogen & Wyeth DE hemiplegic cerebral palsy; perinatal stroke ID RISK-FACTORS; ARTERIAL STROKE; CEREBRAL-PALSY; PREGNANCY; ENCEPHALOPATHY; OUTCOMES; CHILDREN; INFANTS AB Perinatal ischemic stroke is not rare in term and near-term infants and is an important antecedent of long-term neurological disability, including congenital hemiplegia (hemiplegic cerebral palsy) and seizure and cognitive disorders. Changes in maternal hemostasis occur in pregnancy and are amplified in the period immediately surrounding birth; stroke and other thromboembolic events are more frequent in both mother and infant in this period. The vasculature and hemostatic mechanisms of placenta as well as brain are likely to be important in the pathobiology of perinatal stroke. Maternal and infant thrombophilias, genetic and acquired, play a role. Rarely is > 1 child in a sibship affected, and environmental factors-substantially less studied, to date-are likely to be key determinants of risk. (Stroke. 2007;38[part 2]:742-745.) C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), NINDS, NIH, Bldg 10,Room 5S221, Bethesda, MD 20892 USA. EM knelson@helix.nih.gov FU Intramural NIH HHS NR 22 TC 84 Z9 86 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 742 EP 745 DI 10.1161/01.STR.0000247921.97794.5e PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600821 PM 17261729 ER PT J AU Hallenbeck, J AF Hallenbeck, John TI Adaptive immunity - Introduction SO STROKE LA English DT Editorial Material ID CELLS C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Hallenbeck, J (reprint author), NINDS, Stroke Branch, NIH, 49 Convent Dr,MSC 4476, Bethesda, MD 20892 USA. EM hallenbj@ninds.nih.gov NR 6 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 768 EP 769 DI 10.1161/01.STR.0000247867.63924.f9 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600827 ER PT J AU Tilley, BC Galpern, WR AF Tilley, Barbara C. Galpern, Wendy R. TI Screening potential therapies - Lessons learned from new paradigms used in Parkinson disease SO STROKE LA English DT Article; Proceedings Paper CT 25th Princeton Conference on Cerebrovascular Disease CY MAY 19-20, 2006 CL Portland, OR SP AStraZeneca, Bayers, Cardinal Hlth, Johnson & Johnson, Legacy Hlth Syst, Merck, Neurobiol Technol, Novo Nordisk, Oregon Hlth & Sci, Univ Neurol, Pfizer Inc, Portland Dev Commiss, Renovious, Virogen & Wyeth DE futility studies; Phase II clinical trials; Parkinson disease; stroke ID ACUTE ISCHEMIC-STROKE; CLINICAL-TRIALS; NEUROPROTECTIVE AGENTS; SYSTEMATIC ASSESSMENT; FUTILITY AB In Parkinson Disease (PD) as well as in stroke research there is an urgent need to both optimize the use of resources (number of patients, costs, and time) and select potential effective neuroprotective agents. The processes used to identify and study new therapies for PD may be applicable to the search for new therapies in stroke. The National Institute of Neurological Disorders and Stroke (NINDS) organized the Committee to Identify Neuroprotective Agents for Parkinson's (CINAPS). CINAPS broadly solicited suggestions for agents and evaluated these agents using rigorous criteria. NINDS also created the NIH Exploratory Trials in PD program (NET-PD), a clinical network where CINAPS recommendations could be tested. Given multiple recommended agents, NET-PD investigators used Phase II futility designs with calibration controls, tested against an historical standard, to screen agents for testing in Phase III trials. Investigators also used the Phase II trial to assess ancillary outcome measures for use in Phase III. The observed value for the calibration controls in the first NET-PD Phase II trial was outside the 95% CI for the historical standard. Using bootstrap methodology it appeared unlikely this outcome happened by chance. The historical standard was updated using more contemporaneous data than were available at the start of the futility trials and a re-evaluation using the new threshold was conducted. Assessment of ancillary outcome measures led to a reduced set of outcome measures for use in Phase III. The CINAPS process, and lessons learned from NET-PD futility studies, particularly with respect to calibration controls and assessment of outcome measures, could enhance the choice and testing of new agents for stroke treatment. (Stroke. 2007;38[part 2]:800-803.) C1 Med Univ S Carolina, Dept Biostat, Charleston, SC 29425 USA. NINDS, Bethesda, MD 20892 USA. RP Tilley, BC (reprint author), Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, POB 250835,135 Cannon St,Ste 303, Charleston, SC 29425 USA. EM tilleybc@musc.edu FU NINDS NIH HHS [U01NS043128, U10NS44415-44555, U01NS043127] NR 20 TC 8 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2007 VL 38 IS 2 BP 800 EP 803 DI 10.1161/01.STR.0000255227.96365.37 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 134ZE UT WOS:000244122600834 PM 17261742 ER PT J AU Fujita, M Imaizumi, M D'Sa, C Zoghbi, SS Crescenzo, MS Hong, JS Musachio, JL Gee, AD Seidel, J Green, MV Pike, VW Duman, RS Innis, RB AF Fujita, Masahiro Imaizumi, Masao D'Sa, Carrol Zoghbi, Sami S. Crescenzo, Matthew S. Hong, Jinsoo Musachio, John L. Gee, Antony D. Seidel, Jurgen Green, Michael V. Pike, Victor W. Duman, Ronald S. Innis, Robert B. TI In vivo and in vitro measurement of brain phosphodiesterase 4 in rats after antidepressant administration SO SYNAPSE LA English DT Article DE PET; rolipram; imipramine; homogenate binding assay; Western blotting; cAMP ID CAMP-SPECIFIC PHOSPHODIESTERASE; DEPENDENT PROTEIN-KINASE; ELECTROCONVULSIVE SEIZURE; BINDING-SITES; EXPRESSION; PDE4; ROLIPRAM; 4A; PHOSPHORYLATION; TOMOGRAPHY AB Based largely on in vitro measurements, the mechanism of several antidepressant treatments is thought to involve upregulation of 3'-5-cyclic adenosine monophosphate (cAMP) signal transduction cascade and a corresponding increase in phosphodiesterase (PDE) 4, the enzyme that metabolizes cAMP. To assess the in vivo status of PDE4, rats were chronically treated with imipramine and then studied with: (1) in vivo positron emission tomography (PET) measurement of (R)-[C-11]rolipram binding, (2) in vitro measurement of [H-3]rolipram binding in brain homogenates, and (3) Western blotting for protein levels of PDE4 isoforms. Imipramine administration caused no significant change in B-max/K-d, for both in vivo measurements with (R)-[C-11]rolipram and in vitro measurements with [H-3]rolipram in frontal cortex, hippocampus, and diencephalon. None of 10 isoforms of PDE4A, B, and D measured with immunoblots of frontal cortex and hippocampus showed a significant change. In summary, using relatively large brain regions for both in vivo imaging and in vitro measures of radiolabeled ligand binding and protein levels, chronic imipramine treatment via continuous mini-pump administration caused no significant change in PDE4 levels. Most, but not all, prior in vitro studies have found increased PDE4 levels after antidepressant administration. The current results raise questions about the in vivo effects of antidepressant treatment on PDE4 and on other potentially important experimental factors (e.g., continuous infusion vs. intermittent injection of antidepressant) in large brain areas. However, the results do not deny possibility of changes in discrete areas, which were not studied in the current study applying PET. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. GlaxoSmithKline Inc, Addenbrookes Hosp, PET Div, Cambridge, England. Trident Imaging Inc, Rockville, MD USA. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06510 USA. RP Fujita, M (reprint author), Bldg 1,Room B3-10,1 Ctr Dr,MSC-0135, Bethesda, MD 20892 USA. EM masahiro.fujita@nih.gov FU Intramural NIH HHS NR 42 TC 11 Z9 11 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2007 VL 61 IS 2 BP 78 EP 86 DI 10.1002/syn.20347 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 116GE UT WOS:000242789700003 PM 17117418 ER PT J AU Liow, JS Lu, SY McCarron, JA Hong, JS Musachio, JL Pike, VW Innis, RB Zoghbi, SS AF Liow, Jeih-San Lu, Shuiyu McCarron, Julie A. Hong, Jinsoo Musachio, John L. Pike, Victor W. Innis, Robert B. Zoghbi, Sami S. TI Effect of a P-glycoprotein inhibitor, cyclosporin A, on the disposition in rodent brain and blood of the 5-HT1A receptor radioligand, [C-11](R)-(-)-RWAY SO SYNAPSE LA English DT Article DE cyclosporin A; CsA; P-glycoprotein; [C-11](R)-(-)-RWAY; 5-HT1A receptors ID MULTIDRUG-RESISTANCE; GENE POLYMORPHISM; BARRIER; PET; TRANSPORTER; SENSITIVITY; TOMOGRAPHY; DRUGS; SPECT; RATS AB Limited brain uptake of radioligands with otherwise optimal properties for imaging brain receptors can be improved by blocking the effect of P-glycoprotein (P-gp), an efflux pump at the blood-brain barrier. Using small animal positron emission tomography (PET), we investigated how P-gp and its blockade with Cyclosporin A (CsA) affect rodent brain uptake of [C-11](R)-(-)-RWAY, a radioligand for brain 5-HT1A receptors. Brain uptake of radioactivity was compared in control and CsA-treated rats as well as P-gp knockout and wild type mice. Parent radioligand and radiometabolite in plasma and brain samples were determined at 30 min after injection of radioligand. PET binding potential (BP) was calculated with a reference tissue model. P-gp knockout mice had 2.5- and 2.8-fold greater brain uptake of [C-11](R)-(-)-RWAY than wild type ones, measured by in vivo PET and ex vivo tissue sampling, respectively. Similarly, CsA increased rat brain uptake 4.9- and 5.3-fold, in vivo and ex vivo. In addition, CsA increased the plasma free fraction of [C-11](R)-(-)-RWAY in rats by 2.7-fold. Although CsA increased brain uptake in wild type mice by 2.5-fold, it had no effect on plasma free fraction in knockout animals. Three radiometabolites of [C-11](R)-(-)-RWAY were uniformly distributed in rat brain, suggesting they were inactive. CsA treatment increased brain uptake of [C-11](R)-(-)-RWAY and only one of its radiometabolites. Regional rat brain BP increased 27-70% in the CsA-treated rats and the P-gp knockout mice. [C-11](R)-(-)-RWAY is a P-gp substrate in rat and mouse. The effects of CsA in rats are mediated by both P-gp blockade and displacement of the radiotracer from plasma proteins. Studies with wild type and knockout mice showed that CsA affected only P-gp in this species. C1 NIMH, NIH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Liow, JS (reprint author), NIMH, NIH, Mol Imaging Branch, 1 Ctr Dr,Room B3-10,MS 0135, Bethesda, MD 20892 USA. EM liowj@mail.nih.gov OI Lu, Shuiyu/0000-0003-0310-4318 FU Intramural NIH HHS NR 29 TC 43 Z9 45 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2007 VL 61 IS 2 BP 96 EP 105 DI 10.1002/syn.20348 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 116GE UT WOS:000242789700005 PM 17117422 ER PT J AU Topper, RQ Sun, GY AF Topper, Robert Q. Sun, Guangyu TI Proceedings of the 10th Electronic Computational Chemistry Conference SO THEORETICAL CHEMISTRY ACCOUNTS LA English DT Editorial Material C1 Monmouth Univ, Dept Chem Med Technol & Phys, Long Branch, NJ 07764 USA. NCI, Lab Med Chem, CCR NIH, DHHS, Frederick, MD 21702 USA. RP Topper, RQ (reprint author), Monmouth Univ, Dept Chem Med Technol & Phys, Thomas A Edison Hall Sci, Long Branch, NJ 07764 USA. EM rtopper@monmouth.edu RI Topper, Robert/P-9813-2016 OI Topper, Robert/0000-0001-6109-001X NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1432-881X J9 THEOR CHEM ACC JI Theor. Chem. Acc. PD FEB PY 2007 VL 117 IS 2 BP 183 EP 183 DI 10.1007/s00214-006-0187-0 PG 1 WC Chemistry, Physical SC Chemistry GA 130TU UT WOS:000243822700001 ER PT J AU Sun, GY Nicklaus, MC AF Sun, Guangyu Nicklaus, Marc C. TI Natural resonance structures and aromaticity of the nucleobases SO THEORETICAL CHEMISTRY ACCOUNTS LA English DT Article; Proceedings Paper CT 10th Electronic Computational Chemistry Conference CY APR, 2005 CL West Long Branch, NJ DE nucleobase; DFT; natural bond orbital; natural resonance theory; quantum chemical calculations; aromaticity; nucleus-independent chemical shift (NICS) ID DENSITY AB Natural resonance theory (NRT) and nucleus- independent chemical shift (NICS) analyses have been applied to the standard nucleobases adenine, guanine, cytosine, uracil, and thymine. The molecular electron densities were obtained from density functional theory calculations at the B3LYP level and ab initio calculations at the HF, MP2, and CCD levels. Compared with the dominance of the two Kekule structures in benzene, the structural modifications in the forms of endocyclic heteroatoms and exocyclic substituents introduce various degrees of charge separation in nucleobases. As a result, the leading resonance structures for cytosine, uracil, and thymine are found to be covalent structures, but their weightings decrease to similar to 30% in the NRT expansion. For adenine and guanine, the covalent structures have weightings of similar to 20%, and the leading ionic resonance structures have weightings of as high as about 8%. Methods that include electron correlation effects, B3LYP, MP2, and CCD, give smaller weightings for the covalent structures than HF. However, MP2 and CCD results often include "strange" resonance structures with connections between unbonded vicinal atoms, making DFT at the B3LYP level the better choice for calculating these molecules' electron density. The NICS at the ring center shows that the six-membered rings in cytosine, uracil, thymine, and guanine are nonaromatic with NICS within -3 to -1 ppm, while it is -7.3 ppm for the six-membered ring in adenine. The NICS of the five-membered rings of adenine and guanine is around -12 ppm, a slight decrease from the value of -15.0 ppm for pyrrole. C1 NCI, Med Chem Lab, NIH, DHHS, Ft Detrick, MD 21702 USA. RP Nicklaus, MC (reprint author), NCI, Med Chem Lab, NIH, DHHS, 376 Boyles St, Ft Detrick, MD 21702 USA. EM sungy@helix.nih.gov; mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Nicklaus, Marc/0000-0002-4775-7030 NR 17 TC 20 Z9 20 U1 1 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1432-881X J9 THEOR CHEM ACC JI Theor. Chem. Acc. PD FEB PY 2007 VL 117 IS 2 BP 323 EP 332 DI 10.1007/s00214-006-0154-9 PG 10 WC Chemistry, Physical SC Chemistry GA 130TU UT WOS:000243822700019 ER PT J AU Belak, M Jako, J AF Belak, Mihaly Jako, Janos TI National survey of hemapheresis practice in Hungary 2001-2004 SO THERAPEUTIC APHERESIS AND DIALYSIS LA English DT Article DE plasma exchange; hemapheresis; national survey ID THROMBOTIC THROMBOCYTOPENIC PURPURA; GUILLAIN-BARRE-SYNDROME; THERAPEUTIC PLASMA-EXCHANGE; RHEUMATOID-ARTHRITIS; INTRAVENOUS IMMUNOGLOBULIN; RANDOMIZED TRIAL; DOUBLE-BLIND; PLASMAPHERESIS; APHERESIS; VASCULITIS AB In the current study, the authors evaluated data provided by Hungarian hemapheresis centers to the National Health Insurance (NHI) organization between 2001 and 2004 with the intention of having costs reimbursed. The primary objective of the present study was to rank data by frequency of indications of therapeutic plasma exchange (TPE). Furthermore, we compared frequency data with the Canadian TPE Registry and reviewed medical evidence regarding the adequacy of applying TPE at chosen indications based on data in literature. It was concluded that the number of TPEs (and thus the reimbursed costs) increased steadily year by year. It is worth considering the difference between the five most frequent indications of TPE in Hungary or in Canada. Clinicians tend to apply TPE in many cases as a last resort treatment of many diseases unresponsive to conventional therapy. Consequently, there are many illnesses for which the value of TPE is still questionable (or unproven) and its use is considered investigational or experimental. Nevertheless, cumulative medical experience does not always confirm the adequacy of TPE in all treatments, retrospectively. Thus, limited financial resources oblige clinicians to be judicious in providing apheresis services. C1 Natl Med Ctr, Dept Internal Med & Geriatr, Budapest, Hungary. RP Belak, M (reprint author), NIDDKD, Mol Med Branch, NIH, 10 Ctr Dr,10-9N312, Bethesda, MD 20892 USA. EM belakm@mail.nih.gov NR 38 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1744-9979 J9 THER APHER DIAL JI Ther. Apher. Dial. PD FEB PY 2007 VL 11 IS 1 BP 22 EP 29 DI 10.1111/j.1744-9987.2007.00414.x PG 8 WC Hematology; Urology & Nephrology SC Hematology; Urology & Nephrology GA 134QM UT WOS:000244098800005 PM 17309571 ER PT J AU Pinsky, P Freedman, M Oken, M Kvale, P Caporaso, N Gohagan, J AF Pinsky, Paul Freedman, Matthew Oken, Martin Kvale, Paul Caporaso, Neal Gohagan, John TI Prevalence of non-cancer-related abnormalities on low-dose spiral computer tomography versus chest radiograph in a screening population SO THORAX LA English DT Letter ID LUNG-CANCER; TRIAL C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC USA. N Mem Hosp, Hubert Humphrey Canc Ctr, Minneapolis, MN USA. Henry Ford Hlth Syst, Detroit, MI USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pinsky, P (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD FEB PY 2007 VL 62 IS 2 BP 190 EP 190 DI 10.1136/thx.2006.073288 PG 1 WC Respiratory System SC Respiratory System GA 134DX UT WOS:000244064200018 PM 17287309 ER PT J AU Walker, NJ AF Walker, Nigel J. TI Unraveling the complexities of the mechanism of action of dioxins SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material ID SPRAGUE-DAWLEY RATS; SUBCHRONIC EXPOSURE; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; 17-BETA-ESTRADIOL; PROMOTION; TOXICITY; CELLS; TCDD; FOCI C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Walker, NJ (reprint author), NIEHS, NIH, POB 12233,MD EC-34,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM walker3@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 NR 18 TC 8 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2007 VL 95 IS 2 BP 297 EP 299 DI 10.1093/toxsci/kfl170 PG 3 WC Toxicology SC Toxicology GA 130GL UT WOS:000243787800001 PM 17297723 ER PT J AU Shen, J Liu, J Xie, YX Diwan, BA Waalkes, MP AF Shen, Jun Liu, Jie Xie, Yaxiong Diwan, Bhalchandra A. Waalkes, Michael P. TI Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure SO TOXICOLOGICAL SCIENCES LA English DT Article DE inorganic arsenic; transplacental exposure; lung cancer; estrogen signaling ID GROWTH-FACTOR RECEPTOR; POSTNATAL DIETHYLSTILBESTROL; GESTATIONAL EXPOSURE; ESTROGEN-RECEPTOR; EPITHELIAL-CELLS; ANIMAL-MODELS; ADULT MICE; CANCER; LIVER; INDUCTION AB Arsenic is a human pulmonary carcinogen. Our work indicates that in utero arsenic exposure in mice can induce or initiate lung cancer in female offspring. To define early molecular changes, pregnant C3H mice were given 85 ppm arsenic in drinking water from days 8 to 18 of gestation and expression of selected genes in the fetal lung or in lung tumors developing in adults was examined. Transplacental arsenic exposure increased estrogen receptor-alpha (ER-alpha) transcript and protein levels in the female fetal lung. An overexpression of various estrogen-regulated genes also occurred, including trefoil factor-3, anterior gradient-2, and the steroid metabolism genes 17-beta-hydroxysteroid dehydrogenase type 5 and aromatase. The insulin growth factor system, which can be influenced by ER and has been implicated in the pulmonary oncogenic process, was activated in fetal lung after gestational arsenic exposure. In utero arsenic exposure also induced overexpression of (x-fetoprotein, epidermal growth factor receptor, L-myc, and metallothionein-1 in fetal lung, all of which are associated with lung cancer. Lung adenoma and adenocarcinoma from adult female mice exposed to arsenic in utero showed widespread, intense nuclear ER-alpha expression. In contrast, normal adult lung and diethylnitrosamine-induced lung adenocarcinoma showed little evidence of ER-a. expression. Thus, transplacental arsenic exposure at a carcinogenic dose produced aberrant estrogen-linked pulmonary gene expression. ER-a activation was specifically associated with arsenic-induced lung adenocarcinoma and adenoma but not with nitrosamine-induced lung tumors. These data provide evidence that arsenic-induced aberrant ER signaling could disrupt early life stage genetic programing in the lung leading eventually to lung tumor formation much later in adulthood. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. Sci Applicat Int Crop Frederick, Basic Res Program, NCI, Frederick, MD USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS [NIH0011069698]; NCI NIH HHS [N01CO12400, N01-CO-12400]; PHS HHS [NIH0011069698] NR 46 TC 38 Z9 42 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2007 VL 95 IS 2 BP 313 EP 320 DI 10.1093/toxsci/kfl151 PG 8 WC Toxicology SC Toxicology GA 130GL UT WOS:000243787800003 PM 17077188 ER PT J AU Ghanayem, BI AF Ghanayem, Burhan I. TI Inhibition of urethane-induced carcinogenicity in Cyp2e1-/- in comparison to Cyp2e1+/+ mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE Cyp2e1-/- mice; urethane metabolism; urethane carcinogenicity; lung tumors; liver tumors; Harderian gland tumors ID ETHYL CARBAMATE URETHANE; CYTOCHROME-P450 2E1 CYP2E1; WILD-TYPE MICE; VINYL CARBAMATE; B6C3F1 MICE; CELL-PROLIFERATION; P53 MUTATIONS; LUNG-TUMORS; IN-VIVO; KI-RAS AB Urethane is an established animal carcinogen and has been classified as "reasonably anticipated to be a human carcinogen." Until recently, urethane metabolism via esterase was considered the main metabolic pathway of this chemical. However, recent studies in this laboratory showed that CYP2E1, and not esterase, is the primary enzyme responsible for urethane oxidation. Subsequent studies demonstrated significant inhibition of urethane-induced genotoxicity and cell proliferation in Cyp2e1-/-compared to Cyp2e1+/+ mice. Using Cyp2e1-/- mice, current studies were undertaken to assess the relationships between urethane metabolism and carcinogenicity. Urethane was administered via gavage at 1, 10, or 100 mg/kg/day, 5 days/week, for 6 weeks. Animals were kept without chemical administration for 7 months after which they were euthanized, and urethane carcinogenicity was assessed. Microscopic examination showed a significant reduction in the incidences of liver hemangiomas and hemangiosarcomas in Cyp2e1-/- compared to Cyp2e+/+ mice. Lung nodules increased in a dose-dependent manner and were less prevalent in Cyp2e1-/- compared to Cyp2e+/+ mice. Microscopic alterations included bronchoalveolar adenomas, and in one Cyp2e1+/+ mouse treated with 100 mg/kg urethane, a bronchoalveolar carcinoma was diagnosed. Significant reduction in the incidence of adenomas and the number of adenomas/lung were observed in Cyp2e1-/- compared to Cyp2e1+/+ mice. In the Harderian gland, the incidences of hyperplasia and adenomas were significantly lower in Cyp2e1-/- compared to Cyp2e+/+ mice at the 10 mg/kg dose, with no significant differences observed at the high or low doses. In conclusion, this work demonstrated a significant reduction of urethane-induced carcinogenicity in Cyp2e1-/-compared to Cyp2e1+/+ mice and proved that CYP2E1-mediated oxidation plays an essential role in urethane-induced carcinogenicity. C1 NIEHS, Lab Pharmacol & Chem, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. RP Ghanayem, BI (reprint author), NIEHS, Lab Pharmacol & Chem, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. EM ghanayem@niehs.nih.gov FU Intramural NIH HHS NR 52 TC 11 Z9 11 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2007 VL 95 IS 2 BP 331 EP 339 DI 10.1093/toxsci/kfl158 PG 9 WC Toxicology SC Toxicology GA 130GL UT WOS:000243787800005 PM 17093202 ER PT J AU Swartz, KJ AF Swartz, Kenton J. TI Tarantula toxins interacting with voltage sensors in potassium channels SO TOXICON LA English DT Article DE voltage-sensor paddle; membrane partitioning; potassium channel structure; hanatoxin; SGTx1; VSTx1 ID DEPENDENT K+ CHANNEL; KAPPA-CONOTOXIN-PVIIA; GATING MODIFIER TOXINS; OMEGA-GRAMMOTOXIN-SIA; RECEPTOR HOMOLOG ACHBP; SEA-ANEMONE TOXIN; CALCIUM-CHANNELS; PEPTIDE INHIBITOR; SCORPION-VENOM; ION-CHANNELS AB Voltage-activated ion channels open and close in response to changes in membrane voltage, a process that is crucial for electrical signaling in the nervous system. The venom from many poisonous creatures contains a diverse array of small protein toxins that bind to voltage-activated channels and modify the gating mechanism. Hanatoxin and a growing number of related tarantula toxins have been shown to inhibit activation of voltage-activated potassium (K(v)) channels by interacting with their voltage-sensing domains. This review summarizes our current understanding of the mechanism by which these toxins alter gating, the location of the toxin receptor within K(v) channels and the disposition of this receptor with respect to the lipid membrane. The conservation of tarantula toxin receptors among voltage-activated ion channels will also be discussed. Published by Elsevier Ltd. C1 Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov FU Intramural NIH HHS [ZIA NS002945-13] NR 95 TC 104 Z9 107 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD FEB PY 2007 VL 49 IS 2 BP 213 EP 230 DI 10.1016/j.toxicon.2006.09.024 PG 18 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 138QO UT WOS:000244377500009 PM 17097703 ER PT J AU Nedvetsky, PI Stefan, E Frische, S Santamaria, K Wiesner, B Valenti, G Hammer, JA Nielsen, S Goldenring, JR Rosenthal, W Klussmann, E AF Nedvetsky, Pavel I. Stefan, Eduard Frische, Sebastian Santamaria, Katja Wiesner, Burkhard Valenti, Giovanna Hammer, John A., III Nielsen, Soren Goldenring, James R. Rosenthal, Walter Klussmann, Enno TI A role of myosin Vb and Rab11-FIP2 in the aquaporin-2 shuttle SO TRAFFIC LA English DT Article DE AQP2 recycling; aquaporin; principal cells; Rab11; vasopressin ID NEPHROGENIC DIABETES-INSIPIDUS; RENAL PRINCIPAL CELLS; TOAD URINARY-BLADDER; VASOPRESSIN-MEDIATED TRANSLOCATION; MEDULLARY COLLECTING DUCT; PLASMA-MEMBRANE; WATER CHANNEL; RAB11-INTERACTING PROTEINS; INTERACTING PROTEIN-2; EFFECTOR PROTEIN AB Arginine-vasopressin (AVP) regulates water reabsorption in renal collecting duct principal cells. Its binding to G(s)-coupled vasopressin V2 receptors increases cyclic AMP (cAMP) and subsequently elicits the redistribution of the water channel aquaporin-2 (AQP2) from intracellular vesicles into the plasma membrane (AQP2 shuttle), thereby facilitating water reabsorption from primary urine. The AQP2 shuttle is a paradigm for cAMP-dependent exocytic processes. Using sections of rat kidney, the AQP2-expressing cell line CD8, and primary principal cells, we studied the role of the motor protein myosin Vb, its vesicular receptor Rab11, and the myosin Vb- and Rab11-binding protein Rab11-FIP2 in the AQP2 shuttle. Myosin Vb colocalized with AQP2 intracellularly in resting and at the plasma membrane in AVP-treated cells. Rab11 was found on AQP2-bearing vesicles. A dominant-negative myosin Vb tail construct and Rab11-FIP2 lacking the C2 domain (Rab11-FIP2-Delta C2), which disrupt recycling, caused condensation of AQP2 in a Rab11-positive compartment and abolished the AQP2 shuttle. This effect was dependent on binding of myosin Vb tail and Rab11-FIP2-Delta C2 to Rab11. In summary, we identified myosin Vb as a motor protein involved in AQP2 recycling and show that myosin Vb- and Rab11-FIP2-dependent recycling of AQP2 is an integral part of the AQP2 shuttle. C1 Leibniz Inst Mol Pharmakol, D-13125 Berlin, Germany. Free Univ Berlin, Charite Univ Med Berlin, Inst Pharmakol, D-14195 Berlin, Germany. Aarhus Univ, Inst Anat, Water & Salt Res Ctr, DK-8000 Aarhus, Denmark. Univ Bari, Dipartimento Fisiol Gen & Ambientale, I-70126 Bari, Italy. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37232 USA. Nashville Vet Med Ctr, Nashville, TN 37232 USA. RP Klussmann, E (reprint author), Leibniz Inst Mol Pharmakol, Campus Berlin Buch, D-13125 Berlin, Germany. EM klussmann@fmp-berlin.de RI Horstmann, Britta/C-2154-2008; Frische, Sebastian/B-2332-2009; Nedvetsky, Pavel/F-1260-2011; chen, xuanlan/H-4158-2011; OI Frische, Sebastian/0000-0002-0270-3602; VALENTI, GIOVANNA/0000-0003-0233-0778; Stefan, Eduard/0000-0003-3650-4713; Hammer, John/0000-0002-2496-5179 FU NIDDK NIH HHS [DK43405, DK48370] NR 66 TC 66 Z9 72 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD FEB PY 2007 VL 8 IS 2 BP 110 EP 123 DI 10.1111/j.1600-0854.2006.00508.x PG 14 WC Cell Biology SC Cell Biology GA 126JB UT WOS:000243508100003 PM 17156409 ER PT J AU Mett, V Shamloul, AM Hirai, H Zhou, ZH Notkins, A Yusibov, V AF Mett, Vadim Shamloul, Abdel-Moneim Hirai, Hiroki Zhou, Zhaohua Notkins, Abner Yusibov, Vidadi TI Engineering and expression of the intracellular domain of insulinoma-associated tyrosine phosphatase (IA-2ic), a type 1 diabetes autoantigen, in plants SO TRANSGENIC RESEARCH LA English DT Article DE IA-2ic; type 1 diabetes; agroinfiltration; Nicotiana benthamiana; recombinant protein ID GLUTAMIC-ACID DECARBOXYLASE; MAJOR AUTOANTIGEN; GENE-EXPRESSION; MELLITUS; IDENTIFICATION; PANCREAS; PROTEIN; GAD65 AB We have produced the recombinant intracellular domain of human IA-2 (IA-2ic), a diabetes-associated autoantigen, in plants. This was achieved by transient expression using agroinfiltration of Nicotiana benthamiana plants. The resulting plant-derived IA-2ic had the expected size, reacted with polyclonal and monoclonal antibodies specific to human IA-2ic and competitively inhibited radiolabeled IA-2ic in an immunoprecipitation assay. The expression level of recombinant IA-2ic was estimated to be 0.5% of the total soluble protein (TSP). Transient expression in plants has the potential to produce a large amount of human IA-2ic protein at low cost in a short period of time. C1 Fraunhofer USA Ctr Mol Biotechnol, Newark, DE 19711 USA. NIDCR, NIH, Expt Med Sect, Bethesda, MD 20892 USA. RP Yusibov, V (reprint author), Fraunhofer USA Ctr Mol Biotechnol, 9 Innovat Way,Suite 200, Newark, DE 19711 USA. EM vyusibov@fraunhofer.org NR 20 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-8819 J9 TRANSGENIC RES JI Transgenic Res. PD FEB PY 2007 VL 16 IS 1 BP 77 EP 84 DI 10.1007/s11248-006-9033-3 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 123WM UT WOS:000243326900007 PM 17103024 ER PT J AU Hock, R Furusawa, T Ueda, T Bustin, M AF Hock, Robert Furusawa, Takashi Ueda, Tetsuya Bustin, Michael TI HMG chromosomal proteins in development and disease SO TRENDS IN CELL BIOLOGY LA English DT Review ID NUCLEOSOMAL BINDING-PROTEIN; NATURAL-KILLER-CELL; GROUP-A PROTEINS; HISTONE H1; CHROMATIN PROTEIN; TRANSGENIC MICE; MESENCHYMAL TRANSITION; REGULATED EXPRESSION; TRANSCRIPTION FACTOR; GENE-REGULATION AB The high mobility group (HMG) proteins are a superfamily of abundant and ubiquitous nuclear proteins that bind to DNA and nucleosomes and induce structural changes in the chromatin fiber. They are important in chromatin dynamics and influence DNA processing in the context of chromatin. Results emerging from studies of human disease, genetically modified mice and cells with altered HMG expression indicate that the expression of the HMG proteins is developmentally regulated and that changes in HMG protein levels alter the cellular phenotype and can lead to developmental abnormalities and disease. Here, we focus on the biological function of HMG proteins and highlight their possible roles in cellular differentiation and in the etiology of various diseases. C1 Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Hock, R (reprint author), Univ Wurzburg, Bioctr, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. EM rhock@biozentrum.uni-wuerzburg.de RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004496-30] NR 69 TC 158 Z9 169 U1 1 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD FEB PY 2007 VL 17 IS 2 BP 72 EP 79 DI 10.1016/j.tcb.2006.12.001 PG 8 WC Cell Biology SC Cell Biology GA 140VR UT WOS:000244535300004 PM 17169561 ER PT J AU Aronova, MA Kim, YC Zhang, G Leapman, RD AF Aronova, M. A. Kim, Y. C. Zhang, G. Leapman, R. D. TI Quantification and thickness correction of EFTEM phosphorus maps SO ULTRAMICROSCOPY LA English DT Article DE energy filtered transmission electron microscopy (EFTEM); electron energy loss spectroscopy (EELS); plural scattering; elemental mapping; phosphorus ID ELECTRON-ENERGY-LOSS; LOSS SPECTROSCOPY; MICROANALYSIS; TOMOGRAPHY; FILTER; EELS; DISTRIBUTIONS; EXPRESSION; ELEMENTS; CALCIUM AB We describe a method for correcting plural inelastic scattering effects in elemental maps that are acquired in the energy filtering transmission electron microscope (EFTEM) using just two energy windows, one above and one below a core edge in the electron energy loss spectrum (EELS). The technique is demonstrated for mapping low concentrations of phosphorus in biological samples. First, the single-scattering EELS distributions are obtained from specimens of pure carbon and plastic embedding material. Then, spectra are calculated for different specimen thicknesses t, expressed in units of the inelastic mean free path lambda. In this way, standard curves are generated for the ratio k(0) of post-edge to pre-edge intensities at the phosphorus L-2,L-3 excitation energy, as a function of relative specimen thickness t/lambda. Thickness effects in a two-window phosphorus map are corrected by successive acquisition of zero-loss and unfiltered images, from which it is possible to determine a t/lambda, image and hence a background k(0)-ratio image. Knowledge of the thickness-dependent k(0)-ratio at each pixel thus enables a more accurate determination of the phosphorus distribution in the specimen. Systematic and statistical errors are calculated as a function of specimen thickness, and elemental maps are quantified in terms of the number of phosphorus atoms per pixel. Further analysis of the k(0)-curve shows that the EFTEM can be used to obtain reliable two-window phosphorus maps from specimens that are considerably thicker than previously possible. Published by Elsevier B.V. C1 NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. EM leapman@helix.nih.gov FU Intramural NIH HHS; NIH HHS [Z01 OD011058-05] NR 39 TC 15 Z9 15 U1 2 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3991 J9 ULTRAMICROSCOPY JI Ultramicroscopy PD FEB-MAR PY 2007 VL 107 IS 2-3 BP 232 EP 244 DI 10.1016/j.ultramic.2006.07.009 PG 13 WC Microscopy SC Microscopy GA 129EI UT WOS:000243710800019 PM 16979822 ER PT J AU Stantchev, TS Markovic, I Telford, WG Clouse, KA Broder, CC AF Stantchev, Tzanko S. Markovic, Ingrid Telford, William G. Clouse, Kathleen A. Broder, Christopher C. TI The tyrosine kinase inhibitor genistein blocks HIV-1 infection in primary human macrophages SO VIRUS RESEARCH LA English DT Review DE HIV; macrophage tyrosine kinase; genistem; entry; fusion; receptor; CD4; CCR5; CXCR4; envelope glycoprotem; gp120; infection ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMARY T-LYMPHOCYTES; JUN NH2-TERMINAL KINASE; CHEMOKINE RECEPTOR 5; ENVELOPE GLYCOPROTEIN; SIGNAL-TRANSDUCTION; MONONUCLEAR PHAGOCYTES; MEMBRANE MICRODOMAINS; ACTIN POLYMERIZATION; NEUROBLASTOMA-CELLS AB Binding of HIV-1 envelope glycoprotein (Env) to its cellular receptors elicits a variety of signaling events, including the activation of select tyrosine kinases. To evaluate the potential role of such signaling, we examined the effects of the tyrosine kinase inhibitor, genistein, on HIV-1 entry and infection of human macrophages using a variety of assays. Without altering cell viability, cell surface expression of CD4 and CCR5 or their abilities to interact with Env, genistein inhibited infection of macrophages by reporter gene-encoding, P-lactamase containing, or wild type virions, as well as Env-mediated cell-fusion. The observation that genistein blocked virus infection if applied before, during or immediately after the infection period, but not 24 h later: coupled with a more pronounced inhibition of infection in the reporter gene assays as compared to both P-lactamase and p24 particle entry assays, imply that genistein exerts its inhibitory effects on both entry and early post-entry steps. These findings suggest that other exploitable targets, or steps, of the HIV-1 infection process may exist and could serve as additional opportunities for the development of new therapeutics. Published by Elsevier B.V. C1 Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Broder, CC (reprint author), Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM cbroder@usuhs.mil FU NIAID NIH HHS [R01 AI043885, R21 AI043885, AI43885] NR 108 TC 32 Z9 33 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD FEB PY 2007 VL 123 IS 2 BP 178 EP 189 DI 10.1016/j.virusres.2006.09.004 PG 12 WC Virology SC Virology GA 133MP UT WOS:000244017300009 PM 17030448 ER PT J AU Kolesnikov, AV Ala-Laurila, P Shukolyukov, SA Crouch, RK Wiggert, B Estevez, ME Govardovskii, VI Cornwall, MC AF Kolesnikov, A. V. Ala-Laurila, P. Shukolyukov, S. A. Crouch, R. K. Wiggert, B. Estevez, M. E. Govardovskii, V. I. Cornwall, M. C. TI Visual cycle and its metabolic support in gecko photoreceptors SO VISION RESEARCH LA English DT Article DE visual cycle; visual pigments; gecko; photoreceptors; retinal; retinol ID RETINOID-BINDING PROTEIN; ROD OUTER SEGMENTS; ALL-TRANS-RETINOL; GATED ION CHANNELS; DARK-ADAPTATION; PIGMENT REGENERATION; VERTEBRATE RETINA; LIGHT ADAPTATION; NOCTURNAL GECKO; GEKKO-GEKKO AB Photoreceptors of nocturnal geckos are transmuted cones that acquired rod morphological and physiological properties but retained cone-type phototransduction proteins. We have used microspectrophotometry and microfluorometry of solitary isolated green-sensitive photoreceptors of Tokay gecko to study the initial stages of the visual cycle within these cells. These stages are the photolysis of the visual pigment, the reduction of all-trans retinal to all-trans retinol, and the clearance of all-trans retinol from the outer segment (OS) into the interphotoreceptor space. We show that the rates of decay of metaproducts (all-trans retinal release) and retinal-to-retinol reduction are intermediate between those of typical rods and cones. Clearance of retinol from the OS proceeds at a rate that is typical of rods and is greatly accelerated by exposure to interphotoreceptor retinoid-binding protein, IRBP. The rate of retinal release from metaproducts is independent of the position within the OS, while its conversion to retinol is strongly spatially non-uniform, being the fastest at the OS base and slowest at the tip. This spatial gradient of retinol production is abolished by dialysis of saponin-permeabilized OSs with exogenous NADPH or substrates for its production by the hexose monophosphate pathway (NADP + glucose-6-phosphate or 6-phosphogluconate, glucose-6-phosphate alone). Following dialysis by these agents, retinol production is accelerated by several-fold compared to the fastest rates observed in intact cells in standard Ringer solution. We propose that the speed of retinol production is set by the availability of NADPH which in turn depends on ATP supply within the outer segment. We also suggest that principal source of this ATP is from mitochondria located within the ellipsoid region of the inner segment. (c) 2006 Elsevier Ltd. All rights reserved. C1 Russian Acad Sci, Inst Evolut Physiol & Biochem, St Petersburg 196140, Russia. Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02215 USA. Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Govardovskii, VI (reprint author), Russian Acad Sci, Inst Evolut Physiol & Biochem, St Petersburg 196140, Russia. EM vgov@mailbox.alkor.ru OI Cornwall, M./0000-0002-0847-939X; Ala-Laurila, Petri/0000-0002-6139-6825 FU NEI NIH HHS [EY01157, EY04939, EY14850] NR 63 TC 18 Z9 19 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD FEB PY 2007 VL 47 IS 3 BP 363 EP 374 DI 10.1016/j.visres.2006.08.024 PG 12 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 133MC UT WOS:000244016000009 PM 17049961 ER PT J AU Sheliga, BM FitzGibbon, EJ Miles, FA AF Sheliga, B. M. FitzGibbon, E. J. Miles, F. A. TI Human vergence eye movements initiated by competing disparities: Evidence for a winner-take-all mechanism SO VISION RESEARCH LA English DT Article DE disparity energy; nonlinear interactions; mutual inhibition; weighted average ID OCULAR-FOLLOWING RESPONSES; RANDOM-DOT STEREOGRAMS; VISUAL-CORTEX NEURONS; CORTICAL AREA MST; RADIAL OPTIC FLOW; SHORT-LATENCY; BINOCULAR DISPARITY; TARGET SELECTION; DEPTH-PERCEPTION; CONTRAST AB Vergence eye movements were elicited in human subjects at short latencies (similar to 70 ms) by applying binocular disparities briefly (200 ms) to large grating patterns (46 degrees wide, 35 degrees high). The positions of both eyes were recorded with the electromagnetic search coil technique. Using a dichoptic viewing arrangement (Wheatstone stereoscope), each eye viewed two overlapping 1-D sine waves that had the same orientation but different spatial frequencies. These two sine waves each had a binocular disparity that was 1/4 of its wavelength and the effect of varying their relative contrasts was examined (15 contrast ratios ranging from 0. 125 to 8). The first experiment used horizontal gratings and recorded the vertical vergence responses when the two sine waves had spatial frequencies in the ratio 3:5 and vertical disparities of opposite sign. Initial vergence responses showed a highly nonlinear dependence on the contrast ratio. On average, when the contrast of one sine wave exceeded that of the other by a factor of > 2.2, the sine wave with the higher contrast dominated responses and the sine wave with the lower contrast had almost no influence: winner-take-all. A second experiment, which used vertical gratings and recorded the horizontal vergence responses when the two sine waves had spatial frequencies in the ratio 3:5 and horizontal disparities of opposite sign. also uncovered nonlinear interactions but these were much more variable from one subject to another and, on average, one sine wave did not achieve complete dominance until its contrast exceeded that of the other by a factor of > 4.5. When these two experiments were repeated with grating patterns in which the two sine waves had spatial frequencies in the ratio 3:7 and disparities of the same sign, similar nonlinear interactions were apparent. We attribute the nonlinear dependence on relative contrast to mutual inhibition between the neural elements processing the disparities of the two sine waves. We further suggest that this interaction will help to maintain binocular alignment on the objects in the plane of regard because the retinal images of those objects will tend to be better focused-and hence tend to have higher contrasts-than the images of objects in other depth planes. Published bv Elsevier Ltd. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Sheliga, BM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural NIH HHS [Z01 EY000153-22] NR 59 TC 14 Z9 14 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD FEB PY 2007 VL 47 IS 4 BP 479 EP 500 DI 10.1016/j.visres.2006.09.027 PG 22 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 141LR UT WOS:000244580500006 PM 17118422 ER PT J AU Hwang, H Choi, SY Kim, TY AF Hwang, Hayoung Choi, Soo-Young Kim, Tae Yoon TI IL-4 suppresses UVB-induced apoptosis in skin SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE apoptosis; IL-4; keratinocyte; transgenic mice; UVB ID KERATINOCYTE HACAT CELLS; INTESTINAL MAST-CELLS; INDUCED IMMUNOSUPPRESSION; T-CELLS; IN-VIVO; EPIDERMAL-CELLS; B-CELLS; ACTIVATION; SURVIVAL; INTERLEUKIN-4 AB In this study, cutaneous role of IL-4 in UVB-induced apoptosis was investigated using transgenic mice with skin-specific expression of IL-4 (IL-4 Tg mice). The transgenic mice did not show any gross clinical abnormalities. However, epidermis was thickened and increased MHC class II positive cells were detected as well as enhanced expression of inflammatory cytokines such as IL-I and TNF-alpha in skin. In addition, histological analysis revealed increased infiltration of lymphocytes, acanthosis, hyperkeratosis, and parakeratosis in skin of IL-4 Tg mice. The physiological effect of IL-4 overexpression in skin against environmental stimulus such as UVB was investigated by irradiating wild-type and IL-4 Tg mice with UVB followed by evaluation of apoptosis. The result demonstrated suppressed apoptosis in epidermis of IL-4 Tg mice compared with wild-type mice. To further assess anti-apoptotic function of IL-4 in keratinocytes, stable cell clones were made where IL-4 was constitutively overexpressed and examined for UVB-induced apoptosis. The results showed that apoptosis was remarkably decreased in IL-4 over-expressing cell clones compared with that in mock transfected cells. Collectively, data presented here shows that IL-4 has an inhibitory effect against UVB-induced apoptosis in keratinocytes, suggesting that IL-4 may be an important regulator in cutaneous immunity against UVB. C1 Catholic Univ Korea, Lab Dermatol Immunol, Catholic Res Inst Med Sci, Coll Med, Seoul 137701, South Korea. Hallym Univ, Dept Biomed Sci, Chunchon 200702, South Korea. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Kim, TY (reprint author), Catholic Univ Korea, Lab Dermatol Immunol, Catholic Res Inst Med Sci, Coll Med, Seoul 137701, South Korea. EM tykimder@catholic.ac.kr NR 37 TC 7 Z9 7 U1 0 U2 1 PU SPRINGER SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD JAN 31 PY 2007 VL 40 IS 1 BP 36 EP 43 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 129EM UT WOS:000243711300006 PM 17244480 ER PT J AU Chandran, J Lewis, P AF Chandran, Jayanth Lewis, Patrick TI Mad fly disease SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID PRION PROTEIN; MICE C1 Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. RP Chandran, J (reprint author), Johns Hopkins Univ, Dept Biol, 3400 N Charles St,Mudd Hall, Baltimore, MD 21218 USA. EM jchandr2@jhu.edu RI Lewis , Patrick/C-3674-2009; OI Lewis, Patrick/0000-0003-4537-0489 NR 7 TC 2 Z9 2 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 31 PY 2007 VL 27 IS 5 BP 971 EP 972 DI 10.1523/JNEUROSCI.5427-06.2007 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 134FW UT WOS:000244069900002 PM 17274117 ER PT J AU Perez, MA Wise, SP Willingham, DT Cohen, LG AF Perez, Monica A. Wise, Steven P. Willingham, Daniel T. Cohen, Leonardo G. TI Neurophysiological mechanisms involved in transfer of procedural knowledge SO JOURNAL OF NEUROSCIENCE LA English DT Article DE motor cortex; intermanual transfer; interhemispheric inhibition; transcallosal pathways; motor learning; intracortical inhibition ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; INTERHEMISPHERIC INHIBITION; INTRACORTICAL INHIBITION; CORTICAL AREAS; VISUOMOTOR INFORMATION; INTERMANUAL TRANSFER; NERVOUS PROPAGATION; NEURONAL-ACTIVITY; METABOLIC DEMAND AB Learning to perform a motor task with one hand results in performance improvements in the other hand, a process called intermanual transfer. To gain information on its neural mechanisms, we studied this phenomenon using the serial reaction-time task (SRTT). Sixteen, right-handed volunteers trained a 12-item sequence of key presses repeated without the subjects' knowledge. Blocks with no repeating sequence, called random blocks, were interspersed with sequence-training blocks. Response times improved in random and training blocks in both hands. The former result reflects nonspecific improvement in performance, and the latter represents a sequence-specific improvement. To evaluate changes in the primary motor cortex (M1), we tested resting motor thresholds (RMT), recruitments curves to transcranial magnetic stimulation (RC), short intracortical inhibition (SICI), and interhemispheric inhibition (IHI) from the dominant left (learning) to the nondominant right (transfer) hemisphere, before and after SRTT training. Training resulted in (1) increased RC and decreased SICI but no changes in RMT in the learning hemisphere, (2) decreased SICI and no changes in RC or RMT in the transfer hemisphere, and (3) decreased IHI. The amount in IHI after training correlated with nonspecific performance improvements in the transfer hand but not with sequence-specific performance improvements. Our results indicate that modulation of interhemispheric inhibition between the M1 areas may, as a result of the learning that has occurred in one hemisphere after practice with one hand, contribute to faster, more skilled performance of the opposite hand. C1 Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. Univ Virginia, Dept Psychol, Charlottesville, VA 22904 USA. RP Cohen, LG (reprint author), Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov FU Intramural NIH HHS NR 69 TC 78 Z9 78 U1 0 U2 15 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 31 PY 2007 VL 27 IS 5 BP 1045 EP 1053 DI 10.1523/JNEUROSCI.4128-06.2007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 134FW UT WOS:000244069900010 PM 17267558 ER PT J AU Izquierdo, A Murray, EA AF Izquierdo, Alicia Murray, Elisabeth A. TI Selective bilateral amygdala lesions in rhesus monkeys fail to disrupt object reversal learning SO JOURNAL OF NEUROSCIENCE LA English DT Article DE emotion; stimulus-reward association; decision making; reward value; reward contingency; macaque monkey; rhinal cortex; reinforcement ID ORBITAL PREFRONTAL CORTEX; AUDITORY SECONDARY REINFORCEMENT; NEUROTOXIC LESIONS; MACACA-MULATTA; RHINAL CORTEX; ORBITOFRONTAL CORTEX; EMOTIONAL RESPONSES; REWARD PREFERENCE; MEMORY; FOOD AB Neuropsychological studies in nonhuman primates have led to the view that the amygdala plays an essential role in stimulus-reward association. The main evidence in support of this idea is that bilateral aspirative or radiofrequency lesions of the amygdala yield severe impairments on object reversal learning, a task that assesses the ability to shift choices of objects based on the presence or absence of food reward (i.e., reward contingency). The behavioral effects of different lesion techniques, however, can vary. The present study therefore evaluated the effects of selective, excitotoxic lesions of the amygdala in rhesus monkeys on object reversal learning. For comparison, we tested the same monkeys on a task known to be sensitive to amygdala damage, the reinforcer devaluation task. Contrary to previous results based on less selective lesion techniques, monkeys with complete excitotoxic amygdala lesions performed object reversal learning as quickly as controls. As predicted, however, the same operated monkeys were impaired in making object choices after devaluation of the associated food reinforcer. The results suggest two conclusions. First, the results demonstrate that the amygdala makes a selective contribution to stimulus-reward association; the amygdala is critical for guiding object choices after changes in reward value but not after changes in reward contingency. Second, the results implicate a critical contribution to object reversal learning of structures nearby the amygdala, perhaps the subjacent rhinal cortex. C1 NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Izquierdo, A (reprint author), Calif State Univ Los Angeles, Coll Nat & Social Sci, Dept Psychol, 5151 State Univ Dr, Los Angeles, CA 90032 USA. EM Alzquie@calstatela.edu OI Murray, Elisabeth/0000-0003-1450-1642 FU Intramural NIH HHS NR 50 TC 73 Z9 73 U1 2 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 31 PY 2007 VL 27 IS 5 BP 1054 EP 1062 DI 10.1523/JNEUROSCI.3616-06.2007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 134FW UT WOS:000244069900011 PM 17267559 ER PT J AU Fischl, MA Collier, AC Mukherjee, AL Feinberg, JE Demeter, LM Tebas, P Giuliano, M Dehlinger, M Garren, K Brizz, B Bassett, R AF Fischl, Margaret A. Collier, Ann C. Mukherjee, A. Lisa Feinberg, Judith E. Demeter, Lisa M. Tebas, Pablo Giuliano, Marina Dehlinger, Marjorie Garren, Kevin Brizz, Barbara Bassett, Roland CA Adult AIDS Clinical Trials Grp TI Randomized open-label trial of two simplified, class-sparing regimens following a first suppressive three or four-drug regimen SO AIDS LA English DT Article DE simplification therapy; advanced HIV; protease inhibitor; non-nucleoside reverse transcriptase inhibitor ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; PROTEASE INHIBITORS; INITIAL THERAPY; CLINICAL-TRIALS; PLUS INDINAVIR; NAIVE SUBJECTS; LAMIVUDINE; ADULTS AB Objectives: Complex antiretroviral regimens can be associated with increased toxicity and poor adherence. Our aim was to compare the efficacy and safety of switching to two simplified, class-sparing antiretroviral regimens. Methods: We conducted a randomized, open-label study in 236 patients with virologic suppression who were taking a three- or four-drug protease inhibitor or non-nucleoside reverse transcriptase inhibitor regimen for >= 18 months. Patients received lopinavir/ritonavir (LPV/r) 533mg/133mg twice daily+efavirenz (EFV) 600mg once daily or EFV+two nucleoside reverse transcriptase inhibitors (NRTI). Primary study endpoint was time to first virologic failure (VF, confirmed HIV-1 RNA > 200 copies/ml) or discontinuation because of study drug-related toxicity. Results: After 2.1 years of follow up, patients receiving LPV/r+EFV discontinued treatment at a greater rate than patients receiving EFV+NRT1 (P < 0.001). Twenty one patients developed VF (14 receiving LPV/r+EFV and seven receiving EFV+NRTI) and 26 discontinued because of a study drug-related toxicity (20 receiving LPV/r+ EFV and six receiving EFV + NRTI). Time to VF or study drug related-toxicity discontinuation was significantly shorter for LPV/r + EFV than EFV + NRTIs (P= 0.0015). A significantly higher risk of drug-related toxicity occurred with LPV/r + EFV, mainly for increased triglycerides (P= 0021). A trend toward a higher VF rate occurred with LPV/r + EFV in an intent-to-treat and as-treated analyses (P = 0.088 and P = 0.063 respectively). Conclusions: Switching to EFV + NRTI resulted in better outcomes, fewer drug-related toxicity discontinuations and a trend to fewer virologic failures compared to switching to LPV/r + FFV. (c) 2007 Lippincott Williams & Wilkins. C1 Univ Miami, Sch Med, AIDS Clin Res Unit, Dept Med, Miami, FL 33136 USA. Univ Washington, Sch Med, Div Infect Dis, Seattle, WA 98195 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Univ Cincinnati, Coll Med, Div Infect Dis, Cincinnati, OH USA. Univ Rochester, Sch Med & Dent, Div Infect Dis, Rochester, NY USA. Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. Ist Super Sanita, I-00161 Rome, Italy. NIAID, Div Aids, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Silver Spring, MD USA. Abbott Labs, Abbott Pk, IL 60064 USA. RP Fischl, MA (reprint author), Univ Miami, Sch Med, AIDS Clin Res Unit, Dept Med, R-60A,1800 NW 10th Ave, Miami, FL 33136 USA. EM mfischl@med.miami.edu RI Tebas, Pablo/A-7061-2008 FU NCRR NIH HHS [RR 00047, RR 00052, RR 00096, RR 00051, RR 00044, RR 00046, RR 05096]; NIAID NIH HHS [AI 27673, AI 25868, AI 25897, AI 27664, AI 27668, AI 27675, AI 32770, AI 34853, AI 38844, AI 25924, AI 27658, AI 27665, AI 38858, AI 50410] NR 32 TC 19 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 30 PY 2007 VL 21 IS 3 BP 325 EP 333 DI 10.1097/QAD.0b013e328011ddfa PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 137AY UT WOS:000244266400006 PM 17255739 ER PT J AU Yao, B Salenius, S Yue, GH Brown, RW Liu, JZ AF Yao, Bing Salenius, Stephen Yue, Guang H. Brown, Robert W. Liu, Jing Z. TI Effects of surface EMG rectification on power and coherence analyses: An EEG and MEG study SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE power spectrum; frequency; electromyography (EMG); electroencephalography (EEG); magnetoencephalography (MEG) ID CORTICOMUSCULAR COHERENCE; ISOMETRIC CONTRACTION; PHYSIOLOGICAL TREMOR; CORTICAL MYOCLONUS; MOTOR CORTEX; HAND MUSCLE; HUMANS; ELECTROMYOGRAMS; AMPLITUDE; OSCILLATIONS AB Coherence between electromyography (EMG) and electroencephalography (EEG) or magnetoencephalography (MEG) is frequently examined to gain insights on neuromuscular binding. Commonly, EMG signals are rectified before coherence is computed. However, the appropriateness of EMG rectification in computing EMG-EEG/MEG coherence has never been validated. Since rectification is a non-linear operation and alters the EMG power spectrum, such a validation is important to ensure the accuracy of coherence calculation. In this study we experimentally investigated the effects of EMG rectification on EMG power spectra and its coherence with EEG/MEG signals. Subjects performed sustained isometric index finger abduction at similar to 5-10% maximal voluntary force (in both EEG-EMG and MEG-EMG experiments) and index finger tapping at similar to 2-4Hz (in EEG-EMG experiment only). Bipolar surface EMG data from the first dorsal interosseus (FDI) and EEG/MEG signals from the contralateral primary sensorimotor area (C3) were recorded simultaneously. Power spectra and coherence with the EEGIMEG were calculated before and after EMG rectification. The results show that rectification shifts EMG power to lower frequencies, possibly enhancing peaks of motor unit firing. Coherences with the EEG/MEG signals were not significantly changed by EMG rectification, indicating EMG rectification is overall an appropriate procedure in power and coherence analyses. (c) 2006 Elsevier B.V. All rights reserved. C1 Cleveland Clin Fdn, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Phys Med & Rehabil, Cleveland, OH 44195 USA. Case Western Reserve Univ, Dept Phys, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. Helsinki Univ Technol, Low Temp Lab, Brain Res Unit, FI-02150 Espoo, Finland. Univ Helsinki, Dept Psychiat, FI-00014 Espoo, Finland. RP Yao, B (reprint author), NINDS, NIH, LFMI 10 Ctr Dr Bldg 10,Room B1D722,MSC 1065, Bethesda, MD 20892 USA. EM yaob@mail.nih.gov FU NICHD NIH HHS [HD36725]; NINDS NIH HHS [NS37400] NR 37 TC 45 Z9 45 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD JAN 30 PY 2007 VL 159 IS 2 BP 215 EP 223 DI 10.1016/j.jneumerth.2006.07.008 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 130BW UT WOS:000243775200004 PM 16949676 ER PT J AU Sachdev, V Machado, RF Shizukuda, Y Rao, YN Sidenko, S Ernst, I St Peter, M Coles, WA Rosing, DR Blackwelder, WC Castro, O Kato, GJ Gladwin, MT AF Sachdev, Vandana Machado, Roberto F. Shizukuda, Yukitaka Rao, Yesoda N. Sidenko, Stanislav Ernst, Inez St. Peter, Marilyn Coles, Wynona A. Rosing, Douglas R. Blackwelder, William C. Castro, Oswaldo Kato, Gregory J. Gladwin, Mark T. TI Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID RIGHT ATRIAL PRESSURE; LEFT-VENTRICULAR HYPERTROPHY; PULMONARY-HYPERTENSION; DOPPLER-ECHOCARDIOGRAPHY; RELATIVE HYPERTENSION; ASYMPTOMATIC PATIENTS; STANDARDS COMMITTEE; OF-ECHOCARDIOGRAPHY; ANEMIA; HEART AB Objectives The goal of this study was to characterize left ventricular diastolic function in the sickle cell disease (SCD) population and to relate echocardiographic measures of dysfunction with pulmonary hypertension and mortality. Background Pulmonary hypertension has been identified as a predictor of death in the adult SCD population. Although diastolic dysfunction is also observed in this population, its prevalence, association with high pulmonary artery systolic pressure, and attributable mortality remain unknown. Methods Diastolic function assessment using tissue Doppler imaging was performed in a group of 141 SCD patients. Conventional echocardiographic parameters of diastolic function were performed in a total of 235 SCD patients. Results Diastolic dysfunction was present in 18% of patients. A combination of diastolic dysfunction and pulmonary hypertension was present in 11% of patients, and diastolic dysfunction accounted for only 10% to 20% of the variability in tricuspid regurgitation (TR) jet velocity. Diastolic dysfunction, as reflected by a low E/A ratio, was associated with mortality with a risk ratio of 3.5 (95% confidence interval 1.5 to 8.4, p < 0.001), even after adjustment for tricuspid regurgitation (TR) jet velocity. The presence of both diastolic dysfunction and pulmonary hypertension conferred a risk ratio for death of 12.0 (95% confidence interval 3.8 to 38.1, p < 0.001). Conclusions Diastolic dysfunction and pulmonary hypertension each contribute independently to prospective mortality in patients with SCD. Patients with both risk factors have an extremely poor prognosis. These data support the implementation of echocardiographic screening of adult patients with SCD to identify high-risk individuals for further evaluation. C1 NHLBI, Echocardiog Lab, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Echocardiog Lab, Vasc Med Branch, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Howard Univ, Ctr Sickle Cell Dis, Coll Med, Washington, DC 20059 USA. RP Sachdev, V (reprint author), NHLBI, Echocardiog Lab, Cardiovasc Branch, NIH, 10 Ctr Dr,CRC,5-1436, Bethesda, MD 20892 USA. EM sachdevv@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [Z99 HL999999, ZIA HL006012-01] NR 42 TC 121 Z9 124 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 30 PY 2007 VL 49 IS 4 BP 472 EP 479 DI 10.1016/j.jacc.2006.09.038 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 131GZ UT WOS:000243858300009 PM 17258093 ER PT J AU Hirtz, D Thurman, DJ Gwinn-Hardy, K Mohamed, M Chaudhuri, AR Zalutsky, R AF Hirtz, D. Thurman, D. J. Gwinn-Hardy, K. Mohamed, M. Chaudhuri, A. R. Zalutsky, R. TI How common are the "common" neurologic disorders? SO NEUROLOGY LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; TRAUMATIC BRAIN-INJURY; MOTOR-NEURON DISEASE; SPINAL-CORD-INJURY; TO-DOOR SURVEY; PERVASIVE DEVELOPMENTAL DISORDERS; NORTHERN MANHATTAN STROKE; 3 SICILIAN MUNICIPALITIES; POPULATION-BASED SURVEY; AGE-SPECIFIC INCIDENCE AB Objective: To estimate the current incidence and prevalence in the United States of 12 neurologic disorders. Methods: We summarize the strongest evidence available, using data from the United States or from other developed countries when US data were insufficient. Results: For some disorders, prevalence is a better descriptor of impact; for others, incidence is preferable. Per 1,000 children, estimated prevalence was 5.8 for autism spectrum disorder and 2.4 for cerebral palsy; for Tourette syndrome, the data were insufficient. In the general population, per 1,000, the 1-year prevalence for migraine was 121, 7.1 for epilepsy, and 0.9 for multiple sclerosis. Among the elderly, the prevalence of Alzheimer disease was 67 and that of Parkinson disease was 9.5. For diseases best described by annual incidence per 100,000, the rate for stroke was 183, 101 for major traumatic brain injury, 4.5 for spinal cord injury, and 1.6 for ALS. Conclusions: Using the best available data, our survey of a limited number of disorders shows that the burden of neurologic illness affects many millions of people in the United States. C1 NINDS, NIH, NSC, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth & Promot, Atlanta, GA USA. RP Hirtz, D (reprint author), NINDS, NIH, NSC, Room 2212,6001 Execut Blvd, Bethesda, MD 20892 USA. EM hirtzd@ninds.nih.gov RI Gwinn, Katrina/C-2508-2009 NR 260 TC 553 Z9 573 U1 8 U2 78 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 30 PY 2007 VL 68 IS 5 BP 326 EP 337 DI 10.1212/01.wnl.0000252807.38124.a3 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 133EY UT WOS:000243996700003 PM 17261678 ER PT J AU Merchant, KA Best, RB Louis, JM Gopich, IV Eaton, WA AF Merchant, Kusai A. Best, Robert B. Louis, John M. Gopich, Irina V. Eaton, William A. TI Characterizing the unfolded states of proteins using single-molecule FRET spectroscopy and molecular simulations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE molecular dynamics; protein folding; denatured protein; small-angle x-ray scattering; radius of gyration ID RESONANCE ENERGY-TRANSFER; COLD SHOCK PROTEIN; DENATURED STATE; FOLDING KINETICS; STRUCTURAL HETEROGENEITIES; DIFFUSING BIOMOLECULES; DYNAMICS; FLUORESCENCE; COLLAPSE; TRANSITION AB To obtain quantitative information on the size and dynamics of unfolded proteins we combined single-molecule lifetime and intensity FRET measurements with molecular simulations. We compared the unfolded states of the 64-residue, alpha/beta protein Land the 66-residue, all-beta cold-shock protein CspTm. The average radius of gyration (R-g) calculated from FRET data on freely diffusing molecules was identical for the two unfolded proteins at guanidinium chloride concentrations > 3 M, and the FRET-derived R-g of protein L agreed well with the R-g previously measured by equilibrium small-angle x-ray scattering. As the denaturant concentration was lowered, the mean FRET efficiency of the unfolded subpopulation increased, signaling collapse of the polypeptide chain, with protein L being slightly more compact than CspTm. A decrease in R-g with decreasing denaturant was also observed in all-atom molecular dynamics calculations in explicit water/urea solvent, and Langevin simulations of a simplified representation of the polypeptide suggest that collapse can result from either increased interresidue attraction or decreased excluded volume. In contrast to both the FRET and simulation results, previous time-resolved small-angle x-ray scattering experiments showed no collapse for protein L. Analysis of the donor fluorescence decay of the unfolded subpopulation of both proteins gives information about the end-to-end chain distribution and suggests that chain dynamics is slow compared with the donor life-time of approximate to 2 ns, whereas the bin-size independence of the small excess width above the shot noise for the FRET efficiency distributions may result from incomplete conformational averaging on even the 1-ms time scale. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 104, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU Intramural NIH HHS NR 43 TC 203 Z9 205 U1 9 U2 56 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 30 PY 2007 VL 104 IS 5 BP 1528 EP 1533 DI 10.1073/pnas.0607097104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 134KD UT WOS:000244081000018 PM 17251351 ER PT J AU Bazinet, RP BhattachatJee, AK Lee, HJ AF Bazinet, Richard P. BhattachatJee, Abesh K. Lee, Ho-Joo TI Haloperidol targets brain arachidonic acid signaling SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Letter ID DOCOSAHEXAENOIC ACID; UNANESTHETIZED RATS; CHRONIC VALPROATE; PHOSPHOLIPIDS; TURNOVER; DECREASES C1 NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Bazinet, RP (reprint author), NIA, NIH, Brain Physiol & Metab Sect, Bldg 9,Rm 1S 126,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rbazinet@mail.nih.gov NR 19 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD JAN 30 PY 2007 VL 31 IS 1 BP 314 EP 315 DI 10.1016/j.pnpbp.2006.03.038 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 129OE UT WOS:000243738000049 PM 16797815 ER PT J AU Sparks, S Rakocevic, G Joe, G Manoli, I Shrader, J Harris-Love, M Sonies, B Ciccone, C Dorward, H Krasnewich, D Huizing, M Dalakas, MC Gahl, WA AF Sparks, Susan Rakocevic, Goran Joe, Galen Manoli, Irini Shrader, Joseph Harris-Love, Michael Sonies, Barbara Ciccone, Carla Dorward, Heidi Krasnewich, Donna Huizing, Marjan Dalakas, Marinos C. Gahl, William A. TI Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study SO BMC NEUROLOGY LA English DT Article ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; CELL-ADHESION MOLECULE; RIMMED VACUOLES; DISTAL MYOPATHY; GNE MUTATIONS; SIALIC ACIDS; ALPHA-DYSTROGLYCAN; RAT-LIVER; SIALYLATION; GENE AB Background: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as alpha-dystroglycan and neural cell adhesion molecule ( NCAM), has been reported in HIBM. Methods: We treated 4 HIBM patients with intravenous immune globulin ( IVIG), in order to provide sialic acid, because IgG contains 8 mu mol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. Results: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for alpha-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. Conclusion: The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Genet & Metab, Washington, DC 20010 USA. Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD USA. NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. Univ Maryland, Dept Speech & Hearing Sci, College Pk, MD 20742 USA. RP Gahl, WA (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM ssparks@mail.nih.gov; rakocevg@ninds.nih.gov; gjoe@cc.nih.gov; manolii@mail.nih.gov; jshrader@cc.nih.gov; mhuizing@mail.nih.gov; bsonies@comcast.net; cciccone@mail.nih.gov; hdorward@mail.nih.gov; dkras@mail.nih.gov; mhuizing@mail.nih.gov; dalakasm@ninds.nih.gov; bgahl@helix.nih.gov RI Harris-Love, Michael/J-1359-2014; OI Harris-Love, Michael/0000-0002-1842-3269; Manoli, Irini/0000-0003-1543-2941 FU Intramural NIH HHS NR 52 TC 23 Z9 26 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2377 J9 BMC NEUROL JI BMC Neurol. PD JAN 29 PY 2007 VL 7 AR 3 DI 10.1186/1471-2377-7-3 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 133OW UT WOS:000244023200001 PM 17261181 ER PT J AU Zhang, ZP Teng, CT AF Zhang, Zhiping Teng, Christina T. TI Interplay between estrogen-related receptor alpha (ERR alpha) and gamma (ERR gamma) on the regulation of ERR alpha gene expression SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE estrogen-related receptors; ERR alpha; ERR gamma; ERR alpha gene promoter; hormone response element; ChIP; coactivator; fasting liver ID PROLIFERATOR-ACTIVATED RECEPTOR; INDEPENDENT TRANSCRIPTIONAL ACTIVATION; ORPHAN NUCLEAR RECEPTORS; HORMONE RESPONSE ELEMENT; HUMAN LACTOFERRIN GENE; CHAIN ACYL-COENZYME; COACTIVATOR-1-ALPHA PGC-1-ALPHA; DEHYDROGENASE GENE; SKELETAL-MUSCLE; DNA-BINDING AB Estrogen-related receptor alpha (ERR alpha) modulates estrogen receptor (ER)-mediated activity and is participating in the energy homeostasis by regulation of downstream target genes. The ERR alpha gene itself is proposed to be regulated by peroxisome proliferator-activated receptory gamma coactivator (PGC-1 alpha) through an autoregulatory loop under physiological stimulation. We have previously shown that the close family member ERR gamma is a positive regulator of ERR alpha gene expression. ERRa and ERR gamma are coexpressed in metabolically active tissues such as heart, kidney and muscle, yet the physiological role of ERR gamma and its relationship with ERR alpha in gene regulation are currently unknown. The present study examined the interplay of ERR gamma and ERR alpha in regulation of ERR alpha gene expression. Using real-time PCR analyses we found that ERR gamma, like the ERR alpha and PGC-1a is induced in mouse liver during fasting. Overexpression of ERR gamma in the HEC-1B cells robustly stimulated the multi-hormone response element (MHRE) of the ERR alpha gene promoter and this activity was repressed by increasing expression of ERR alpha. The two ERRs bind MHRE simultaneously in electrophoretic mobility shift assay (EMSA) and they were detected as multimeric complexes in cells by commumoprecipitation. Although ERR alpha and ERR gamma share high sequence identity, they differ in biochemical and molecular characteristics as examined by trypsin digestion, reporter activation and coactivator interaction and utilization. Using chromatin immunoprecipitation (ChIP) assay, we showed that ectopic expression of both ERR alpha and ERR gamma modifies chromatin structure at the MHRE region while ectopic expression of PGC-1 alpha in HEC-1B cells promotes ERR gamma but not ERR alpha occupancy at the MHRE region of the ERRa gene promoter and enhances the recruitment of coactivator SRC1. These data suggested that ERR alpha and ERR gamma regulate ERR alpha gene expression with different molecular mechanisms. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Teng, CT (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Gene Regulat Sect, NIH, POB 12233,MD E2-01, Res Triangle Pk, NC 27709 USA. EM teng1@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES070067-23] NR 62 TC 25 Z9 26 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 29 PY 2007 VL 264 IS 1-2 BP 128 EP 141 DI 10.1016/j.mce.2006.11.002 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 135MN UT WOS:000244157800016 PM 17157980 ER PT J AU Cendales, LC Kirk, AD AF Cendales, Linda C. Kirk, Allan D. TI Nonhuman primates for the study of composite tissue allotransplantation SO TRANSPLANTATION LA English DT Letter ID TRANSPLANTATION; INDUCTION; TOLERANCE; HAND C1 NIDDK, Transplantat Branch, NIH, Bethesda, MD USA. RP Cendales, LC (reprint author), 10 Ctr Dr,MSC 1102,CRC Room 1-5140, Bethesda, MD 20892 USA. EM cendalesl@mail.nih.gov RI Kirk, Allan/B-6905-2012 FU Intramural NIH HHS NR 11 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JAN 27 PY 2007 VL 83 IS 2 BP 241 EP 241 DI 10.1097/01.tp.0000242527.32735.0d PG 1 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 132PP UT WOS:000243955000022 PM 17264827 ER PT J AU Burbelo, PD Ching, KH Mattson, TL Light, JS Bishop, LR Kovacs, JA AF Burbelo, Peter D. Ching, Kathryn H. Mattson, Thomas L. Light, Jason S. Bishop, Lisa R. Kovacs, Joseph A. TI Rapid antibody quantification and generation of whole proteome antibody response profiles using LIPS (luciferase immunoprecipitation systems) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE humoral response; proteome; HIV; HBV; HCV; diagnosis ID HEPATITIS-C VIRUS; INFECTION; ANTIGEN; INTERFERON; GENOTYPE; SAMPLES AB The application of LIPS to the rapid quantification of antibody responses to infectious agents is described. Chimeric genes encoding pathogen antigens fused to Renilla luciferase are expressed in mammalian cells; crude extracts are prepared and, without purification, employed in immunoprecipitation assays to quantify pathogen-specific antibodies. In cross-sectional and longitudinal studies, antibody levels to the MSG-14 antigen of Pneumocystis jirovecii measured by this assay correlated well with levels previously obtained with an optimized ELISA. We also correctly predicted Hepatitis B (HBV), Hepatitis C (HCV), and HIV infection status in all but 2 of 99 assays analyzing 33 patient sera. We then used 15 HIV-encoded proteins comprising the whole HIV proteome to generate antibody response profiles for these 33 sera. Each HIV antigen was recognized by antibodies in serum from at least one HIV-infected individual. Data generated with these simple, quantitative antibody-detection assays have both clinical and research applications. (c) 2006 Elsevier Inc. All rights reserved. C1 Georgetown Univ, Ctr Med, Dept Oncol, Washington, DC 20057 USA. Clin Ctr, Crit Care Med Dept, NIH, Bethesda, MD 20892 USA. RP Burbelo, PD (reprint author), Georgetown Univ, Ctr Med, Dept Oncol, Washington, DC 20057 USA. EM burbp1@yahoo.com FU Intramural NIH HHS NR 14 TC 42 Z9 42 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 26 PY 2007 VL 352 IS 4 BP 889 EP 895 DI 10.1016/j.bbrc.2006.11.140 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 123SX UT WOS:000243317100011 PM 17157815 ER PT J AU Comer, FI Parent, CA AF Comer, Frank I. Parent, Carole A. TI Phosphoinositides specify polarity during epithelial organ development SO CELL LA English DT Editorial Material ID APICAL-POLARITY; CELLS; MORPHOGENESIS; MEMBRANE; TUBES AB The molecular mechanisms that integrate cellular polarity with tissue architecture during epithelial morphogenesis are poorly understood. Using a three-dimensional model of epithelial morphogenesis, Martin-Belmonte et al. (2007) report that the phosphatase PTEN and phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P-2] regulate the GTPase Cdc42 and the kinase aPKC to generate the apical plasma membrane domain and maintain apical-basolateral polarity. C1 NCI, Cellular & Mol Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Bldg 37,Room 2066, Bethesda, MD 20892 USA. EM parentc@helix.nih.gov NR 10 TC 48 Z9 51 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 26 PY 2007 VL 128 IS 2 BP 239 EP 240 DI 10.1016/j.cell.2007.01.010 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 139GO UT WOS:000244420500009 PM 17254962 ER PT J AU Kaldis, P AF Kaldis, Philipp TI Another piece of the p27(Kip1) puzzle SO CELL LA English DT Review ID KINASE INHIBITOR P27; SUBCELLULAR-LOCALIZATION; DEPENDENT DEGRADATION; CDK INHIBITORS; MICE LACKING; HYPERPLASIA; COMPLEXES; PATHWAY; PHASE; G1 AB How extracellular signals communicate with the cell cycle is poorly understood. In this issue, two papers (Grimmler et al., 2007; Chu et al., 2007) address this problem by reporting phosphorylation of the cyclin-dependent kinase inhibitor p27(Kip1) on a tyrosine residue by nonreceptor tyrosine kinases, which decreases p27 stability. This new mechanism could explain how cells enter the cell cycle from a quiescent state. C1 NCI, Mouse Canc Genet Program, Canc Res Ctr, Frederick, MD 21702 USA. RP Kaldis, P (reprint author), NCI, Mouse Canc Genet Program, Canc Res Ctr, Bldg 560-22-56,1050 Boyles St, Frederick, MD 21702 USA. EM kaldis@ncifcrf.gov RI Kaldis, Philipp/G-2714-2010 OI Kaldis, Philipp/0000-0002-7247-7591 FU Intramural NIH HHS NR 21 TC 41 Z9 42 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 26 PY 2007 VL 128 IS 2 BP 241 EP 244 DI 10.1016/j.cell.2007.01.006 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 139GO UT WOS:000244420500010 PM 17254963 ER PT J AU Rieg, T Schnermann, J Vallon, V AF Rieg, Timo Schnermann, Juergen Vallon, Volker TI Adenosine A(1) receptors determine effects of caffeine on total fluid intake but not caffeine appetite SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE adenosine A(1) receptor; caffeine; fluid intake; knockout mice; methylxanthine; renin ID TUBULOGLOMERULAR FEEDBACK; MICE; ADENOSINE-A1-RECEPTORS; BRAIN AB Adenosine A(1) receptor wild-type (+/+) and knockout (-/-) mice were used to elucidate the role of adenosine A, receptors in caffeine self-administration in a two-bottle choice test and in the effect of caffeine on total fluid intake and plasma renin concentration. With access to water only, adenosine A(1) receptor -/- mice showed greater basal fluid intake and greater plasma renin concentration than +/+ mice. Free access to both water and a caffeinated solution (30 mg/100 ml) for 14 days increased total fluid intake only in adenosine A(1) receptor +/+ mice (by 23 +/- 3%), and both total fluid intake and plasma renin concentration were no longer different between genotypes. Mean intake of water and caffeinated solution was not different between adenosine A(1) receptor +/+ and -/- mice. These data reveal that adenosine A(1) receptors do not contribute to caffeine consumption, but determine the effects of caffeine on fluid intake and plasma renin concentration. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Calif San Diego, Dept Med, La Jolla, CA 92161 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92161 USA. VA San Diego Healthcare Syst, La Jolla, CA 92161 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Vallon, V (reprint author), Univ Calif San Diego, Dept Med, 3350 La Jolla Village Dr 9151, La Jolla, CA 92161 USA. EM vvallon@ucsd.edu FU NIDDK NIH HHS [DK56248]; NIGMS NIH HHS [GM66232] NR 18 TC 13 Z9 13 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 26 PY 2007 VL 555 IS 2-3 BP 174 EP 177 DI 10.1016/j.ejphar.2006.10.039 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 134ZT UT WOS:000244124100012 PM 17126319 ER PT J AU Spiegel, S Milstien, S AF Spiegel, Sarah Milstien, Sheldon TI Functions of the multifaceted family of sphingosine kinases and some close relatives SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID CERAMIDE KINASE; LYSOPHOSPHATIDIC ACID; CELL-MIGRATION; DEPENDENT TRANSLOCATION; PLASMA-MEMBRANE; POOR SURVIVAL; LIPID KINASE; IN-VIVO; 1-PHOSPHATE; SPHINGOSINE-1-PHOSPHATE C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu FU Intramural NIH HHS; NCI NIH HHS [CA61774]; NIAID NIH HHS [AI50094]; NIGMS NIH HHS [GM43880] NR 50 TC 110 Z9 116 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2007 VL 282 IS 4 BP 2125 EP 2129 DI 10.1074/jbc.R600028200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127NM UT WOS:000243593200002 PM 17135245 ER PT J AU McElhinny, SAN Stith, CM Burgers, PMJ Kunkel, TA AF McElhinny, Stephanie A. Nick Stith, Carrie M. Burgers, Peter M. J. Kunkel, Thomas A. TI Inefficient proofreading and biased error rates during inaccurate DNA synthesis by a mutant derivative of Saccharomyces cerevisiae DNA polymerase delta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OKAZAKI FRAGMENT MATURATION; ACTIVE-SITE; REPLICATION FIDELITY; MISMATCH REPAIR; MOTIF-A; YEAST; ALPHA; MUTATIONS; EPSILON; COMPLEX AB DNA polymerase delta(pol delta) is a high fidelity eukaryotic enzyme that participates in DNA repair and is essential for DNA replication. Toward the goal of dissecting its multiple biological functions, here we describe the biochemical properties of Saccharomyces cerevisiae pol delta with a methionine replacing conserved leucine 612 at the polymerase active site. Compared with wild type pol delta, L612M pol delta has normal processivity and slightly higher polymerase specific activity. L612M pol delta also has normal 3' exonuclease activity, yet it is impaired in partitioning mismatches to the exonuclease active site, thereby reducing DNA synthesis fidelity. Error rates in vitro for L612M pol delta are elevated for both base substitutions and single base deletions but in a highly biased manner. For each of the six possible pairs of reciprocal mismatches that could arise during replication of complementary DNA strands to account for any particular base substitution in vivo (e.g. T-dGMP or A-dCMP for T to C transitions), L612M pol delta error rates are substantially higher for one mismatch than the other. These results provide a biochemical explanation for our observation, which confirms earlier genetic studies, that a haploid pol3-L612M S. cerevisiae strain has an elevated spontaneous mutation rate that is likely due to reduced replication fidelity in vivo. C1 NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 37 TC 47 Z9 48 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2007 VL 282 IS 4 BP 2324 EP 2332 DI 10.1074/jbc.M609591200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127NM UT WOS:000243593200024 ER PT J AU Jiang, M Pabla, N Murphy, RF Yang, TX Yin, XM Degenhardt, K White, E Dong, Z AF Jiang, Man Pabla, Navjotsin Murphy, Robert F. Yang, Tianxin Yin, Xiao-Ming Degenhardt, Kurt White, Eileen Dong, Zheng TI Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; SMALL-MOLECULE ANTAGONISTS; CYTOCHROME-C RELEASE; MDM2 ANTAGONISTS; EMBRYONIC LETHALITY; P53 ACTIVATION; APOPTOSIS; DEATH; PATHWAY; BAX AB Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cis-platin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca2+, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis. C1 Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA 30912 USA. Vet Affairs Med Ctr, Augusta, GA 30912 USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Utah, Dept Internal Med, Salt Lake City, UT 84148 USA. Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. Rutgers State Univ, Canc Inst New Jersey, Dept Mol Biol & Biochem, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. RP Dong, Z (reprint author), Med Coll Georgia, Dept Cellular Biol & Anat, 1459 Laney Walker Blvd, Augusta, GA 30912 USA. EM zdong@mail.mcg.edu RI Pabla, Navjotsingh /H-3568-2011 FU NCI NIH HHS [R37 CA053370, R37 CA053370-16, R37 CA053370-17] NR 44 TC 66 Z9 68 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 26 PY 2007 VL 282 IS 4 BP 2636 EP 2645 DI 10.1074/jbc.M606928200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127NM UT WOS:000243593200056 PM 17130128 ER PT J AU Kimchi-Sarfaty, C Oh, JM Kim, IW Sauna, ZE Calcagno, AM Ambudkar, SV Gottesman, MM AF Kimchi-Sarfaty, Chava Oh, Jung Mi Kim, In-Wha Sauna, Zuben E. Calcagno, Anna Maria Ambudkar, Suresh V. Gottesman, Michael M. TI A "silent" polymorphism in the MDR1 gene changes substrate specificity SO SCIENCE LA English DT Article ID SYNONYMOUS CODON USAGE; SINGLE-NUCLEOTIDE POLYMORPHISMS; MULTIDRUG-RESISTANCE GENE; VIRUS EXPRESSION SYSTEM; HUMAN P-GLYCOPROTEIN; MESSENGER-RNA; IN-VITRO; FUNCTIONAL-CHARACTERIZATION; PROTEIN-STRUCTURE; VIVO C1 NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), US FDA, Ctr Biol Evaluat & Res, 29 Lincoln Dr,Room 316, Bethesda, MD 20892 USA. EM kimchi@cber.fda.gov; jmoh@snu.ac.kr; mgottesman@nih.gov RI Calcagno, Anna Maria/A-5617-2012; OI Calcagno, Anna Maria/0000-0002-0804-2753; Oh, JungMi/0000-0002-1836-1707 FU Intramural NIH HHS NR 29 TC 1332 Z9 1398 U1 10 U2 82 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 26 PY 2007 VL 315 IS 5811 BP 525 EP 528 DI 10.1126/science.1135308 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 129JU UT WOS:000243726600050 PM 17185560 ER PT J AU Shivachandra, SB Li, Q Peachman, KK Matyas, GR Leppla, SH Alving, CR Rao, M Rao, VB AF Shivachandra, Sathish B. Li, Qin Peachman, Kristina K. Matyas, Gary R. Leppla, Stephen H. Alving, Carl R. Rao, Mangala Rao, Venigalla B. TI Multicomponent anthrax toxin display and delivery using bacteriophage T4 SO VACCINE LA English DT Article DE bacteriophage T4; virus assembly; phage display; anthrax toxin; Hoc; multi-component vaccine ID FULL-LENGTH PROTEINS; PROTECTIVE ANTIGEN; BACILLUS-ANTHRACIS; LETHAL FACTOR; MOLECULAR-CLONING; CRYSTAL-STRUCTURE; CAPSID SURFACE; EDEMA FACTOR; EXPRESSION; PHAGE AB We describe a multicomponent antigen display and delivery system using bacteriophage T4. Two dispensable outer capsid proteins, Hoc (highly antigenic outer capsid protein, 155 copies) and Soc (small outer capsid protein, 810 copies), decorate phage T4 capsid. These proteins bind to the symmetrically localized capsid sites, which appear following prohead assembly and expansion. We hypothesized that multiple antigens fused to Hoc can be displayed on the same capsid and such particles can elicit broad immunological responses. Anthrax toxin proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF), and their functional domains, were fused to Hoc with an N-terminal hexa-histidine tag and the recombinant proteins were over-expressed in E. coli and purified. Using a defined in vitro assembly system, the anthrax-Hoc fusion proteins were efficiently displayed on T4 capsid, either individually or in combinations. All of the 155 Hoc binding sites can be occupied by one antigen, or they can be split among two or more antigens by varying their molar ratio in the binding reaction. Immunization of mice with T4 phage carrying PA, LF, and EF elicited strong antigen-specific antibodies against all antigens as well as lethal toxin neutralization titers. The triple antigen T4 phage elicited stronger PA-specific immune responses than the phage displaying PA alone. These features offer novel avenues to develop customized multicomponent vaccines against anthrax and other pathogenic diseases. (c) 2006 Elsevier Ltd. All rights reserved. C1 Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. Henry M Jackson Fdn, USMHRP, Rockville, MD 20850 USA. Walter Reed Army Inst Res, Div Retrovirol, Silver Spring, MD 20910 USA. NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Rao, VB (reprint author), Catholic Univ Amer, Dept Biol, 103 McCort Ward Hall,620 Michigan Ave,NE, Washington, DC 20064 USA. EM rao@cua.edu OI Matyas, Gary/0000-0002-2074-2373 FU Intramural NIH HHS; NIAID NIH HHS [AI056443, R01 AI102725, U01 AI056443] NR 37 TC 41 Z9 44 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 26 PY 2007 VL 25 IS 7 BP 1225 EP 1235 DI 10.1016/j.vaccine.2006.10.010 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 133MI UT WOS:000244016600011 PM 17069938 ER PT J AU Hefner, K Holmes, A AF Hefner, Kathryn Holmes, Andrew TI Ontogeny of fear-, anxiety- and depression-related behavior across adolescence in C57BL/6J mice SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE mouse; development; juvenile; ontogeny; adolescence; learning; memory; elevated plus-maze; forced swim; open held ID ELEVATED PLUS-MAZE; ADULT RATS; D-AMPHETAMINE; FEMALE RATS; PERIADOLESCENT MICE; BRAIN-DEVELOPMENT; CONDITIONED FEAR; NOVELTY-SEEKING; RISK-TAKING; OPEN-FIELD AB Adolescence is characterized by behavioral traits such as emotional lability and impulsivity that are associated with increased vulnerability to affective illness and addictions. Research in rodents has found that adolescent rats and mice differ from adults on measures of anxiety-like behavior, novelty seeking and stress-responsivity. The present study sought to extend these data by evaluating fear-, anxiety- and depression-related behaviors in male C57BL/6J mice aged four (early adolescent), six (peri-adolescent) or eight (early adult) weeks of age. Age groups were compared on: Pavlovian fear conditioning and extinction, anxiety-like behavior and exploratory locomotion (using elevated plus-maze and novel open field), and depression-related behavior (via forced swim test). Results showed that early adolescent mice exhibited enhanced fear conditioning, but extinguished at a similar rate as adults. There were no major differences in anxiety-like behavior across age groups, although early adolescent and peri-adolescent mice exhibited less exploratory locomotion than adults. Depression-related immobility behavior in the forced swim test was lower in early adolescents than adult mice across three test exposures. Present findings in the C57BL/6J inbred strain add to growing evidence of changes in rodent fear- and stress-related behaviors across the developmental transition from juvenility through adulthood. Understanding the neural basis of these ontogenic changes could provide insight into the pathogenesis and treatment of affective disorders that have their origins in adolescence. (c) 2006 Elsevier B.V. All rights reserved. C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIMH, Rockville, MD 20852 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIMH, 5625 Fishers Lane Room 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov OI Hefner, Kathryn/0000-0002-5208-7860 FU NIAAA NIH HHS [Z01 AA000411-02] NR 53 TC 85 Z9 87 U1 3 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 25 PY 2007 VL 176 IS 2 BP 210 EP 215 DI 10.1016/j.bbr.2006.10.001 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 128RU UT WOS:000243677000004 PM 17098297 ER PT J AU Le Menach, A Takala, S McKenzie, FE Perisse, A Harris, A Flahault, A Smith, DL AF Le Menach, Arnaud Takala, Shannon McKenzie, F. Ellis Perisse, Andre Harris, Anthony Flahault, Antoine Smith, David L. TI An elaborated feeding cycle model for reductions in vectorial capacity of night-biting mosquitoes by insecticide-treated nets SO MALARIA JOURNAL LA English DT Article ID MALARIA TRANSMISSION; PLASMODIUM-FALCIPARUM; GAMBIAN CHILDREN; WESTERN KENYA; BEDNETS; MORTALITY; INFECTION; BEHAVIOR; PERMETHRIN; MORBIDITY AB Background: Insecticide Treated Nets (ITNs) are an important tool for malaria control. ITNs are effective because they work on several parts of the mosquito feeding cycle, including both adult killing and repelling effects. Methods: Using an elaborated description of the classic feeding cycle model, simple formulas have been derived to describe how ITNs change mosquito behaviour and the intensity of malaria transmission, as summarized by vectorial capacity and EIR. The predicted changes are illustrated as a function of the frequency of ITN use for four different vector populations using parameter estimates from the literature. Results: The model demonstrates that ITNs simultaneously reduce mosquitoes' lifespans, lengthen the feeding cycle, and by discouraging human biting divert more bites onto non-human hosts. ITNs can substantially reduce vectorial capacity through small changes to all of these quantities. The total reductions in vectorial capacity differ, moreover, depending on baseline behavior in the absence of ITNs. Reductions in lifespan and vectorial capacity are strongest for vector species with high baseline survival. Anthropophilic and zoophilic species are affected differently by ITNs; the feeding cycle is lengthened more for anthrophilic species, and the proportion of bites that are diverted onto non-human hosts is higher for zoophilic species. Conclusion: This model suggests that the efficacy of ITNs should be measured as a total reduction in transmission intensity, and that the quantitative effects will differ by species and by transmission intensity. At very high rates of ITN use, ITNs can generate large reductions in transmission intensity that could provide very large reductions in transmission intensity, and effective malaria control in some areas, especially when used in combination with other control measures. At high EIR, ITNs will probably not substantially reduce the parasite rate, but when transmission intensity is low, reductions in vectorial capacity combine with reductions in the parasite rate to generate very large reductions in EIR. C1 Univ Paris 06, UMRS 707, F-75012 Paris, France. INSERM, UMRS 707, F-75012 Paris, France. Univ Maryland, Ctr Vaccine Dev, Baltimore, MD 21201 USA. NIH, Div Epidemiol, Bethesda, MD 20892 USA. NIH, Populat Studies Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Maryland, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Le Menach, A (reprint author), Univ Paris 06, UMRS 707, F-75012 Paris, France. EM arnaud.lemenach@u707.jussieu.fr; Stakala@medicine.umaryland.edu; mckenzel@mail.nih.gov; Aperisse@epi.umaryland.edu; aharris@epi.umaryland.edu; antoine.flahault@u707.jussieu.fr; smitdave@helix.nih.gov RI Smith, David/L-8850-2013; Barley, Kamal/F-9579-2011 OI Smith, David/0000-0003-4367-3849; Barley, Kamal/0000-0003-1874-9813 FU Intramural NIH HHS [Z99 TW999999] NR 28 TC 57 Z9 59 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD JAN 25 PY 2007 VL 6 AR 10 DI 10.1186/1475-2875-6-10 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 138JR UT WOS:000244359400001 PM 17254339 ER PT J AU Jaluria, P Konstantopoulos, K Betenbaugh, M Shiloach, J AF Jaluria, Pratik Konstantopoulos, Konstantinos Betenbaugh, Michael Shiloach, Joseph TI A perspective on microarrays: current applications, pitfalls, and potential uses SO MICROBIAL CELL FACTORIES LA English DT Review ID GENE-EXPRESSION DATA; DNA MICROARRAYS; ESCHERICHIA-COLI; GENOMIC DNA; IDENTIFICATION; PATTERNS; CELLS; BIOINFORMATICS; TRANSCRIPTOME; TECHNOLOGY AB With advances in robotics, computational capabilities, and the fabrication of high quality glass slides coinciding with increased genomic information being available on public databases, microarray technology is increasingly being used in laboratories around the world. In fact, fields as varied as: toxicology, evolutionary biology, drug development and production, disease characterization, diagnostics development, cellular physiology and stress responses, and forensics have benefiting from its use. However, for many researchers not familiar with microarrays, current articles and reviews often address neither the fundamental principles behind the technology nor the proper designing of experiments. Although, microarray technology is relatively simple, conceptually, its practice does require careful planning and detailed understanding of the limitations inherently present. Without these considerations, it can be exceedingly difficult to ascertain valuable information from microarray data. Therefore, this text aims to outline key features in microarray technology, paying particular attention to current applications as outlined in recent publications, experimental design, statistical methods, and potential uses. Furthermore, this review is not meant to be comprehensive, but rather substantive; highlighting important concepts and detailing steps necessary to conduct and interpret microarray experiments. Collectively, the information included in this text will highlight the versatility of microarray technology and provide a glimpse of what the future may hold. C1 NIDDKD, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Shiloach, J (reprint author), NIDDKD, Biotechnol Unit, NIH, 9000 Rockville Pike,Bldg 14A,Room 170, Bethesda, MD 20892 USA. EM pratikj@mail.nih.gov; kkonsta1@jhu.edu; beten@jhu.edu; yossi@nih.gov RI Konstantopoulos, Konstantinos/A-7045-2011; Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 NR 50 TC 41 Z9 41 U1 5 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2859 J9 MICROB CELL FACT JI Microb. Cell. Fact. PD JAN 25 PY 2007 VL 6 AR 4 DI 10.1186/1475-2859-6-4 PG 14 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 138KD UT WOS:000244360600001 PM 17254338 ER PT J AU Meaburn, KJ Misteli, T AF Meaburn, Karen J. Misteli, Tom TI Cell biology - Chromosome territories SO NATURE LA English DT Editorial Material ID NUCLEAR ARCHITECTURE; GENOME C1 NCI, NIH, Bethesda, MD 20892 USA. RP Meaburn, KJ (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Meaburn, Karen/0000-0002-1327-5957 NR 7 TC 182 Z9 189 U1 0 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 25 PY 2007 VL 445 IS 7126 BP 379 EP 381 DI 10.1038/445379a PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 128WD UT WOS:000243689500028 PM 17251970 ER PT J AU Cornely, OA Maertens, J Winston, DJ Perfect, J Ullmann, AJ Walsh, TJ Helfgott, D Holowiecki, J Stockelberg, D Goh, Y Petrini, M Hardalo, C Suresh, R Angulo-Gonzalez, D AF Cornely, Oliver A. Maertens, Johan Winston, Drew J. Perfect, John Ullmann, Andrew J. Walsh, Thomas J. Helfgott, David Holowiecki, Jerzy Stockelberg, Dick Goh, Yeow-Tee Petrini, Mario Hardalo, Cathy Suresh, Ramachandran Angulo-Gonzalez, David TI Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; STEM-CELL TRANSPLANTS; ANTIFUNGAL PROPHYLAXIS; HEMATOLOGIC MALIGNANCIES; MARROW TRANSPLANTATION; CONTROLLED-TRIALS; ORAL FLUCONAZOLE; RANDOMIZED-TRIAL; CANCER-PATIENTS; DOUBLE-BLIND AB BACKGROUND: Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections. METHODS: In this randomized, multicenter study involving evaluators who were unaware of treatment assignments, we compared the efficacy and safety of posaconazole with those of fluconazole or itraconazole as prophylaxis for patients with prolonged neutropenia. Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first. We compared the incidence of proven or probable invasive fungal infections during treatment (the primary end point) between the posaconazole and fluconazole or itraconazole groups; death from any cause and time to death were secondary end points. RESULTS: A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and 25 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, -6%; 95% confidence interval, -9.7 to -2.5%; P<0.001), fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P=0.04). Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P=0.01). The most common treatment-related adverse events in both groups were gastrointestinal tract disturbances. CONCLUSIONS: In patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival. There were more serious adverse events possibly or probably related to treatment in the posaconazole group. C1 Univ Cologne, Cologne, Germany. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Calif Los Angeles, Los Angeles, CA USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Mainz, D-6500 Mainz, Germany. NCI, Bethesda, MD 20892 USA. Weill Cornell Med Coll, New York, NY USA. Silesian Med Univ, Katowice, Poland. Sahlgrens Univ Hosp, Gothenburg, Sweden. Singapore Gen Hosp, Singapore 0316, Singapore. Univ Pisa, Pisa, Italy. Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA. RP Cornely, OA (reprint author), Klinikum Univ Koln, Innere Med Klin, D-50924 Cologne, Germany. EM oliver.cornely@uni-koeln.de NR 35 TC 683 Z9 713 U1 1 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 25 PY 2007 VL 356 IS 4 BP 348 EP 359 DI 10.1056/NEJMoa061094 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 128FT UT WOS:000243644300005 PM 17251531 ER PT J AU Burroughs, AM Balaji, S Iyer, LM Aravind, L AF Burroughs, A. Maxwell Balaji, S. Iyer, Lakshminarayan M. Aravind, L. TI A novel superfamily containing the beta-grasp fold involved in binding diverse soluble ligands SO BIOLOGY DIRECT LA English DT Article ID BACILLUS-SUBTILIS; CRYSTAL-STRUCTURE; GENOMIC CONTEXT; PROTEIN; DOMAIN; TRANSPORT; EVOLUTION; COMPLEX; IDENTIFICATION; PREDICTION AB Background: Domains containing the beta-grasp fold are utilized in a great diversity of physiological functions but their role, if any, in soluble or small molecule ligand recognition is poorly studied. Results: Using sensitive sequence and structure similarity searches we identify a novel superfamily containing the beta-grasp fold. They are found in a diverse set of proteins that include the animal vitamin B12 uptake proteins transcobalamin and intrinsic factor, the bacterial polysaccharide export proteins, the competence DNA receptor ComEA, the cob(I) alamin generating enzyme PduS and the NqoI subunit of the respiratory electron transport chain. We present evidence that members of this superfamily are likely to bind a range of soluble ligands, including B12. There are two major clades within this superfamily, namely the transcobalamin-like clade and the NqoI-like clade. The former clade is typified by an insert of a beta-hairpin after the helix of the beta-grasp fold, whereas the latter clade is characterized by an insert between strands 4 and 5 of the core fold. Conclusion: Members of both clades within this superfamily are predicted to interact with ligands in a similar spatial location, with their specific inserts playing a role in the process. Both clades are widely represented in bacteria suggesting that this superfamily was derived early in bacterial evolution. The animal lineage appears to have acquired the transcobalamin-like proteins from low GC Gram-positive bacteria, and this might be correlated with the emergence of the ability to utilize B12 produced by gut bacteria. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM burrough@ncbi.nlm.nih.gov; sbalaji@ncbi.nlm.nih.gov; lakshmin@ncbi.nlm.nih.gov; aravind@ncbi.nlm.nih.gov NR 50 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JAN 24 PY 2007 VL 2 DI 10.1186/1745-6150-2-4 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 134PX UT WOS:000244096900001 ER PT J AU Karakas, E Truglio, JJ Croteau, D Rhau, B Wang, LQ Van Houten, B Kisker, C AF Karakas, Erkan Truglio, James J. Croteau, Deborah Rhau, Benjamin Wang, Liqun Van Houten, Bennett Kisker, Caroline TI Structure of the C-terminal half of UvrC reveals an RNase H endonuclease domain with an argonaute-like catalytic triad SO EMBO JOURNAL LA English DT Article DE DNA damage; DNA repair; endonuclease; nucleotide excision repair; UvrC; RNase H ID NUCLEOTIDE EXCISION-REPAIR; DNA-POLYMERASE-I; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; ACTIVE-SITE; HELICASE-II; 3-DIMENSIONAL STRUCTURE; SYNAPTIC COMPLEX; SLICER ACTIVITY; PROTEIN AB Removal and repair of DNA damage by the nucleotide excision repair pathway requires two sequential incision reactions, which are achieved by the endonuclease UvrC in eubacteria. Here, we describe the crystal structure of the C-terminal half of UvrC, which contains the catalytic domain responsible for 50 incision and a helix-hairpin helix-domain that is implicated in DNA binding. Surprisingly, the 50 catalytic domain shares structural homology with RNase H despite the lack of sequence homology and contains an uncommon DDH triad. The structure also reveals two highly conserved patches on the surface of the protein, which are not related to the active site. Mutations of residues in one of these patches led to the inability of the enzyme to bind DNA and severely compromised both incision reactions. Based on our results, we suggest a model of how UvrC forms a productive protein-DNA complex to excise the damage from DNA. C1 Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, Inst Biol Struct, D-97078 Wurzburg, Germany. SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC USA. RP Kisker, C (reprint author), Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, Inst Biol Struct, Versbacher Str 9, D-97078 Wurzburg, Germany. EM caroline.kisker@virchow.uni-wuerzburg.de FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM070873, GM070873] NR 45 TC 28 Z9 28 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 24 PY 2007 VL 26 IS 2 BP 613 EP 622 DI 10.1038/sj.emboj.7601497 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 129LJ UT WOS:000243730700031 PM 17245438 ER PT J AU Ryan, JF Mazza, ME Pang, K Matus, DQ Baxevanis, AD Martindale, MQ Finnerty, JR AF Ryan, Joseph F. Mazza, Maureen E. Pang, Kevin Matus, David Q. Baxevanis, Andreas D. Martindale, Mark Q. Finnerty, John R. TI Pre-Bilaterian Origins of the Hox Cluster and the Hox Code: Evidence from the Sea Anemone, Nematostella vectensis SO PLOS ONE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BAYESIAN PHYLOGENETIC INFERENCE; HOMEOBOX GENES; EXPRESSION PATTERNS; PARAHOX GENES; EVOLUTIONARY IMPLICATIONS; SCHISTOCERCA-GREGARIA; ANTENNAPEDIA COMPLEX; ACROPORA-MILLEPORA; MOLECULAR EVIDENCE AB Background. Hox genes were critical to many morphological innovations of bilaterian animals. However, early Hox evolution remains obscure. Phylogenetic, developmental, and genomic analyses on the cnidarian sea anemone Nematostella vectensis challenge recent claims that the Hox code is a bilaterian invention and that no "true'' Hox genes exist in the phylum Cnidaria. Methodology/Principal Findings. Phylogenetic analyses of 18 Hox-related genes from Nematostella identify putative Hox1, Hox2, and Hox9+ genes. Statistical comparisons among competing hypotheses bolster these findings, including an explicit consideration of the gene losses implied by alternate topologies. In situ hybridization studies of 20 Hox-related genes reveal that multiple Hox genes are expressed in distinct regions along the primary body axis, supporting the existence of a pre-bilaterian Hox code. Additionally, several Hox genes are expressed in nested domains along the secondary body axis, suggesting a role in "dorsoventral'' patterning. Conclusions/Significance. A cluster of anterior and posterior Hox genes, as well as ParaHox cluster of genes evolved prior to the cnidarian-bilaterian split. There is evidence to suggest that these clusters were formed from a series of tandem gene duplication events and played a role in patterning both the primary and secondary body axes in a bilaterally symmetrical common ancestor. Cnidarians and bilaterians shared a common ancestor some 570 to 700 million years ago, and as such, are derived from a common body plan. Our work reveals several conserved genetic components that are found in both of these diverse lineages. This finding is consistent with the hypothesis that a set of developmental rules established in the common ancestor of cnidarians and bilaterians is still at work today. C1 [Ryan, Joseph F.; Finnerty, John R.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Mazza, Maureen E.; Finnerty, John R.] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Pang, Kevin; Matus, David Q.; Martindale, Mark Q.] Univ Hawaii, Pacific Biosci Res Ctr, Kewalo Marine Lab, Honolulu, HI 96822 USA. [Ryan, Joseph F.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Finnerty, JR (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM jrf3@bu.edu RI Matus, David/E-9972-2010 OI Matus, David/0000-0002-1570-5025 FU National Science Foundation [DEB51 9727244, IBN-0212773]; National Atmospheric and Space Administration [NAG2-1374, NAG2-1519]; National Human Genome Research Institute; National Institutes of Health; Boston University Women's Guild FX This research was supported by the National Science Foundation and the National Atmospheric and Space Administration (NSF grant number DEB51 9727244 to M. Q. M. and J.R.F.; NSF grant number IBN-0212773 to J.R.F.; NASA grant number NAG2-1374 and NAG2-1519s to M. Q. M.) and by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. M. E. M. received financial support from the Boston University Women's Guild. NR 129 TC 131 Z9 133 U1 0 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 24 PY 2007 VL 2 IS 1 AR e153 DI 10.1371/journal.pone.0000153 PG 23 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DG UT WOS:000207444100001 PM 17252055 ER PT J AU Kellogg, ME Burkett, S Dennis, TR Stone, G Gray, BA McGuire, PM Zori, RT Stanyon, R AF Kellogg, Margaret E. Burkett, Sandra Dennis, Thomas R. Stone, Gary Gray, Brian A. McGuire, Peter M. Zori, Roberto T. Stanyon, Roscoe TI Chromosome painting in the manatee supports Afrotheria and Paenungulata SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PLACENTAL MAMMAL RADIATION; COMPARATIVE GENOME MAPS; EUTHERIAN RELATIONSHIPS; ANCESTRAL KARYOTYPE; FLORIDA MANATEE; PHYLOGENY; DIVERSIFICATION; MITOCHONDRIAL; EULIPOTYPHLA; LATIROSTRIS AB Background: Sirenia (manatees, dugongs and Stellar's sea cow) have no evolutionary relationship with other marine mammals, despite similarities in adaptations and body shape. Recent phylogenomic results place Sirenia in Afrotheria and with elephants and rock hyraxes in Paenungulata. Sirenia and Hyracoidea are the two afrotherian orders as yet unstudied by comparative molecular cytogenetics. Here we report on the chromosome painting of the Florida manatee. Results: The human autosomal and X chromosome paints delimited a total of 44 homologous segments in the manatee genome. The synteny of nine of the 22 human autosomal chromosomes (4, 5, 6, 9, 11, 14, 17, 18 and 20) and the X chromosome were found intact in the manatee. The syntenies of other human chromosomes were disrupted in the manatee genome into two to five segments. The hybridization pattern revealed that 20 (15 unique) associations of human chromosome segments are found in the manatee genome: 1/15, 1/19, 2/3 (twice), 3/7 (twice), 3/13, 3/21, 5/21, 7/16, 8/22, 10/12 (twice), 11/20, 12/22 (three times), 14/15, 16/19 and 18/19. Conclusion: There are five derived chromosome traits that strongly link elephants with manatees in Tethytheria and give implicit support to Paenungulata: the associations 2/3, 3/13, 8/22, 18/19 and the loss of the ancestral eutherian 4/8 association. It would be useful to test these conclusions with chromosome painting in hyraxes. The manatee chromosome painting data confirm that the associations 1/19 and 5/21 phylogenetically link afrotherian species and show that Afrotheria is a natural clade. The association 10/12/22 is also ubiquitous in Afrotheria (clade I), present in Laurasiatheria (clade IV), only partially present in Xenarthra (10/12, clade II) and absent in Euarchontoglires (clade III). If Afrotheria is basal to eutherians, this association could be part of the ancestral eutherian karyotype. If afrotherians are not at the root of the eutherian tree, then the 10/12/22 association could be one of a suite of derived associations linking afrotherian taxa. C1 Univ Florence, Dept Anim Biol & Genet, I-50122 Florence, Italy. Univ Florida, Coll Vet Med, Gainesville, FL 32610 USA. NCI, Comparat Mol Cytogenet Core, Frederick, MD 21702 USA. Univ Florida, UFHSC, Div Genet, Dept Pediat, Gainesville, FL 32610 USA. Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Stanyon, R (reprint author), Univ Florence, Dept Anim Biol & Genet, Via Proconsolo 12, I-50122 Florence, Italy. EM kelloggm@gmail.com; sburkett@ncifcrf.gov; tdennis@tgen.org; gstone@ncifcrf.gov; grayb@pathology.ufl.edu; pmcguire@biochem.med.ufl.edu; zorirt@peds.ufl.edu; roscoe.stanyon@unifi.it OI Stanyon, Roscoe/0000-0002-7229-1092 NR 40 TC 27 Z9 27 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD JAN 23 PY 2007 VL 7 AR 6 DI 10.1186/1471-2148-7-6 PG 7 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 133ZU UT WOS:000244053200001 PM 17244368 ER PT J AU Ritt, DA Zhou, M Conrads, TP Veenstra, TD Copeland, TD Morrison, DK AF Ritt, Daniel A. Zhou, Ming Conrads, Thomas P. Veenstra, Timothy D. Copeland, Terry D. Morrison, Deborah K. TI CK2 is a component of the KSR1 scaffold complex that contributes to Raf kinase activation SO CURRENT BIOLOGY LA English DT Article ID PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNALING MODULES; GROWTH-FACTORS; SERINE 338; SUPPRESSOR; PHOSPHORYLATION; C-RAF-1; DOMAIN; PAK3 AB Kinase Suppressor of Ras (KSR) is a molecular scaffold that interacts with the core kinase components of the ERK cascade, Ralf, MEK, and ERK and provides spatial and temporal regulation of Ras-dependent ERK cascade signaling. In this report, we identify the hetero-tetrameric protein kinase, casein kinase 2 (CK2), as a new KSR1-binding partner. Moreover, we find that the KSR1/CK2 interaction is required for KSR1 to maximally facilitate ERK cascade signaling and contributes to the regulation of Raf kinase activity. Binding of the CK2 holoenzyme is constitutive and requires the basic surface region of the KSR1 atypical Cl domain. Loss of CK2 binding does not alter the membrane translocation of KSR1 or its interaction with ERK cascade components; however, disruption of the KSR1/CK2 interaction or inhibition of CK2 activity significantly reduces the growth-factor-induced phosphorylation of C-Raf and B-Raf on the activating serine site in the negative-charge regulatory region (N-region). This decrease in Raf N-region phosphorylation further correlates with impaired Raf, MEK, and ERK activation. These findings identify CK2 as a novel component of the KSR1 scaffolding complex that facilitates ERK cascade signaling by functioning as a Raf family N-Region kinase. C1 NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. Sci Applicat Int Corp, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM dmorrison@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 25 TC 48 Z9 52 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 23 PY 2007 VL 17 IS 2 BP 179 EP 184 DI 10.1016/j.cub.2006.11.061 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 130PJ UT WOS:000243811200028 PM 17174095 ER PT J AU Wilson, DM Mattson, MP AF Wilson, David M., III Mattson, Mark P. TI Neurodegeneration: Nicked to death SO CURRENT BIOLOGY LA English DT Editorial Material ID STRAND BREAK REPAIR; DNA-DAMAGE; SPINOCEREBELLAR ATAXIA; PROTEIN APRATAXIN; DISEASE; GENE; XRCC1 AB Ataxia oculomotor apraxia-1 is a neurological disorder that arises from mutations in the gene encoding the protein aprataxin. A recent study demonstrates that aprataxin is critical for the processing of obstructive DNA termini, suggesting a broader role for DNA single-strand break repair in neurodegenerative disease. C1 NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 20 TC 12 Z9 12 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 23 PY 2007 VL 17 IS 2 BP R55 EP R58 DI 10.1016/j.cub.2006.12.012 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 130PJ UT WOS:000243811200012 PM 17240329 ER PT J AU Lonser, RR Schiffman, R Robison, RA Butman, JA Quezado, Z Walker, ML Morrison, PF Walbridge, S Murray, GJ Park, DM Brady, RO Oldfield, EH AF Lonser, R. R. Schiffman, R. Robison, R. A. Butman, J. A. Quezado, Z. Walker, M. L. Morrison, P. F. Walbridge, S. Murray, G. J. Park, D. M. Brady, R. O. Oldfield, E. H. TI Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease SO NEUROLOGY LA English DT Review ID INHERITED ENZYME DEFICIENCY; REPLACEMENT THERAPY; ENHANCED DELIVERY; PRIMATE BRAIN; COMPUTERIZED-TOMOGRAPHY; MALIGNANT GLIOMA; GLOBUS-PALLIDUS; DRUG-DELIVERY; INFUSION; MACROMOLECULES AB Objective: To determine if convection-enhanced delivery (CED) of glucocerebrosidase could be used to treat targeted sites of disease progression in the brain and brainstem of a patient with neuronopathic Gaucher disease while monitoring enzyme distribution using MRI. Methods: A CED paradigm in rodents (n = 8) and primates (n = 5) that employs co-infusion of a surrogate MRI tracer (gadolinium diethylenetriamine penta-acetic acid [Gd-DTPA]) with glucocerebrosidase to permit real-time monitoring of distribution was developed. The safety and feasibility of this delivery and monitoring paradigm were evaluated in a patient with type 2 Gaucher disease. Results: Animal studies revealed that real-time, T1-weighted, MRI of Gd-DTPA accurately tracked enzyme distribution during CED. Targeted perfusion of clinically affected anatomic sites in a patient with neuronopathic Gaucher disease (frontal lobe and brainstem) with glucocerebrosidase was successfully performed. Real-time MRI revealed progressive and complete filling of the targeted region with enzyme and Gd-DTPA infusate. The patient tolerated the infusions without evidence of toxicity. Conclusions: Convection-enhanced delivery can be used to safely perfuse large regions of the brain and brainstem with therapeutic levels of glucocerebrosidase. Co-infused imaging surrogate tracers can be used to monitor and control the distribution of therapeutic agents in vivo. Patients with neuronopathic Gaucher disease and other intrinsic CNS disorders may benefit from a similar treatment paradigm. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Off Res Serv, Neuroradiol Sect, NIH, Bethesda, MD USA. Off Res Serv, Dept Diagnost Radiol, NIH, Bethesda, MD USA. Off Res Serv, Dept Anesthesiol, NIH, Bethesda, MD USA. Off Res Serv, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. Off Res Serv, Div Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. Univ Utah, Hlth Sci Ctr, Div Pediat Neurosurg, Salt Lake City, UT USA. Univ Utah, Hlth Sci Ctr, Dept Neurosurg, Primary Childrens Med Ctr, Salt Lake City, UT USA. RP Lonser, RR (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Rm 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; Park, Deric/C-5675-2013; Quezado, Zenaide/O-4860-2016; OI Quezado, Zenaide/0000-0001-9793-4368; Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS NR 31 TC 54 Z9 54 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 23 PY 2007 VL 68 IS 4 BP 254 EP 261 DI 10.1212/01.wnl.0000247744.10990.e6 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 128EA UT WOS:000243639800004 PM 17065591 ER PT J AU Shen, X Hong, MS Moss, J Vaughan, M AF Shen, Xiaoyan Hong, Myoung-Soon Moss, Joel Vaughan, Martha TI BIG1, a brefeldin A-inhibited guanine nucleotide-exchanae protein, is required for correct glycosylation and function of integrin beta 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adhesion; ADP-ribosylation factor; migration ID ADP-RIBOSYLATION FACTORS; GTPASE-ACTIVATING PROTEIN; CELL-ADHESION; ACTIN CYTOSKELETON; EPITHELIAL-CELLS; N-GLYCOSYLATION; GOLGI STRUCTURE; RHOA; BETA-1-INTEGRINS; EXPRESSION AB Glycosylation of beta 1 integrin (beta 1) in the Golgi complex has been related to its function in multiple cell processes, e.g., invasiveness, matrix adhesion, and migration. Brefeldin A-inhibited guanine nucleotide-exchange proteins (BIG) 1 and BIG2 activate human ADP-ribosylation factors (ARF) 1 and ARF3 by catalyzing the replacement of ARF-bound GDP with GTP to regulate Golgi vesicular transport. We show here a requirement for BIG1 (but not BIG2) in glycosylation and function of beta 1. In HepG2 cells treated for 48 or 72 h with BIG1, but not BIG2, siRNA, both the amount and electrophoretic mobility of the initially 130-kDa beta 1 were increased. BIG1 content had risen by 48 h after removal of BIG1 siRNA, and the faster-migrating, aberrant 130-kDa beta 1 was not seen. Peptide N-glycosidase F, but not endoglycosidase H, digestion converted all beta 1 to an approximate to 85-kDa (core protein) form. By electron microscopy, Golgi membranes in BIG1-depleted cells were less sharply defined than those in mock or BIG2 siRNA-treated cells, with more vesicle-like structures at the transface. Amounts of active RhoA-GTP also were decreased in such cells and restored by overexpression of HA-BIG1. Aberrant All was present on the cell surface, but its function in cell spreading, adhesion, and migration was impaired. By immunofluorescence microscopy, BIG1 siRNA-treated cells showed less spreading and concentration of beta 1 at the cell surface. These results indicate a previously unrecognized role for BIG1 in the glycosylation of beta 1 by Golgi enzymes, which is critical for its function in developmental and other vital cell processes. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Shen, X (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 5N307,MSC 1434, Bethesda, MD 20892 USA. EM shenx2@nhlbi.nih.gov; vaughanm@mail.nih.gov FU Intramural NIH HHS NR 45 TC 23 Z9 25 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 23 PY 2007 VL 104 IS 4 BP 1230 EP 1235 DI 10.1073/pnas.0610535104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131EB UT WOS:000243849900023 PM 17227842 ER PT J AU Bozzacco, L Trumpfheller, C Siegal, FP Mehandru, S Markowitz, M Carrington, M Nussenzweig, MC Piperno, AG Steinman, RM AF Bozzacco, Leonia Trumpfheller, Christine Siegal, Frederick P. Mehandru, Saurabh Markowitz, Martin Carrington, Mary Nussenzweig, Michel C. Piperno, Angela Granelli Steinman, Ralph M. TI DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8(+) T cells in a spectrum of human MHC I haplotypes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CD205, CD209; cross-presentation; DC-SIGN; vaccine ID CROSS-PRESENTATION; ANTIGEN PRESENTATION; EXOGENOUS ANTIGENS; VIRUS-REPLICATION; PRIMARY INFECTION; IMMUNE-RESPONSES; LANGERHANS CELLS; VIVO; LYMPHOCYTES; VACCINE AB Optimal HIV vaccines should elicit CD8(+) T cells specific for HIV proteins presented on MHC class I products, because these T cells contribute to host resistance to viruses. We had previously found that the targeting of antigen to dendritic cells (DCs) in mice efficiently induces CD8+ T cell responses. To extend this finding to humans, we introduced the HIV p24 gag protein into a mAb that targets DEC-205/CD205, an enclocytic receptor of DCs. We then assessed cross-presentation, which is the processing of nonreplicating internalized antigen onto MIHC class I for recognition by CD8(+) T cells. Low doses of alpha DEC-gag, but not control Ig-gag, stimulated proliferation and IFN-gamma production by CD8(+) T cells isolated from the blood of HIV-infected donors. alpha CID205 fusion mAb was more effective for cross-presentation than alpha CD209/DCSIGN, another abundant DC uptake receptor. Presentation was diverse, because we identified eight different gag pepticles that were recognized via DEC-205 in 11 individuals studied consecutively. Our results, based on humans with highly polymorphic MHC products, reveal that DCs and DEC-205 can cross-present several different pepticles from a single protein. Because of the consistency in eliciting CD8(+) T cell responses, these data support the testing of alpha DEC-205 fusion nnAb as a protein-based vaccine. C1 Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA. Rockefeller Univ, Lab Mol Immunol, Chris Browne Ctr Immunol & Immune Dis, New York, NY 10021 USA. St Vincents Hosp & Med Ctr, Comprehens HIV Ctr, New York, NY 10011 USA. Rockefeller Univ Hosp, New York, NY 10011 USA. Aaron Diamond AIDS Res Ctr, New York, NY 10011 USA. NCI, Lab Genom Divers, SAIC Frederick Inc, Ft Detrick, MD 21702 USA. RP Steinman, RM (reprint author), Rockefeller Univ, Cellular Physiol & Immunol Lab, 1230 York Ave, New York, NY 10021 USA. EM steinma@rockefeller.edu RI Steinman, Ralph/F-7729-2012 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI040874, AI40874] NR 53 TC 156 Z9 164 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 23 PY 2007 VL 104 IS 4 BP 1289 EP 1294 DI 10.1073/pnas.0610383104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131EB UT WOS:000243849900033 PM 17229838 ER PT J AU Ekstrand, MI Terzioglu, M Galter, D Zhu, SW Hofstetter, C Lindqvist, E Thams, S Bergstrand, A Hansson, FS Trifunovic, A Hoffer, B Cullheim, S Mohammed, AH Olson, L Larsson, NG AF Ekstrand, Mats I. Terzioglu, Mugen Galter, Dagmar Zhu, Shunwei Hofstetter, Christoph Lindqvist, Eva Thams, Sebastian Bergstrand, Anita Hansson, Fredrik Sterky Trifunovic, Aleksandra Hoffer, Barry Cullheim, Staffan Mohammed, Abdul H. Olson, Lars Larsson, Nils-Gran TI Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inclusion; mitochondria; mtDNA; neurodegeneration; Parkinson ID MITOCHONDRIAL TRANSCRIPTION FACTOR; LACKING ALPHA-SYNUCLEIN; CYTOCHROME-C-OXIDASE; DNA GENE-EXPRESSION; STEM-CELLS; DISEASE; MTDNA; DROSOPHILA-PINK1; IMPAIRMENT; MUTATIONS AB Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson's disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function. However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria. We have used a reverse genetic approach to investigate this question and created conditional knockout mice (termed MitoPark mice), with disruption of the gene for mitochondrial transcription factor A (Tfam) in DA neurons. The knockout mice have reduced mtDNA expression and respiratory chain deficiency in midbrain DA neurons, which, in turn, leads to a parkinsonism phenotype with adult onset of slowly progressive impairment of motor function accompanied by formation of intraneuronal inclusions and dopamine nerve cell death. Confocal and electron microscopy show that the inclusions contain both mitochondrial protein and membrane components. These experiments demonstrate that respiratory chain dysfunction in DA neurons may be of pathophysiological importance in PD. C1 Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, S-14186 Huddinge, Sweden. Karolinska Univ Hosp, Karolinska Inst, Neurotec, S-14186 Huddinge, Sweden. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. Natl Inst Drug Abuse, NIH, Baltimore, MD 21224 USA. RP Larsson, NG (reprint author), Karolinska Univ Hosp, Karolinska Inst, Dept Lab Med, S-14186 Huddinge, Sweden. EM nils-goran.larsson@ki.se RI Galter, Dagmar/C-4826-2011; OI Galter, Dagmar/0000-0001-6485-6244; Ekstrand, Mats/0000-0003-0019-9462 NR 32 TC 250 Z9 256 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 23 PY 2007 VL 104 IS 4 BP 1325 EP 1330 DI 10.1073/pnas.0605208103 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 131EB UT WOS:000243849900039 PM 17227870 ER PT J AU Ranjit, N Diez-Roux, AV Shea, S Cushman, M Seeman, T Jackson, SA Ni, H AF Ranjit, Nalini Diez-Roux, Ana V. Shea, Steven Cushman, Mary Seeman, Teresa Jackson, Sharon A. Ni, Hanyu TI Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID C-REACTIVE PROTEIN; CORONARY-HEART-DISEASE; DEPRESSIVE SYMPTOMS; INSULIN-RESISTANCE; RISK-FACTORS; US ADULTS; STRESS; MARKERS; ASSOCIATION; POPULATION AB Background: Psychosocial factors are associated with the development and progress of cardiovascular disease, but the pathological mechanisms remain unclear. We examined the associations of psychosocial risk factors for cardiovascular disease with concentrations of inflammatory markers among healthy adults and assessed the extent to which these associations are mediated by behaviors, body mass index (BMI), and diabetes mellitus. Methods: This cross-sectional study used data from the baseline examination of the Multi-Ethnic Study of Atherosclerosis, a multisite study of 6814 men and women aged 45 to 84 years. Regression analyses were used to estimate associations of cynical distrust, chronic stress, and depression with serum levels of C-reactive protein, IL-6, and fibrinogen before and after adjustment for socioeconomic position, behaviors, BMI, and diabetes. Results: Higher levels of cynical distrust were associated with higher levels of inflammatory markers. The percentage differences (95% confidence intervals [CIs]) comparing the 80th and 20th percentiles of the scale were 7% (3%-11%) for IL-6; 9% (2%-16%) for C-reactive protein; and 1.3% (0.1%-2.4%) for fibrinogen. Higher levels of chronic stress were associated with higher concentrations of IL-6 and C-reactive protein. The percentage differences (95% CIs) comparing 2 and 0 ongoing stressful circumstances were 4% (1%-8%) for IL-6 and 5% (1%-11%) for C-reactive protein. Depression was positively associated with the level of IL-6 (percentage difference [95% CI] comparing the Center for Epidemiologic Studies -Depression Scale scores of >= 21 vs < 21 was 7% [1%-14%]). Associations of psychosocial factors with inflammatory markers were reduced by 20% to 55% after adjustment for behavioral factors and by 45% to 100% after adjustment for BMI and diabetes, mostly owing to the effect of BMI. No associations remained after controlling for socioeconomic position, behaviors, BMI, and diabetes. Conclusions: Psychosocial factors are associated with higher levels of inflammatory markers, most consistently for cynical distrust. Results are compatible with a mediating role of BMI, behaviors, and diabetes. C1 Univ Michigan, Ctr Social Epidemiol & Populat Hlth, Ann Arbor, MI 48104 USA. Columbia Univ, Coll Phys & Surg, Div Gen Med, New York, NY USA. Columbia Univ, Sch Publ Hlth, Div Epidemiol, New York, NY USA. Univ Calif Los Angeles, Sch Med, Div Geriatr, Los Angeles, CA USA. Univ Vermont, Dept Med, Burlington, VT USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Northrop Grumman Corp, Atlanta, GA USA. RP Ranjit, N (reprint author), Univ Michigan, Ctr Social Epidemiol & Populat Hlth, 1214 S Univ Ave, Ann Arbor, MI 48104 USA. EM nranjit@umich.edu FU NHLBI NIH HHS [1R01HL076831, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169]; NICHD NIH HHS [R24HD047861] NR 34 TC 131 Z9 134 U1 0 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JAN 22 PY 2007 VL 167 IS 2 BP 174 EP 181 DI 10.1001/archinte.167.2.174 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 128US UT WOS:000243685100010 PM 17242319 ER PT J AU Villarino, AV Tato, CM Stumhofer, JS Yao, ZJ Cui, YZK Hennighausen, L O'Shea, JJ Hunter, CA AF Villarino, Alejandro V. Tato, Cristina M. Stumhofer, Jason S. Yao, Zhengju Cui, Yongzhi K. Hennighausen, Lothar O'Shea, John J. Hunter, Christopher A. TI Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID IN-VIVO; INTERLEUKIN-2; LYMPHOCYTES; DIFFERENTIATION; ACTIVATION; IMMUNOTHERAPY; TRANSCRIPTION; EXPANSION; MEMORY; GENE AB Although required for many fundamental immune processes, ranging from self-tolerance to pathogen immunity, interleukin (IL)-2 production is transient, and the mechanisms underlying this brevity remain unclear. These studies reveal that helper T cell IL-2 production is limited by a classic negative feedback loop that functions autonomously or in collaboration with other common.. chain (IL-4 and IL-7) and IL-6/IL-12 family cytokines (IL-12 and IL-27). Consistent with this model for cytokine-dependent regulation, they also demonstrate that the inhibitory effect can be mediated by several signal transducer and activator of transcription (STAT) family transcription factors, namely STAT5, STAT4, and STAT6. Collectively, these findings establish that IL-2 production is limited by a network of autocrine and paracrine signals that are readily available during acute inflammatory responses and, thus, provide a cellular and molecular basis for its transient pattern of expression. C1 Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. NIAMSD, Lab Mol Immunol & Inflammat, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. EM alejandro.villarino@ucsf.edu; chunter@vet.upenn.edu RI Hunter, Christopher/H-1970-2011; OI Villarino, Alejandro/0000-0001-8068-2176 FU NIAID NIH HHS [AI41158, R01 AI041158]; PHS HHS [A10662, 42334] NR 30 TC 76 Z9 80 U1 2 U2 4 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 JAN 22 PY 2007 VL 204 IS 1 BP 65 EP 71 DI 10.1084/jem.20061198 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 129TS UT WOS:000243753600011 PM 17227909 ER PT J AU Casellas, R Zhang, QZ Zheng, NY Mathias, MD Smith, K Wilson, PC AF Casellas, Rafael Zhang, Qingzhao Zheng, Nai-Ying Mathias, Melissa D. Smith, Kenneth Wilson, Patrick C. TI Ig kappa allelic inclusion is a consequence of receptor editing SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID AUTOREACTIVE B-CELLS; BONE-MARROW; NORMAL MICE; TOLERANCE; EXCLUSION; MOUSE; AUTOANTIBODY; EXPRESSION; GENES; RECOMBINATION AB The discovery of lymphocytes bearing two light chains in mice carrying self-reactive antibody transgenes has challenged the "one lymphocyte-one antibody" rule. However, the extent and nature of allelically included cells in normal mice is unknown. We show that 10% of mature B cells coexpress both Ig kappa alleles. These cells are not the result of failure in allelic exclusion per se, but arise through receptor editing. We find that under physiological conditions, editing occurs both by deletion and by inclusion with equal probability. In addition, we demonstrate that B lymphocytes carrying two B-cell receptors are recruited to germinal center reactions, and thus fully participate in humoral immune responses. Our data measure the scope of allelic inclusion and provide a mechanism whereby autoreactive B cells might "escape" central tolerance. C1 Oklahoma Med Res Fdn, Mol Immunogenet Res Program, Oklahoma City, OK 73104 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Univ Oklahoma Hlth Sci, Dept Pathol, Oklahoma City, OK 73104 USA. Univ Oklahoma Hlth Sci, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. RP Wilson, PC (reprint author), Oklahoma Med Res Fdn, Mol Immunogenet Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM wilsonp@omrf.ouhsc.edu FU Intramural NIH HHS; NCRR NIH HHS [P20 RR018758, P20RR018758-01, P20RR15577-02, P20 RR015577] NR 38 TC 49 Z9 49 U1 0 U2 2 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 JAN 22 PY 2007 VL 204 IS 1 BP 153 EP 160 DI 10.1084/jem.20061918 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 129TS UT WOS:000243753600019 PM 17210730 ER PT J AU Li, ZT Gildersleeve, JC AF Li, Zhitao Gildersleeve, Jeffrey C. TI An armed-disarmed approach for blocking aglycon transfer of thioglycosides SO TETRAHEDRON LETTERS LA English DT Article ID GLYCOSYLATION CONDITIONS; OLIGOSACCHARIDE SYNTHESIS; SELECTIVE OXIDATION; EFFICIENT SYNTHESIS; SULFOXIDES; DONORS; TRICHLOROACETIMIDATE; GLYCOSIDES; STRATEGY; SULFIDES AB Th ioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thioglycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this letter, it is shown that aglycon transfer can be blocked by matching thioglycoside-containing acceptors with more armed glycosyl donors. Published by Elsevier Ltd. C1 NCI, Canc Res Ctr, Lab Med Chem, Frederick, MD 21702 USA. RP Gildersleeve, JC (reprint author), NCI, Canc Res Ctr, Lab Med Chem, Frederick, MD 21702 USA. EM gildersleevej@ncificrf.gov RI Gildersleeve, Jeffrey/N-3392-2014 FU Intramural NIH HHS [Z01 BC010675-03] NR 44 TC 11 Z9 11 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD JAN 22 PY 2007 VL 48 IS 4 BP 559 EP 562 DI 10.1016/j.tetlet.2006.11.126 PG 4 WC Chemistry, Organic SC Chemistry GA 129BS UT WOS:000243704000010 PM 19043616 ER PT J AU Ellis, JA Martin, BV Waldner, C Dyer, KD Domachowske, JB Rosenberg, HE AF Ellis, John A. Martin, Brittany V. Waldner, Cheryl Dyer, Kimberly D. Domachowske, Joseph B. Rosenberg, Helene F. TI Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice SO VACCINE LA English DT Article DE vaccination; respiratory virus; mucosal response ID RESPIRATORY SYNCYTIAL VIRUS; PNEUMONIA VIRUS; T-CELLS; INFECTION; VACCINE; BRONCHIOLITIS; CALVES; RESPONSES; EFFICACY; INFANTS AB Protective mechanisms underlying the responses to mucosal vaccination are not yet clearly defined. Using the natural mouse pneumovirus pathogen. pneumonia virus of mice (PVM), we explore responses of wild type and interferon-gamma (IFN gamma) receptor gene-deleted mice to virulent challenge after mucosal vaccination with an attenuated virus strain. Serum neutralizing antibodies develop after intranasal inoculation with 30 pfu of attenuated, replication-competent PVM strain 15, which correlate with diminished gross and microscopic pulmonary pathology and protection from weight loss in response to subsequent challenge with the virulent parent PVM strain J3666. Virus replication in response to challenge was blunted in PVM strain 15 vaccinated mice, as was local production of secretory mediators IFN gamma, TNF-alpha, MIP-1 alpha, and MIP-2. Interestingly, responses of vaccinated IFN gamma receptor gene-deleted mice were indistinguishable from those of the wild type, suggesting that IFN gamma signaling may not be crucial for the generation of adaptive responses to pneumovirus infection in vivo. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. Univ Saskatchewan, Western Coll Vet Med, Saskatoon, SK S7N 0W0, Canada. SUNY Syracuse, Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Rosenberg, HE (reprint author), NIAID, NIH, Lab Allerg Dis, Bldg 10,Room 11C215,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [Z01 AI000943-02] NR 57 TC 19 Z9 19 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 22 PY 2007 VL 25 IS 6 BP 1085 EP 1095 DI 10.1016/j.vaccine.2006.09.081 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 134BK UT WOS:000244057400018 PM 17052820 ER PT J AU Watanabe, D Brockman, MA Ndung'u, T Mathews, L Lucas, WT Murphy, CG Felber, BK Pavlakis, GN Deluca, NA Knipe, DM AF Watanabe, Daisuke Brockman, Mark A. Ndung'u, Thumbi Mathews, Lydia Lucas, William T. Murphy, Cynthia G. Felber, Barbara K. Pavlakis, George N. Deluca, Neal A. Knipe, David M. TI Properties of a herpes simplex virus multiple immediate-early gene-deleted recombinant as a vaccine vector SO VIROLOGY LA English DT Article DE replication-defective virus; vaccine vector; SIV ID SIMIAN IMMUNODEFICIENCY VIRUS; DNA-BINDING PROTEIN; IMMUNE-RESPONSES; BETA-GALACTOSIDASE; DENDRITIC CELLS; TYPE-1; REPLICATION; EXPRESSION; ICP27; CHALLENGE AB Herpes simplex virus (HSV) recombinants induce durable immune responses in rhesus macaques and mice and have induced partial protection in rhesus macaques against mucosal challenge with virulent simian immunodeficiency virus (SIV). In this study, we evaluated the properties of a new generation HSV vaccine vector, an HSV-1 multiple immediate-early (IE) gene deletion mutant virus, d106, which contains deletions in the ICP4, ICP27, ICP22, and ICP47 genes. Because several of the HSV IF genes have been implicated in immune evasion, inactivation of the genes encoding these proteins was expected to result in enhanced immunogenicity. The d106 virus expresses few HSV gene products and shows minimal cytopathic effect in cultured cells. When d106 was inoculated into mice, viral DNA accumulated at high levels in draining lymph nodes, consistent with an ability to transduce dendritic cells and activate their maturation and movement to lymph nodes. A d106 recombinant expressing Escherichia coli beta-galactosidase induced durable beta-gal-specific IgG and CD8(+) T cell responses in naive and HSV-immune mice. Finally, d106-based recombinants have been constructed that express simian immunodeficiency virus (SIV) gag, env, or a rev-tat-nef fusion protein for several days in cultured cells. Thus, d106 shows many of the properties desirable in a vaccine vector: limited expression of HSV gene products and cytopathogenicity, high level expression of transgenes, ability to induce durable immune responses, and an ability to transduce dendritic cells and induce their maturation and migration to lymph nodes. (c) 2006 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Natl Canc Inst, Frederick, MD 21702 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RP Knipe, DM (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, 200 Longwood Ave, Boston, MA 02115 USA. EM david_knipe@hms.harvard.edu OI Ndung'u, Thumbi/0000-0003-2962-3992; Brockman, Mark/0000-0001-6432-1426 FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [AI46006] NR 46 TC 23 Z9 24 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2007 VL 357 IS 2 BP 186 EP 198 DI 10.1016/j.virol.2006.08.015 PG 13 WC Virology SC Virology GA 117JU UT WOS:000242870200008 PM 16996101 ER PT J AU Kaur, A Sanford, HB Garry, D Lang, S Klumpp, SA Watanabe, D Bronson, RT Lifson, JD Rosati, M Pavlakis, GN Felber, BK Knipe, DM Desrosiers, RC AF Kaur, Amitinder Sanford, Hannah B. Garry, Deirdre Lang, Sabine Klumpp, Sherry A. Watanabe, Daisuke Bronson, Roderick T. Lifson, Jeffrey D. Rosati, Margherita Pavlakis, George N. Felber, Barbara K. Knipe, David M. Desrosiers, Ronald C. TI Ability of herpes simplex virus vectors to boost immune responses to DNA vectors and to protect against challenge by simian immunodeficiency virus SO VIROLOGY LA English DT Article DE AIDS vaccine; recombinant HSV vectors; DNA prime; SIV; rhesus macaque ID COMPLEX CLASS-I; REPLICATION-DEFECTIVE ADENOVIRUS; T-LYMPHOCYTE RESPONSES; RHESUS-MACAQUES; DISEASE PROGRESSION; VACCINIA VIRUS; SIVMAC251 CHALLENGE; CELL RESPONSES; VIRAL ENCEPHALITIS; NONHUMAN-PRIMATES AB The immunogenicity and protective capacity of replication-defective herpes simplex virus (HSV) vector-based vaccines were examined in rhesus macaques. Three macaques were inoculated with recombinant HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV). Three other macaques were primed with recombinant DNA vectors expressing Gag, Env, and a Pol-Tat-Nef-Vif fusion protein prior to boosting with the HSV vectors. Robust anti-Gag and anti-Env cellular responses were detected in all six macaques. Following intravenous challenge with wild-type, cloned SIV239, peak and 12-week plasma virema levels were significantly lower in vaccinated compared to control macaques. Plasma SIV RNA in vaccinated macaques was inversely correlated with anti-Rev ELISPOT responses oil the day of challenge (P value < 0.05), anti-Tat ELISPOT responses at 2 weeks post challenge (P value < 0.05) and peak neutralizing antibody titers prechallenge (P value 0.06). These findings support continued study of recombinant herpesviruses as a vaccine approach for AIDS. (c) 2006 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, New England Primate Res Ctr, Southborough, MA 01772 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Rodent Histopathol Core, Boston, MA 02115 USA. SAIC Frederick Inc, Natl Canc Inst, AIDS Vaccine Program, Frederick, MD 21702 USA. NCI, Human Retrovirus Sect, Vaccine Branch, Frederick, MD 21702 USA. NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Frederick, MD 21702 USA. RP Kaur, A (reprint author), Harvard Univ, Sch Med, New England Primate Res Ctr, 1 Pine Hill Dr,POB 9102, Southborough, MA 01772 USA. EM amitinder_kaur@hms.harvard.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NCRR NIH HHS [RR00168, K26 RR000168, P51 RR000168]; NIAID NIH HHS [P01 AI046006, AI46006] NR 66 TC 35 Z9 35 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2007 VL 357 IS 2 BP 199 EP 214 DI 10.1016/j.virol.2006.08.007 PG 16 WC Virology SC Virology GA 117JU UT WOS:000242870200009 PM 16962628 ER PT J AU Pazgier, M Prahl, A Hoover, DM Lubkowski, J AF Pazgier, Marzena Prahl, Adam Hoover, David M. Lubkowski, Jacek TI Studies of the biological properties of human beta-defensin 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BETA-DEFENSINS; CHEMOKINE RECEPTOR CCR6; ANTIMICROBIAL ACTIVITY; ALPHA-DEFENSINS; ANTIBACTERIAL ACTIVITIES; INDUCIBLE PEPTIDE; DISULFIDE BONDS; INNATE IMMUNITY; LIGAND-BINDING; MESSENGER-RNA AB Defensins are small (30 - 45 amino acid residues) cationic proteins with broad antimicrobial activity against many bacteria and fungi, some enveloped viruses, and other activities such as chemoattraction of a range of different cell types to the sites of inflammation. These proteins represent attractive targets for developing novel antimicrobial agents and modulators of immune responses with therapeutic applicability. In this report, we present the results of functional and structural studies of 26 single-site mutants of human beta-defensin 1 (hBD1). All mutants were assayed for antimicrobial activity against Escherichia coli ( ATCC strain 25922) and for chemotactic activity with CCR6-transfected HEK293 cells. To analyze the structural implications of mutagenesis and to verify the correctness of the disulfide connectivity, we used x-ray crystallography to conduct complete structural studies for 10 mutants in which the topology of disulfides was the same as in the native hBD1. Mutations did not induce significant changes of the tertiary structure, suggesting that the observed alterations of biological properties of the mutants were solely associated with changes in the respective side chains. We found that cationic residues located near the C terminus (Arg(29), Lys(31), Lys(33), and Lys(36)) of hBD1 define most of the anti-E. coli in vitro activity of this protein. In turn, nearly all mutations altering the CCR6-mediated chemotaxis are located at one area of the protein, defined by the N-terminal alpha-helical region (Asp(1) ... Ser(8)) and a few topologically adjacent residues (Lys(22), Arg(29), and Lys(33)). These experimental results allow for the first time drafting of the CCR6-epitope for a defensin molecule. C1 NCI, Macromol Crystallog Lab, Program Struct Biol, NIH, Frederick, MD 21702 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Program Struct Biol, NIH, 7th St,Bldg 539,POB B,Rm 141B, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov RI Pazgier, Marzena/B-7295-2012; Prahl, Adam/H-7654-2014 FU Intramural NIH HHS NR 58 TC 56 Z9 57 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 19 PY 2007 VL 282 IS 3 BP 1819 EP 1829 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 125OK UT WOS:000243451300033 PM 17071614 ER PT J AU Ramakrishnan, B Qasba, PK AF Ramakrishnan, Boopathy Qasba, Pradman K. TI Role of a single amino acid in the evolution of glycans of invertebrates and vertebrates SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE vertbrate beta 4Gal-T1; invertbrate beta 4GalNAc-T1; single mutation; evolutionary relationship; donor substrate specificity ID ALPHA-LACTALBUMIN; CAENORHABDITIS-ELEGANS; LACTOSE SYNTHETASE; MOLECULAR-CLONING; LYSOZYME; BETA-1,4-GALACTOSYLTRANSFERASE; IDENTIFICATION; BIOSYNTHESIS; PROTEIN; GENE AB Structures of glycoconjugate N-glycans and glycolipids of invertebrates show significant differences from those of vertebrates. These differences are due largely to the vertebrate beta 1,4-galactosyltransferase-1 (beta 4Gal-T1), which is found as a 1,4-N-acetylgalactosaminyltransferase (beta 4GalNAc-T1) in invertebrates. Mutation of Tyr285 to Ile or Leu in human beta 4Gal-T1 converts the enzyme into an equally efficient 4GaINAc-Tl. A comparison of all the human beta 4Gal-T1 ortholog enzymes shows that this Tyr285 residue in human beta 4Gal-T1 is conserved either as Tyr or Phe in all vertebrate enzymes, invertebrate enzymes conserved an Ile Leu. We find mutation corresponding residue beta 4GlNAc-T1 converts the enzyme to a beta 4Gal-T1 by reducing its N-acetylgalactosaminyltransferase activity by nearly 1000-fold, while enhancing its galactosyltransferase activity by 80-fold. Furthermore, we find that, similar to the vertebrate/mammalian beta 4Gal-T1 enzymes, the wild-type Drosophila beta 4GalNAc-T1 enzyme binds to a mammary gland-specific protein, alpha-lactalbumin (alpha-LA). Thus, it would seem that, during the evolution of vertebrates from invertebrates over 500 million years ago, beta 4Gal-T1 appeared as a result of the single amino acid substitution of Tyr or Phe for Leu or Ile in the invertebrate beta 4GalNAc-T1. Subsequently, the preexisting alpha-LA-binding site was utilized during mammalian evolution to synthesize lactose in the mammary gland during lactation. (c) 2006 Published by Elsevier Ltd. C1 NCI, Canc Res Ctr, Struct Glycobiol Sect, CCR Nanobiol Program, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Sci Program, Canc Res Ctr, NCI, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Canc Res Ctr, Struct Glycobiol Sect, CCR Nanobiol Program, Frederick, MD 21702 USA. EM qasba@hehx.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400, Z01 BC009304-11] NR 28 TC 16 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 570 EP 576 DI 10.1016/j.jmb.2006.10.034 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500004 PM 17084860 ER PT J AU Fiala, KA Brown, JA Ling, H Kshetry, AK Zhang, J Taylor, JS Yang, W Suo, ZC AF Fiala, Kevin A. Brown, Jessica A. Ling, Hong Kshetry, Ajay K. Zhang, Jun Taylor, John-Stephen Yang, Wei Suo, Zucai TI Mechanism of template-independent nucleotide incorporation catalyzed by a template-dependent DNA polymerase SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE pre-steady state kinetics; X-ray crystal structure; blunt-end addition; Dpo4; pyrene nucleoside 5 '-triphosphate ID SULFOLOBUS-SOLFATARICUS P2; CRYSTAL-STRUCTURE; ACTIVE-SITE; FIDELITY; REPLICATION; DPO4; BYPASS; ETA; LESION; IV AB Numerous template-dependent DNA polymerases are capable of catalyzing template-independent nucleotide additions onto blunt-end DNA. Such non-canonical activity has been hypothesized to increase the genomic hypermutability of retroviruses including human immunodeficiency viruses. Here, we employed pre-steady state kinetics and X-ray crystallography to establish a mechanism for blunt-end additions catalyzed by Sulfolobus solfataricus Dpo4. Our kinetic studies indicated that the first blunt-end dATP incorporation was 80-fold more efficient than the second, and among natural deoxynucleotides, dATP was the preferred substrate due to its stronger intrahelical base-stacking ability. Such base-stacking contributions are supported by the 41-fold higher ground-state binding affinity of a nucleotide analog, pyrene nucleoside 5-triphosphate, which lacks hydrogen bonding ability but possesses four conjugated aromatic rings. A 2.05 angstrom resolution structure of Dpo4 center dot(blunt-end DNA)center dot ddATP revealed that the base and sugar of the incoming ddATP, respectively, stack against the 5'-base of the opposite strand and the T-base of the elongating strand. This unprecedented base-stacking pattern can be applied to subsequent blunt-end additions only if all incorporated dAMPs are extrahelical, leading to predominantly single non-templated dATP incorporation. (c) 2006 Elsevier Ltd. All rights reserved. C1 Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. Univ Western Ontario, Dept Biochem, London, ON N6A 5C1, Canada. Washington Univ, Dept Chem, St Louis, MO 63130 USA. NIDDKD, NIH, Lab Mol Biol, Bethesda, MD 20892 USA. RP Suo, ZC (reprint author), Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. EM suo.3@osu.edu RI Ling, Hong/E-3729-2010; Yang, Wei/D-4926-2011; Brown, Jessica/E-2172-2017 OI Yang, Wei/0000-0002-3591-2195; FU NCI NIH HHS [R37 CA040463, R01 CA040463, R01 CA040463-23]; NIGMS NIH HHS [T32 GM008512] NR 44 TC 32 Z9 33 U1 2 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 590 EP 602 DI 10.1016/j.jmb.2006.10.008 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500006 PM 17095011 ER PT J AU Datta, SAK Zhao, Z Clark, PK Tarasov, S Alexandratos, JN Campbell, SJ Kvaratskhelia, M Lebowitz, J Rein, A AF Datta, Siddhartha A. K. Zhao, Zhuojun Clark, Patrick K. Tarasov, Sergey Alexandratos, Jerry N. Campbell, Stephen J. Kvaratskhelia, Mamuka Lebowitz, Jacob Rein, Alan TI Interactions between HIV-1 Gag molecules in solution: An inositol phosphate-mediated switch SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; virus assembly; analytical ultracentrifugation; inositol phosphates; protein-protein interaction ID IMMUNODEFICIENCY-VIRUS TYPE-1; ASSEMBLY IN-VITRO; AMINO-TERMINAL DOMAIN; ROUS-SARCOMA-VIRUS; CAPSID PROTEIN; PLASMA-MEMBRANE; MATRIX PROTEIN; DIMERIZATION DOMAIN; RNA; IMMATURE AB Retrovirus particle assembly is mediated by the Gag protein. Gag is a multidomain protein containing discrete domains connected by flexible linkers. When recombinant HIV-1 Gag protein (lacking myristate at its N terminus and the p6 domain at its C terminus) is mixed with nucleic acid, it assembles into virus-like particles (VLPs) in a fully defined system in vitro. However, this assembly is defective in that the radius of curvature of the VLPs is far smaller than that of authentic immature virions. This defect can be corrected to varying degrees by addition of inositol phosphates to the assembly reaction. We have now explored the binding of inositol hexakisphosphate (IP6) to Gag and its effects upon the interactions between Gag protein molecules in solution. Our data indicate that basic regions at both ends of the protein contribute to IP6 binding. Gag is in monomer-dimer equilibrium in solution, and mutation of the previously described dimer interface within its capsid domain drastically reduces Gag dimerization. In contrast, when IP6 is added, Gag is in monomer-trimer rather than monomer-dimer equilibrium. The Gag protein with a mutation at the dimer interface also remains almost exclusively monomeric in IP6; thus the "dimer interface" is essential for the trimeric interaction in IP6. We discuss possible explanations for these results, including a change in conformation within the capsid domain induced by the binding of IP6 to other domains within the protein. The participation of both ends of Gag in IP6 interaction suggests that Gag is folded over in solution, with its ends near each other in three-dimensional space; direct support for this conclusion is provided in a companion manuscript. As Gag is an extended rod in immature virions, this apparent proximity of the ends in solution implies that it undergoes a major conformational change during particle assembly. (c) 2006 Elsevier Ltd. All rights reserved. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. NCI, Basic Res Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Struct Biophys Lab, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM rein@ncifcrf.gov OI Datta, Siddhartha/0000-0002-4098-7490 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC010511-03, N01 CO 12400, N01CO12400] NR 51 TC 72 Z9 72 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 799 EP 811 DI 10.1016/j.jmb.2006.10.072 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500024 PM 17098251 ER PT J AU Datta, SAK Curtis, JE Ratcliff, W Clark, PK Crist, RM Lebowitz, J Krueger, S Rein, A AF Datta, Siddhartha A. K. Curtis, Joseph E. Ratcliff, William Clark, Patrick K. Crist, Rachael M. Lebowitz, Jacob Krueger, Susan Rein, Alan TI Conformation of the HIV-1 Gag protein in solution SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; virus assembly; molecular modeling; small angle neutron scattering; analytical ultracentrifugation ID IMMUNODEFICIENCY-VIRUS TYPE-1; AMINO-TERMINAL DOMAIN; ROUS-SARCOMA-VIRUS; ASSEMBLY IN-VITRO; RELATE 2 SETS; CAPSID PROTEIN; NUCLEOCAPSID PROTEIN; 3-DIMENSIONAL STRUCTURE; DIMERIZATION DOMAIN; CRYSTAL-STRUCTURE AB A single multi-domain viral protein, termed Gag, is sufficient for assembly of retrovirus-like particles in mammalian cells. We have purified the human immunodeficiency virus type 1 (HIV-1) Gag protein (lacking myristate at its N terminus and the p6 domain at its C terminus) from bacteria. This protein is capable of assembly into virus-like particles in a defined in vitro system. We have reported that it is in monomer-dimer equilibrium in solution, and have described a mutant Gag protein that remains monomeric at high concentrations in solution. We report that the mutant protein retains several properties of wild-type Gag. This mutant enabled us to analyze solutions of monomeric protein. Hydrodynamic studies on the mutant protein showed that it is highly asymmetric, with a frictional ratio of 1.66. Small-angle neutron scattering (SANS) experiments confirmed its asymmetry and yielded an R-g value of 34 angstrom. Atomic-level structures of individual domains within Gag have previously been determined, but these domains are connected in Gag by flexible linkers. We constructed a series of models of the mutant Gag protein based on these domain structures, and tested each model computationally for its agreement with the experimental hydrodynamic and SANS data. The only models consistent with the data were those in which Gag was folded over, with its N-terminal matrix domain near its C-terminal nucleocapsid domain in three-dimensional space. Since Gag is a rod-shaped molecule in the assembled immature virion, these findings imply that Gag undergoes a major conformational change upon virus assembly. (c) 2006 Elsevier Ltd. All rights reserved. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Natl Inst Stand & Technol, Ctr Neutron Res, Gaithersburg, MD 20899 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM rein@ncifcrf.gov RI Crist, Rachael/K-7603-2012; OI Datta, Siddhartha/0000-0002-4098-7490 FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400, N01CO12400, Z01 BC010511-03] NR 51 TC 78 Z9 78 U1 0 U2 8 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 812 EP 824 DI 10.1016/j.jmb.2006.10.073 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500025 PM 17097677 ER PT J AU Kato, H Feng, HQ Bai, YW AF Kato, Hidenori Feng, Hanqiao Bai, Yawen TI The folding pathway of T4 lysozyme: The high-resolution structure and folding of a hidden intermediate SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE intermediate structure; T4 lysozyme; hydrogen exchange; protein folding; hidden intermediate ID NONNATIVE HYDROPHOBIC INTERACTIONS; STATE HYDROGEN-EXCHANGE; RD-APOCYTOCHROME B(562); RATE-LIMITING STEP; T4 LYSOZYME; PROTEIN; STABILITY; DOMAIN; NMR; RELAXATION AB Folding intermediates have been detected and characterized for many proteins. However, their structures at atomic resolution have only been determined for two small single domain proteins: Rd-apocytochrome b(562) and engrailed homeo domain. T4 lysozyme has two easily distinguishable but energetically coupled domains: the N and C-terminal domains. An early native-state hydrogen exchange experiment identified an intermediate with the C-terminal domain folded and the N-terminal domain unfolded. We have used a native-state hydrogen exchange-directed protein engineering approach to populate this intermediate and demonstrated that it is on the folding pathway and exists after the rate-limiting step. Here, we determined its high-resolution structure and the backbone dynamics by multidimensional NMR methods. We also characterized the folding behavior of the intermediate using stopped-flow fluorescence, protein engineering, and native-state hydrogen exchange. Unlike the folding intermediates of the two single-domain proteins, which have many non-native side-chain interactions, the structure of the hidden folding intermediate of T4 lysozyme is largely native-like. It folds like many small single domain proteins. These results have implications for understanding the folding mechanism and evolution of multi-domain proteins. Published by Elsevier Ltd. C1 NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Ctr Canc Res, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov FU Intramural NIH HHS [Z01 BC010276-10] NR 35 TC 30 Z9 30 U1 2 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 870 EP 880 DI 10.1016/j.jmb.2006.10.047 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500029 PM 17109883 ER PT J AU Kato, H Vu, ND Feng, HQ Zhou, Z Bai, YW AF Kato, Hidenori Vu, Ngoc-Diep Feng, Hanqiao Zhou, Zheng Bai, Yawen TI The folding pathway of T4 lysozyme: An on-pathway hidden folding intermediate SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE T4 lysozyme; hydrogen exchange; protein folding; hidden intermediate; protein engineering ID STATE HYDROGEN-EXCHANGE; LIMITING TRANSITION-STATE; CYTOCHROME-C; DIHYDROFOLATE-REDUCTASE; 2-DIMENSIONAL NMR; NATIVE CONDITIONS; MOLTEN GLOBULE; RIBONUCLEASE-A; SMALL PROTEINS; BARNASE AB T4 lysozyme has two easily distinguishable but energetically coupled domains: the N and C-terminal domains. In earlier studies, an amide hydrogen/deuterium exchange pulse-labeling experiment detected a stable submillisecond intermediate that accumulates before the rate-limiting transition state. It involves the formation of structures in both the N and C-terminal regions. However, a native-state hydrogen exchange experiment.Y subsequently detected an equilibrium intermediate that only involves the formation of the C-terminal domain. Here, using stopped-flow circular dichroism and fluorescence, amide hydrogen exchange-folding competition, and protein engineering methods, we re-examined the folding pathway of T4-lysozyme. We found no evidence for the existence of a stable folding intermediate before the rate-limiting transition state at neutral pH. In addition, using native-state hydrogen exchange-directed protein engineering, we created a mimic of the equilibrium intermediate. We found that the intermediate mimic folds with the same rate as the wild-type protein, suggesting that the equilibrium intermediate is an on-pathway intermediate that exists after the rate-limiting transition state. Published by Elsevier Ltd. C1 NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Ctr Canc Res, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov FU Intramural NIH HHS [Z01 BC010276-08] NR 49 TC 24 Z9 24 U1 2 U2 4 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 19 PY 2007 VL 365 IS 3 BP 881 EP 891 DI 10.1016/j.jmb.2006.10.048 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127BY UT WOS:000243561500030 PM 17097105 ER PT J AU Walters, JR Hu, D Itoga, CA Parr-Brownlie, LC Bergstrom, DA AF Walters, J. R. Hu, D. Itoga, C. A. Parr-Brownlie, L. C. Bergstrom, D. A. TI Phase relationships support a role for coordinated activity in the indirect pathway in organizing slow oscillations in basal ganglia output after loss of dopamine SO NEUROSCIENCE LA English DT Article DE Parkinson's disease; subthalamic nucleus; substantia nigra; globus pallidus; bursting; local field potentials ID SUBTHALAMIC NUCLEUS NEURONS; ADVANCED PARKINSONS-DISEASE; PARS RETICULATA NEURONS; DEEP-BRAIN-STIMULATION; MEMBRANE-POTENTIAL FLUCTUATIONS; HIGH-FREQUENCY STIMULATION; EXTERNAL GLOBUS-PALLIDUS; NIGROSTRIATAL PATHWAY; FIRING RATE; IN-VITRO AB The goal of the present study was to determine the phase relationships of the slow oscillatory activity that emerges in basal ganglia nuclei in anesthetized rats after dopamine cell lesion in order to gain insight into the passage of this oscillatory activity through the basal ganglia network. Spike train recordings from striatum, subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNpr) were paired with simultaneous local field potential (LFP) recordings from SNpr or motor cortex ipsilateral to a unilateral lesion of substantia nigra dopamine neurons in urethane-anesthetized rats. Dopamine cell lesion induced a striking increase in incidence of slow oscillations (0.3-2.5 Hz) in firing rate in all nuclei. Phase relationships assessed through paired recordings using SNpr LFP as a temporal reference showed that slow oscillatory activity in GP spike trains is predominantly antiphase with oscillations in striatum, and slow oscillatory activity in STN spike trains is in-phase with oscillatory activity in cortex but predominantly antiphase with GP oscillatory activity. Taken together, these results imply that after dopamine cell lesion in urethane-anesthetized rats, increased oscillatory activity in GP spike trains is shaped more by increased phasic inhibitory input from the striatum than by phasic excitatory input from STN. In addition, results show that oscillatory activity in SNpr spike trains is typically antiphase with GP oscillatory activity and in-phase with STN oscillatory activity. While these observations do not rule out additional mechanisms contributing to the emergence of slow oscillations in the basal ganglia after dopamine cell lesion in the anesthetized preparation, they are compatible with 1) increased oscillatory activity in the GP facilitated by an effect of dopamine loss on striatal 'filtering' of slow components of oscillatory cortical input, 2) increased oscillatory activity in STN spike trains supported by convergent antiphase inhibitory and excitatory oscillatory input from GP and cortex, respectively, and 3) increased oscillatory C1 NINDS, Neurophysiol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. RP Walters, JR (reprint author), NINDS, Neurophysiol Pharmacol Sect, NIH, 35 Convent Dr,Bldg 35,Room 1C905, Bethesda, MD 20892 USA. EM waltersj@ninds.nih.gov OI Parr-Brownlie, Louise/0000-0002-3001-7669 FU NINDS NIH HHS [Z01 NS002139-31] NR 82 TC 63 Z9 69 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 19 PY 2007 VL 144 IS 2 BP 762 EP 776 DI 10.1016/j.neuroscience.2006.10.006 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 124ZT UT WOS:000243412000034 PM 17112675 ER PT J AU Collins, FS Manolio, TA AF Collins, Francis S. Manolio, Teri A. TI Necessary but not sufficient SO NATURE LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. NR 2 TC 40 Z9 41 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 18 PY 2007 VL 445 IS 7125 BP 259 EP 259 DI 10.1038/445259a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 126HT UT WOS:000243504700022 PM 17230172 ER PT J AU Takemura, A Murata, Y Kawano, K Miles, FA AF Takemura, Aya Murata, Yumi Kawano, Kenji Miles, F. A. TI Deficits in short-latency tracking eye movements after chemical lesions in monkey cortical areas MT and MST SO JOURNAL OF NEUROSCIENCE LA English DT Article DE visual tracking eye movement; ocular following response; vergence; disparity; optic flow; radial flow; extrastriate; ibotenic acid; oculomotor; visual motion ID OCULAR FOLLOWING RESPONSES; TEMPORAL VISUAL AREA; RADIAL OPTIC FLOW; MACAQUE MONKEY; BINOCULAR DISPARITY; FUNCTIONAL-PROPERTIES; VERGENCE; SENSITIVITY; DEPENDENCE; NEURONS AB Past work has suggested that the medial superior temporal area (MST) is involved in the initiation of three kinds of eye movements at short latency by large-field visual stimuli. These eye movements consist of (1) version elicited by linear motion (the ocular following response), (2) vergence elicited by binocular parallax (the disparity vergence response), and (3) vergence elicited by global motion toward or away from the fovea (the radial-flow vergence response). We investigated this hypothesis by recording the effects of ibotenic acid injections in the superior temporal sulcus (STS) of both hemispheres in five monkeys. After the injections, all three kinds of eye movements were significantly impaired, with the magnitude of the impairments often showing a strong correlation with the extent of the morphological damage in the three subregions of the STS: dorsal MST on the anterior bank, lateral MST and middle temporal area on the posterior bank. However, the extent of the lesions in the three subregions often covaried, rendering it difficult to assess their relative contributions to the various deficits. The effects of the lesions on other aspects of oculomotor behavior that are known to be important for the normal functioning of the three tracking mechanisms (e. g., ocular stability, fixation disparity) were judged to be generally minor and to contribute little to the impairments. We conclude that, insofar as MST sustained significant damage in all injected hemispheres, our findings are consistent with the hypothesis that MST is a primary site for initiating all three visual tracking eye movements at ultra-short latencies. C1 Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki 3058568, Japan. Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058574, Japan. Kyoto Univ, Grad Sch Med, Dept Integrat Brian Sci, Kyoto 6068501, Japan. NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. RP Takemura, A (reprint author), Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, 1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan. EM a.takemura@aist.go.jp OI Murata, Yumi/0000-0002-6318-2951 FU Intramural NIH HHS [Z01 EY000153-24] NR 45 TC 41 Z9 42 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 17 PY 2007 VL 27 IS 3 BP 529 EP 541 DI 10.1523/JNEUROSCI.3455-06.2007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 126UJ UT WOS:000243540700009 PM 17234585 ER PT J AU Wellman, CL Izquierdo, A Garrett, JE Martin, KP Carroll, J Millstein, R Lesch, KP Murphy, DL Holmes, A AF Wellman, C. L. Izquierdo, A. Garrett, J. E. Martin, K. P. Carroll, J. Millstein, R. Lesch, K. -P. Murphy, D. L. Holmes, A. TI Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE serotonin transporter; gene; stress; prefrontal cortex; amygdala; extinction ID MEDIAL PREFRONTAL CORTEX; GENETIC-VARIATION; ENVIRONMENT INTERACTIONS; AMYGDALA INTERACTIONS; DENDRITIC MORPHOLOGY; BEHAVIORAL-RESPONSES; INFRALIMBIC CORTEX; PYRAMIDAL NEURONS; CONDITIONED FEAR; IN-VIVO AB A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear-and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear-and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes. C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97080 Wurzburg, Germany. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov RI Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X FU Intramural NIH HHS; NIMH NIH HHS [MH067607] NR 70 TC 212 Z9 214 U1 3 U2 23 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 17 PY 2007 VL 27 IS 3 BP 684 EP 691 DI 10.1523/JNEUROSCI.4595-06.2007 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 126UJ UT WOS:000243540700024 PM 17234600 ER PT J AU Moaddel, R Wainer, IW AF Moaddel, Ruin Wainer, Irving W. TI Conformational mobility of immobilized proteins SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Review DE nicotinic receptor; P-glycoprotein transporter; conformational activity; affinity chromatography; displacement chromatography ID CHROMATOGRAPHIC STATIONARY-PHASE; HUMAN SERUM-ALBUMIN; NICOTINIC ACETYLCHOLINE-RECEPTORS; PERFORMANCE LIQUID-CHROMATOGRAPHY; P-GLYCOPROTEIN; BINDING-SITES; LIGAND-BINDING; DRUG DISCOVERY; COLUMN; ALPHA-3-BETA-4 AB Cellular membrane fragments have been immobilized on the surface of a silica-based liquid chromatographic support and on the surface of glass capillaries to create immobilized receptor and drug transporter columns. These columns have included phases containing one subtype of the nicotinic receptor (alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, alpha 4 beta 4) and the P-glycoprotein transporter. A key question in the application of these columns to drug discovery and development is the ability of the immobilized receptor or transporter to undergo ligand and/or co-factor induced conformational changes. Using frontal affinity chromatographic techniques and non-linear chromatographic techniques it has been demonstrated that the immobilized nicotinic receptors undergo agonist-induced conformational shifts from the resting to desensitized states with corresponding changes in binding affinities and enantioselectivities. Ligand-induced allosteric interactions and ATP-driven conformational changes have also been demonstrated with the immobilized Pgp stationary phase. The results demonstrate that the immobilized proteins retained their ability to undergo conformational mobility and that this is an attractive alternative to allow for the full characterization of multiple protein conformations. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Moaddel, R (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov; rmoaddel@comcast.net NR 33 TC 18 Z9 18 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 17 PY 2007 VL 43 IS 2 BP 399 EP 406 DI 10.1016/j.jpba.2006.08.021 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 130MC UT WOS:000243802700001 PM 17095178 ER PT J AU Taylor, PR AF Taylor, Philip R. TI Prevention of gastric cancer: A miss SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID VITAMIN MINERAL SUPPLEMENTATION; HELICOBACTER-PYLORI ERADICATION; NUTRITION INTERVENTION TRIALS; RANDOMIZED CONTROLLED-TRIAL; DISEASE-SPECIFIC MORTALITY; GENERAL-POPULATION; HISTOLOGICAL DYSPLASIA; ALPHA-TOCOPHEROL; BETA-CAROTENE; DOUBLE-BLIND C1 NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Taylor, PR (reprint author), NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, 6120 Execut Blvd,Rm 7006, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov NR 19 TC 11 Z9 12 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2007 VL 99 IS 2 BP 101 EP 103 DI 10.1093/jnci/djk026 PG 3 WC Oncology SC Oncology GA 126QA UT WOS:000243528300003 PM 17227989 ER PT J AU Dupuy, A Simon, RM AF Dupuy, Alain Simon, Richard M. TI Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID GENE-EXPRESSION; CLASS PREDICTION; CLASSIFICATION; VALIDATION; DISCOVERY; ABILITY; MARKER AB Background Both the validity and the reproducibility of microarray-based clinical research have been challenged. There is a need for critical review of the statistical analysis and reporting in published microarray studies that focus on cancer-related clinical outcomes. Methods Studies published through 2004 in which microarray-based gene expression profiles were analyzed for their relation to a clinical cancer outcome were identified through a Medline search followed by hand screening of abstracts and full text articles. Studies that were eligible for our analysis addressed one or more outcomes that were either an event occurring during follow-up, such as death or relapse, or a therapeutic response. We recorded descriptive characteristics for all the selected studies. A critical review of outcome-related statistical analyses was undertaken for the articles published in 2004. Results Ninety studies were identified, and their descriptive characteristics are presented. Sixty-eight (76%) were published in journals of impact factor greater than 6. A detailed account of the 42 studies (47%) published in 2004 is reported. Twenty-one (50%) of them contained at least one of the following three basic flaws: 1) in outcome-related gene finding, an unstated, unclear, or inadequate control for multiple testing; 2) in class discovery, a spurious claim of correlation between clusters and clinical outcome, made after clustering samples using a selection of outcome-related differentially expressed genes; or 3) in supervised prediction, a biased estimation of the prediction accuracy through an incorrect cross-validation procedure. Conclusions The most common and serious mistakes and misunderstandings recorded in published studies are described and illustrated. Based on this analysis, a proposal of guidelines for statistical analysis and reporting for clinical microarray studies, presented as a checklist of "Do's and Don'ts," is provided. C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ Paris 07, Paris, France. Hop St Louis, Serv Dermatol, F-75475 Paris, France. RP Simon, RM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@nih.gov NR 25 TC 391 Z9 401 U1 1 U2 24 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 17 PY 2007 VL 99 IS 2 BP 147 EP 157 DI 10.1093/jnci/dik018 PG 11 WC Oncology SC Oncology GA 126QA UT WOS:000243528300011 PM 17227998 ER PT J AU Pulliam, JRC Dushoff, JG Levin, SA Dobson, AP AF Pulliam, Juliet R. C. Dushoff, Jonathan G. Levin, Simon A. Dobson, Andrew P. TI Epidemic Enhancement in Partially Immune Populations SO PLOS ONE LA English DT Article AB We observe that a pathogen introduced into a population containing individuals with acquired immunity can result in an epidemic longer in duration and/or larger in size than if the pathogen were introduced into a naive population. We call this phenomenon "epidemic enhancement,'' and use simple dynamical models to show that it is a realistic scenario within the parameter ranges of many common infectious diseases. This finding implies that repeated pathogen introduction or intermediate levels of vaccine coverage can lead to pathogen persistence in populations where extinction would otherwise be expected. C1 [Pulliam, Juliet R. C.; Dushoff, Jonathan G.; Levin, Simon A.; Dobson, Andrew P.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Dushoff, Jonathan G.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Pulliam, JRC (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM pulliam@princeton.edu RI Pulliam, Juliet/A-6516-2008 OI Pulliam, Juliet/0000-0003-3314-8223 FU NIH/NSF [R01-TW05869]; NIH [P50 GM071508]; Pew Charitable Trusts FX This study was funded by an NIH/NSF "Ecology of Infectious Disease'' grant (R01-TW05869), by an NIH grant to the Center for Quantitative Biology at Princeton University (P50 GM071508), and by a grant from the Pew Charitable Trusts (2000-002558). The funding bodies have had no role in the conception or performance of the study nor in the preparation of the manuscript. NR 7 TC 12 Z9 12 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 17 PY 2007 VL 2 IS 1 AR e165 DI 10.1371/journal.pone.0000165 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DF UT WOS:000207444000015 PM 17225866 ER PT J AU Schiffmann, R AF Schiffmann, Raphael TI Enzyme replacement in Fabry disease: The essence is in the kidney SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID ALPHA-GALACTOSIDASE; AGALSIDASE-ALPHA; RENAL-DISEASE; THERAPY; SAFETY; PREVALENCE; EFFICACY C1 NINDS, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), NIH, Bldg 10,,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM RS4e@nih.gov NR 20 TC 12 Z9 12 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 16 PY 2007 VL 146 IS 2 BP 142 EP 144 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 131WF UT WOS:000243901000008 PM 17179053 ER PT J AU Sucato, CA Upton, TG Kashemirov, BA Batra, VK Martinek, V Xiang, Y Beard, WA Pedersen, LC Wilson, SH McKenna, CE Florian, J Warshel, A Goodman, MF AF Sucato, Christopher A. Upton, Thomas G. Kashemirov, Boris A. Batra, Vinod K. Martinek, Vaclav Xiang, Yun Beard, William A. Pedersen, Lars C. Wilson, Samuel H. McKenna, Charles E. Florian, Jan Warshel, Arieh Goodman, Myron F. TI Modifying the beta,gamma leaving-group bridging oxygen alters nucleotide incorporation efficiency, fidelity, and the catalytic mechanism of DNA polymerase beta SO BIOCHEMISTRY LA English DT Article ID REPLICATION FIDELITY; ALKALINE-PHOSPHATASE; TRANSITION-STATE; COMPLEXES; HYDROLYSIS; PROBES; STABILITY; CONSTANTS; REPAIR; ACID AB DNA polymerase catalysis and fidelity studies typically compare incorporation of "right" versus "wrong" nucleotide bases where the leaving group is pyrophosphate. Here we use dGTP analogues replacing the beta,gamma-bridging O with CH2, CHF, CF2, or CCl2 to explore leaving-group effects on the nucleotidyl transfer mechanism and fidelity of DNA polymerase (pol) beta. T center dot G mismatches occur with fidelities similar to dGTP with the exception of the CH2 analogue, which is incorporated with 5-fold higher fidelity. All analogues are observed to bind opposite template C with K(d)s between 1 and 4 mu M, and structural evidence suggests that the analogues bind in essentially the native conformation, making them suitable substrates for probing linear free energy relationships (LFERs) in transient-kinetics experiments. Importantly, Bronsted correlations of log(k(pol)) versus leaving-group pK(a) for both right and wrong base incorporation reveal similar sensitivities (beta(lg) approximate to -0.8) followed by departures from linearity, suggesting that a chemical step rather than enzyme conformational change is rate-limiting for either process. The location of the breaks relative to pK(a)s of CF2, O, and the sterically bulky CCl2-bridging compounds suggests a modification-induced change in the mechanism by stabilization of leaving-group elimination. The results are addressed theoretically in terms of the energetics of successive primer 3'-O addition (bond forming) and pyrophosphate analogue elimination (bond breaking) reaction energy barriers. C1 Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. Loyola Univ, Dept Chem, Chicago, IL 60626 USA. Charles Univ Prague, Fac Sci, Dept Biochem, Prague, Czech Republic. Charles Univ Prague, Inst Phys, Prague, Czech Republic. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM mgoodman@usc.edu RI Florian, Jan/E-1554-2012; Upton, Thomas/E-3749-2012; Martinek, Vaclav/E-6710-2011 OI Florian, Jan/0000-0003-2669-4293; Martinek, Vaclav/0000-0003-3321-4526 FU Intramural NIH HHS; NCI NIH HHS [1U19CA10501]; NIGMS NIH HHS [R37GM21422] NR 51 TC 67 Z9 67 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 16 PY 2007 VL 46 IS 2 BP 461 EP 471 DI 10.1021/bi061517b PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 123ZT UT WOS:000243337200014 PM 17209556 ER PT J AU Drukteinis, JS Roman, MJ Fabsitz, RR Lee, ET Best, LG Russell, M Devereux, RB AF Drukteinis, Jennifer S. Roman, Mary J. Fabsitz, Richard R. Lee, Elisa T. Best, Lyle G. Russell, Marie Devereux, Richard B. TI Cardiac and systemic hemodynamic characteristics of hypertension and prehypertension in adolescents and young adults - The Strong Heart Study SO CIRCULATION LA English DT Article DE echocardiography; hemodynamics; hypertension; hypertrophy; prehypertension ID LEFT-VENTRICULAR HYPERTROPHY; CARDIOVASCULAR-DISEASE RISK; JOINT NATIONAL COMMITTEE; BLOOD-PRESSURE; AMERICAN-INDIANS; BODY-COMPOSITION; CHILDREN; GEOMETRY; OBESITY; MASS AB Background - The epidemic of overweight is increasing the prevalence of both prehypertension and early-onset hypertension, but few population-based data exist on their impact on cardiac structure and function in adolescents and young adults. Methods and Results - We analyzed clinical characteristics, hemodynamic parameters, and left ventricular structure and function in 1940 participants, 14 to 39 years of age, in the Strong Heart Study. Hypertension occurred in 294 participants ( 15%), who were more often men ( 70% versus 30%), older ( age, 31 +/- 7 versus 25 +/- 8 years), and more commonly diabetic ( 23% versus 4.5%; all P < 0.001) than their normotensive counterparts. Prehypertension occurred in 675 ( 35%) of participants with similar trends in gender, age, and diabetes status. After adjustment for covariates, both hypertensive and prehypertensive participants had higher left ventricular wall thickness ( 0.83 and 0.78 versus 0.72 cm), left ventricular mass ( 182 and 161 versus 137 g), and relative wall thickness ( 0.30 and 0.29 versus 0.28 cm) and 3- and 2- fold- higher prevalences of left ventricular hypertrophy than their normotensive counterparts ( all P < 0.001). Hypertension and prehypertension also were associated with higher mean pulse pressure/ stroke volume index ( 1.24 and 1.15 versus 1.02 mm Hg/ mL (.) m(2)) and total peripheral resistance index ( 3027 and 2805 versus 2566 dynes (.) s (.) cm (-5) (.) m(2); all P < 0.001). Conclusions - In a population with high prevalences of obesity and diabetes, hypertension and prehypertension are associated with increases in both cardiac output and peripheral resistance index. Despite the young age of participants with hypertension and prehypertension, they had prognostically adverse preclinical cardiovascular disease, including left ventricular hypertrophy and evidence of increased arterial stiffness. C1 Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Missouri Breaks Ind Res Inc, Timber Lake, SD USA. MedStar Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Presbyterian Hosp, Div Cardiol, Box 222,525 E 68th St, New York, NY 10021 USA. EM rbdevere@med.cornell.edu FU NCRR NIH HHS [M10RR0047-34]; NHLBI NIH HHS [HL41642, HL41652, HL65521, HL41654] NR 43 TC 103 Z9 117 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 16 PY 2007 VL 115 IS 2 BP 221 EP 227 DI 10.1161/CIRCULATIONAHA.106.668921 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 126OL UT WOS:000243523600013 PM 17210838 ER PT J AU Davis, BR Piller, LB Dunn, K AF Davis, Barry R. Piller, Linda B. Dunn, Kay TI Response to letter regarding article, "Role of diuretics in the prevention of heart failure: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)" SO CIRCULATION LA English DT Letter C1 Univ Texas, Sch Publ Hlth, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Univ Calif Irvine, Irvine, CA USA. Univ Ottawa, Inst Heart, Ottawa, ON, Canada. Creighton Cardiac Ctr, Omaha, NE USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Univ Washington, Seattle, WA 98195 USA. Penderbrook Med Ctr, Fairfax, VA USA. Ctr Cardiovasc Caguas, Caguas, PR USA. Univ Minnesota, Minneapolis, MN USA. RP Davis, BR (reprint author), Univ Texas, Sch Publ Hlth, Houston, TX USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 16 PY 2007 VL 115 IS 2 BP E19 EP E19 DI 10.1161/CIRCULATIONAHA.106.651539 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 126OL UT WOS:000243523600027 ER PT J AU Melenovsky, V Borlaug, BA Rosen, B Hay, I Ferruci, L Morell, CH Lakatta, EG Najjar, SS Kass, DA AF Melenovsky, Vojtech Borlaug, Barry A. Rosen, Boaz Hay, Ilan Ferruci, Luigi Morell, Christopher H. Lakatta, Edward G. Najjar, Sainer S. Kass, David A. TI Cardiovascular features of heart failure with preserved ejection fraction versus nonfailing hypertensive left ventricular hypertrophy in the urban Baltimore community - The role of atrial remodeling/dysfunction SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID GENETIC EPIDEMIOLOGY NETWORK; DIASTOLIC DYSFUNCTION; FILLING PRESSURES; SYSTOLIC FUNCTION; STROKE VOLUME; ECHOCARDIOGRAPHIC-ASSESSMENT; TISSUE DOPPLER; ARTERIAL; AGE; DIAGNOSIS AB Objectives The purpose of this study was to identify cardiovascular features of patients with heart failure with preserved ejection fraction (HFpEF) that differ from those in individuals with hypertensive left ventricular hypertrophy (HLVH) of similar age, gender, and racial background but without failure. Background Heart failure with preserved ejection fraction often develops in HLVH patients and involves multiple abnormalities. Clarification of changes most specific to HFpEF may help elucidate underlying pathophysiology. Methods A cross-sectional study comparing HFpEF patients (n = 37), HLVH subjects without HF (n = 40), and normotensive control subjects without LVH (n = 56). All subjects had an EF of > 50%, sinus rhythm, and insignificant valvular or active ischemic disease, and groups were matched for age, gender, and ethnicity. Comprehensive echo-Doppler and pressure analysis was performed. Results The HFpEF patients were predominantly Africa n-American women with hypertension, LVH, and obesity. They had vascular and systolic-ventricular stiffening and abnormal diastolic function compared with the control subjects. However, most of these parameters either individually or combined were similarly abnormal in the HLVH group and poorly distinguished between these groups. The HFpEF group had quantitatively greater concentric LVH and estimated mean pulmonary artery wedge pressure (20 mm Hg vs. 16 mm Hg) and shorter isovolumic relaxation time than the HLVH group. They also had left atrial dilation/dysfunction unlike in HLVH and greater total epicardial volume. The product of LV mass index and maximal left atrial (LA) volume best identified HFpEF patients (84% sensitivity, 82% specificity). Conclusions In an urban, principally African American, cohort, HFpEF patients share many abnormalities of systolic, diastolic, and vascular function with nonfailing HLVH subjects but display accentuated LVH and LA dilation/failure. These latter factors may help clarify pathophysiology and define an important HFpEF population for clinical trials. C1 Johns Hopkins Med Inst, Div Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Clin Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Loyola Coll, Dept Math Sci, Baltimore, MD 21210 USA. RP Kass, DA (reprint author), Johns Hopkins Med Inst, Div Med, Ross 835,720 Rutland Ave, Baltimore, MD 21205 USA. EM dkass@jhmi.edu OI Melenovsky, Vojtech/0000-0001-8921-7078 FU Intramural NIH HHS; NIA NIH HHS [AG 18324] NR 51 TC 217 Z9 220 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JAN 16 PY 2007 VL 49 IS 2 BP 198 EP 207 DI 10.1016/j.jacc.2006.08.050 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 126YD UT WOS:000243550600005 PM 17222731 ER PT J AU Ainslie, KM Bachelder, EM Borkar, S Zahr, AS Sen, A Badding, JV Pishko, MV AF Ainslie, Kristy M. Bachelder, Eric M. Borkar, Sachin Zahr, Alisar S. Sen, Ayusman Badding, John V. Pishko, Michael V. TI Cell adhesion on nanofibrous polytetrafluoroethylene (nPTFE) SO LANGMUIR LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; PROTEIN ADSORPTION; IN-VITRO; CARBON NANOTUBES; POLY(ETHYLENE GLYCOL); INFLAMMATORY RESPONSE; ORTHOPEDIC IMPLANTS; MONOCYTE ACTIVATION; ENDOTHELIAL-CELLS; SILICON SURFACES AB Here, we described the in vitro biocompatibility of a novel nanostructured surface composed of PTFE as a potential polymer for the prevention of adverse host reactions to implanted devices. The foreign body response is characterized at the tissue-material interface by several layers of macrophages and large multinucleated cells known as foreign body giant cells (FBGC), and a fibrous capsule. The nanofibers of nanofibrous PTFE (nPTFE) range in size from 20 to 30 nm in width and 3-4 mm in length. Glass surfaces coated with nPTFE (produced by jet-blowing of PTFE 601A) were tested under in vitro conditions to characterize the amount of protein adsorption, cell adhesion, and cell viability. We have shown that nPTFE adsorbs 495 +/- 100 ng of bovine serum albumin (BSA) per cm(2). This level was considerably higher than planar PTFE, most likely due to the increase in hydrophobicity and available surface area, both a result of the nanoarchitecture. Endothelial cells and macrophages were used to determine the degree of cell adsorption on the surface of the nanostructured polymer. Both cell types were significantly more round and occupied less area on nPTFE as compared to tissue culture polystyrene (TCPS). Furthermore, a larger majority of the cells on the nPTFE were dead compared to TCPS, at dead-to-live ratios of 778 +/- 271 to 1 and 23 +/- 5.6 to 1, respectively. Since there was a high amount of cell death (due to either apoptosis or necrosis), and the foreign body response is a form of chronic inflammation, an 18 cytokine Luminex panel was performed on the supernatant from macrophages adherent on nPTFE and TCPS. As a positive control for inflammation, lipopolysaccharide (LPS) was added to macrophages on TCPS to estimate the maximum inflammation response of the macrophages. From the data presented with respect to IL-1, TNF-alpha, IFN-gamma, and IL-5, we concluded that nPTFE is nonimmunogenic and should not yield a huge inflammatory response in vivo, and cell death observed on the surface of nPTFE was likely due to apoptosis resulting from the inability of cells to spread on these surface. On the basis of the production of IL-1, IL-6, IL-4, and GM-CSF, we concluded that FBGC formation on nPTFE may be decreased as compared to materials known to elicit FBGC formation in vivo. C1 Penn State Univ, Dept Chem, University Pk, PA 16802 USA. Penn State Univ, Dept Chem Engn, University Pk, PA 16802 USA. Penn State Univ, Dept Mat Sci & Engn, University Pk, PA 16802 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Chem & Biomol Engn, Lincoln, NE 68588 USA. RP Sen, A (reprint author), Penn State Univ, Dept Chem, University Pk, PA 16802 USA. EM asen@psu.edu; jbadding@chem.psu.edu; mpishko@psu.edu RI Badding, John/A-2737-2011; Sen, Ayusman/A-9406-2009; OI Badding, John/0000-0002-4517-830X; Sen, Ayusman/0000-0002-0556-9509; Ainslie, Kristy/0000-0002-1820-8382 FU NIBIB NIH HHS [5R01EB000684] NR 75 TC 27 Z9 27 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD JAN 16 PY 2007 VL 23 IS 2 BP 747 EP 754 DI 10.1021/la060948s PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 124AF UT WOS:000243338500058 PM 17209629 ER PT J AU Puccioni-Sohler, M Yamano, Y Rios, M Carvalho, SMF Vasconcelos, CCF Papais-Alvarenga, R Jacobson, S AF Puccioni-Sohler, M. Yamano, Y. Rios, M. Carvalho, S. M. F. Vasconcelos, C. C. F. Papais-Alvarenga, R. Jacobson, S. TI Differentiation of HAM/TSP from patients with multiple sclerosis infected with HTLV-I SO NEUROLOGY LA English DT Article ID VIRUS TYPE-I; PROVIRAL LOAD; INTRATHECAL SYNTHESIS; DIAGNOSTIC-CRITERIA; CEREBROSPINAL-FLUID; PREDICT CONVERSION; MRI CRITERIA; MYELOPATHY; ANTIBODY; IGG AB Objective: To better differentiate patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) from patients with multiple sclerosis (MS) who are HTLV-I seropositive, we compared the HTLV-I antibodies and HTLV-I proviral DNA loads in CSF and peripheral blood mononuclear cells (PBMC). Methods: Intrathecal synthesis of HTLV-I antibodies and HTLV-I proviral DNA loads in CSF and PBMC were measured and compared in 39 Brazilian patients: 17 HAM/TSP and 22 HTLV-I-seropositive non-HAM/ TSP (7 with other neurologic diseases, 11 asymptomatic carriers, and 4 HTLV-I-seropositive patients with an MS-like phenotype). In addition, we followed immunologic and virologic markers in comparison to the clinical course ( by Kurtzke Expanded Disability Status Scale) of seven patients (five with HAM/TSP and two with an MS-like phenotype) for a mean period of 16 (SD +/- 5) months. Results: The proviral load in CSF and PBMC was higher in HAM/TSP than in non-HAM/TSP patients, except in the two HTLV-I-seropositive patients with an MS-like phenotype that also fulfilled the criteria for HAM/TSP. Higher HTLV-I proviral DNA load in CSF was associated with the higher proviral DNA load in PBMC and lower intrathecal synthesis of HTLV-I antibodies. These laboratory findings remained stable during follow-up. Conclusion: The high proviral load in peripheral blood mononuclear cells or in CSF or both may be a good marker of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and can differentiate patients with HAM/TSP from patients with multiple sclerosis infected with HTLV-I. C1 Univ Fed Rio de Janeiro, Gaffree Guinle Univ Hosp, Serv Neurol, BR-21941 Rio De Janeiro, Brazil. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. Univ Fed Fluminense, Antonio Pedro Hosp, Neurol Serv, Rio De Janeiro, Brazil. Inst Estadual Hematol Arthur De S Cavalcanti, Neuolife Cerebrosinal Fluid Lab, Rio De Janeiro, Brazil. RP Puccioni-Sohler, M (reprint author), Rua Dezenove De Fevereiro 185-705, BR-22280030 Rio De Janeiro, Brazil. EM mpuccioni@hucff.ufrj.br NR 26 TC 21 Z9 22 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 16 PY 2007 VL 68 IS 3 BP 206 EP 213 DI 10.1212/01.wnl.0000251300.24540.c4 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 126CB UT WOS:000243488700010 PM 17224575 ER PT J AU Imaizumi, M Kim, HJ Zoghbi, SS Briard, E Hong, J Musachio, JL Ruetzler, C Chuang, DM Pike, VW Innis, RB Fujita, M AF Imaizumi, Masao Kim, Hyun-Ju Zoghbi, Sami S. Briard, Ernmanuelle Hong, Jinsoo Musachio, John L. Ruetzler, Christl Chuang, De-Maw Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI PET imaging with [C-11]PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat SO NEUROSCIENCE LETTERS LA English DT Article DE peripheral benzodiazepine receptor; neuroinflammation; small animal PET; cerebral ischemia; activated microglia ID IN-VIVO; MICROGLIAL ACTIVATION; BINDING-SITES; BRAIN-LESIONS; HIGH-AFFINITY; STROKE; LIGAND; MOUSE; QUANTIFICATION; PHASE AB Peripheral benzodiazepine, receptors (PBRs) are upregulated on activated microglia. We recently developed a promising positron emission tomography (PET) ligand, [C-11]PBR28, with high affinity and excellent ratio of specific to nonspecific binding. We assessed the ability of [C-11]PBR28 PET to localize PBRs in a rat permanent middle cerebral artery occlusion (MCAO) model of neuroinflammation. [C-11]PBR28 was intravenously administered to rats at 4 and 7 days after permanent MCAO. In all experiments, arterial blood was sampled for compartmental modeling of regional distribution volumes, and rat brains were sampled after imaging for in vitro [H-3]PK11195 autoradiography and histological evaluation. [C-11]PBR28 PET and [H-3]PK 11195 autoradiography showed similar areas of increased PBRs, especially in the peri-ischemic core. Results from these in vivo and in vitro methods were strongly correlated. In this first study to demonstrate neuroinflammation in vivo with small animal PET, [C-11]PBR28 had adequate sensitivity to localize and quantify the associated increase in PBRs. Published by Elsevier Ireland Ltd. C1 NIMH, NIH, Mol Imaging Branch, Bethesda, MD 20892 USA. NIMH, NIH, Mol Neurobiol Sect, Bethesda, MD 20892 USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Imaizumi, M (reprint author), NIMH, NIH, Mol Imaging Branch, Bldg 1,Room B3-10,1 Ctr Dr,MSC 0135, Bethesda, MD 20892 USA. EM imaizumim@intra.nimh.nih.gov FU Intramural NIH HHS NR 19 TC 79 Z9 79 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JAN 16 PY 2007 VL 411 IS 3 BP 200 EP 205 DI 10.1016/j.neulet.2006.09.093 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 134JC UT WOS:000244078300008 PM 17127001 ER PT J AU Hwang, KJ Mahmoodian, F Ferretti, JA Korn, ED Gruschus, JM AF Hwang, Kae-Jung Mahmoodian, Fatemeh Ferretti, James A. Korn, Edward D. Gruschus, James M. TI Intramolecular interaction in the tail of Acanthamoeba myosin IC between the SH3 domain and a putative pleckstrin homology domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE NMR; homology modeling ID SECONDARY STRUCTURE PREDICTION; STRUCTURAL INSIGHTS; NUCLEOTIDE EXCHANGE; CRYSTAL-STRUCTURE; PROTEIN; BINDING; PHOSPHOINOSITIDES; LOCALIZATION; IDENTIFICATION; PURIFICATION AB The 466-aa tail of the heavy chain of Acanthamoeba myosin IC (AMIC) comprises an IN-terminal 220-residue basic region (BR) followed by a 56-residue Gly/Pro/Ala-rich region (GPA1), a 55-residue Src homology 3 (SH3) domain, and a C-terminal 135-residue Gly/Pro/Ala-rich region (GPA2). Cryo-electron microscopy of AMIC had shown previously that the AMIC tail is folded back on itself, suggesting the possibility of interactions between its N- and C-terminal regions. We now show specific differences between the NMR spectrum of bacterially expressed full-length tail and the sum of the spectra of individually expressed BR and GPA1-SH3-GPA2 (GSG) regions. These results are indicative of interactions between the two subdomains in the full-length tail. From the NMR data, we could assign many of the residues in BR and GSG that are involved in these interactions. By combining homology modeling with the NMR data, we identify a putative pleckstrin homology (PH) domain within BR, and show that the PH domain interacts with the SH3 domain. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Room 2517, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012 NR 46 TC 9 Z9 9 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2007 VL 104 IS 3 BP 784 EP 789 DI 10.1073/pnas.0610231104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 129WP UT WOS:000243761100020 PM 17215368 ER PT J AU Huang, Y Yang, HY Borg, BB Su, XW Rhodes, SL Yang, K Tong, XM Tang, G Howell, CD Rosen, HR Thio, CL Thomas, DL Alter, HJ Sapp, RK Liang, TJ AF Huang, Ying Yang, Huiying Borg, Brian B. Su, Xiaowen Rhodes, Shannon L. Yang, Kai Tong, Xiaomei Tang, George Howell, Charles D. Rosen, Hugo R. Thio, Chloe L. Thomas, David L. Alter, Harvey J. Sapp, Ronda K. Liang, T. Jake TI A functional SNP of interferon-gamma gene is important for interferon-alpha-induced and spontaneous recovery from hepatitis C virus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetics; human study; cytokine; viral clearance; antiviral treatment ID NF-KAPPA-B; PLUS RIBAVIRIN; NUCLEAR FACTOR; DNA-BINDING; IFN-GAMMA; T-CELLS; EXPRESSION; PROMOTER; POLYMORPHISMS; ACTIVATION AB Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-alpha-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-gamma promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients. C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Colorado, Hlth Sci Ctr, Div Gastroenterol Hepatol, Denver, CO 80262 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. RP Liang, TJ (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. EM jliang@nih.gov FU NIDA NIH HHS [R37 DA004334, R01 DA013324, K08 DA000441, DA 04334, DA 13324, DA 00441, R56 DA004334, R01 DA004334]; NIDDK NIH HHS [U01 DK060341, U01 DK 60341] NR 35 TC 78 Z9 82 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2007 VL 104 IS 3 BP 985 EP 990 DI 10.1073/pnas.0609954104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 129WP UT WOS:000243761100055 PM 17215375 ER PT J AU Hill, DA Pillai, AD Nawaz, F Hayton, K Doan, L Lisk, G Desai, SA AF Hill, David A. Pillai, Ajay D. Nawaz, Fatima Hayton, Karen Doan, Lanxuan Lisk, Godfrey Desai, Sanjay A. TI A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug resistance; malaria; nutrient acquisition; fitness cost ID RED-BLOOD-CELLS; MALARIA PARASITES; INFECTED ERYTHROCYTES; PROTEIN-SYNTHESIS; MAMMALIAN-CELLS; PERMEABILITY; INHIBITION; PERMEATION; DANTROLENE; MEMBRANE AB Erythrocytes infected with malaria parasites exhibit marked increases in permeability to organic and inorganic solutes. The plasmodial surface anion channel (PSAC), an unusual voltage-dependent ion channel induced on the host membrane after infection, may play a central role in these permeability changes. Here, we identified a functional PSAC mutant through in vitro selection with blasticidin S. Resistance to blasticidin S was generated during culture and correlated with significant reductions in permeability to multiple solutes, consistent with uptake via a common pathway. Single channel recordings revealed marked changes in PSAC gating with the addition of a subconductance state not present in wild-type channels. The channel's selectivity profile and pharmacology also were significantly altered. Eventual loss of the mutant phenotype upon removal of selective pressure and slower growth of mutant parasites suggest that PSAC serves an important role in intracellular parasite survival. These findings provide solid evidence for the uptake of diverse solutes via PSAC and implicate one or more parasite genes in expression of this channel. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM sdesai@niaid.nih.gov RI Desai, Sanjay/B-7110-2009; OI Hill, David/0000-0001-9286-4268 FU Intramural NIH HHS NR 35 TC 38 Z9 39 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 16 PY 2007 VL 104 IS 3 BP 1063 EP 1068 DI 10.1073/pnas.0610353104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 129WP UT WOS:000243761100068 PM 17213308 ER PT J AU Villanueva, CM Cantor, KP Grimalt, JO Malats, N Silverman, D Tardon, A Garcia-Closas, R Serra, C Carrato, A Castano-Vinyals, G Marcos, R Rothman, N Real, FX Dosemeci, M Kogevinas, M AF Villanueva, Cristina M. Cantor, Kenneth P. Grimalt, Joan O. Malats, Nuria Silverman, Debra Tardon, Adonina Garcia-Closas, Reina Serra, Consol Carrato, Alfredo Castano-Vinyals, Gemma Marcos, Ricard Rothman, Nathaniel Real, Francisco X. Dosemeci, Mustafa Kogevinas, Manolis TI Bladder cancer and exposure to water disinfection by-products through ingestion, bathing, showering, and swimming in pools SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bladder neoplasms; disinfection; drinking; inhalation; skin absorption; trihalomethanes; water supply ID CHLORINATED DRINKING-WATER; EPITHELIAL-CELLS; TRIHALOMETHANES; CHLOROFORM; MICRONUCLEI; INDUCTION; FINLAND; COHORT; RISK AB Bladder cancer has been associated with exposure to chlorination by-products in drinking water, and experimental evidence suggests that exposure also occurs through inhalation and dermal absorption. The authors examined whether bladder cancer risk was associated with exposure to trihalomethanes (THMs) through ingestion of water and through inhalation and dermal absorption during showering, bathing, and swimming in pools. Lifetime personal information on water consumption and water-related habits was collected for 1,219 cases and 1,271 controls in a 1998-2001 case-control study in Spain and was linked with THM levels in geographic study areas. Long-term THM exposure was associated with a twofold bladder cancer risk, with an odds ratio of 2.10 (95% confidence interval: 1.09, 4.02) for average household THM levels of > 49 versus <= 8 mu g/liter. Compared with subjects not drinking chlorinated water, subjects with THM exposure of > 35 mu g/day through ingestion had an odds ratio of 1.35 (95% confidence interval: 0.92, 1.99). The odds ratio for duration of shower or bath weighted by residential THM level was 1.83 (95% confidence interval: 1.17, 2.87) for the highest compared with the lowest quartile. Swimming in pools was associated with an odds ratio of 1.57 (95% confidence interval: 1.18, 2.09). Bladder cancer risk was associated with long-term exposure to THMs in chlorinated water at levels regularly occurring in industrialized countries. C1 Municipal Inst Med Res, CREAL, Barcelona 08003, Spain. Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NCI, Bethesda, MD USA. CSIC, Dept Environm Chem, Barcelona, Spain. Univ Oviedo, Dept Prevent Med & Publ Hlth, Oviedo, Spain. Hosp Univ Canarias, Dept Prevent Med, Tenerife, Spain. Univ Pompeu Fabra, Dept Expt & Hlth Sci, Unit Res Occupat Hlth, Barcelona, Spain. Corp Parc Tauli, Sabadell, Spain. Hosp Gen Elche, Dept Med Oncol, Elche, Spain. Univ Autonoma Barcelona, Dept Genet & Microbiol, Mutagenesis Grp, Barcelona, Spain. Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain. IMIM, Cellular & Mol Biol Res Unit, Barcelona, Spain. Univ Crete, Sch Med, Dept Social Med, Iraklion, Greece. RP Kogevinas, M (reprint author), Municipal Inst Med Res, CREAL, 80 Dr Aiguader Rd, Barcelona 08003, Spain. EM kogevinas@imim.es RI Grimalt, Joan/E-2073-2011; Serra, C/E-6879-2014; Villanueva, Cristina/N-1942-2014; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Grimalt, Joan/0000-0002-7391-5768; Serra, C/0000-0001-8337-8356; Villanueva, Cristina/0000-0002-0783-1259; Real, Francisco X/0000-0001-9501-498X; Castano-Vinyals, Gemma/0000-0003-4468-1816; Malats, Nuria/0000-0003-2538-3784; Marcos, Ricard/0000-0001-7891-357X NR 23 TC 119 Z9 125 U1 10 U2 65 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 JAN 15 PY 2007 VL 165 IS 2 BP 148 EP 156 DI 10.1093/aje/kwj364 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 126EQ UT WOS:000243495400005 ER PT J AU Baird, DD Dunson, DB Hill, MC Cousins, D Schectman, JM AF Baird, Donna Day Dunson, David B. Hill, Michael C. Cousins, Deborah Schectman, Joel M. TI Association of physical activity with development of uterine leiomyoma SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; causality; exercise; leiomyoma; ultrasonics ID POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; OVARIAN-FUNCTION; BODY-SIZE; RISK; EXERCISE; FIBROIDS; DISEASE; CANCER AB The relation between physical activity and uterine leiomyomata (fibroids) has received little study, but exercise is protective for breast cancer, another hormonally mediated tumor. Participants in this study were randomly selected members of a health plan based in Washington, DC, aged 35-49 years (734 African Americans, 455 Whites) enrolled between 1996 and 1999. Fibroid status was based on ultrasound screening. Physical activity was based on detailed interview questions. Logistic regression with adjustment for body mass index and other risk factors showed that women in the highest category of physical activity were significantly less likely to have fibroids (odds ratio = 0.6, 95% confidence interval = 0.4, 0.9 for the highest vs. the lowest category (equivalent to approximately >= 7 hours/week vs. < 2 hours/week)). There was a dose-response pattern; a significant trend was seen for both African-American and White women. A multistate Bayesian analysis indicated that exercise was associated with tumor onset more strongly than with tumor growth. When data for women who reported major fibroid-related symptoms were excluded, results remained essentially unchanged, suggesting that the observed association could not be attributed to reverse causation (fibroids preventing exercise). The authors concluded that regular exercise might help women prevent fibroids. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, Dept Hlth & Human SErv, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC USA. Coda Res Inc, Res Triangle Pk, NC USA. George Washington Univ, Ctr Med, Dept Radiol, Washington, DC USA. George Washington Univ, Ctr Med, Dept Hlth Care Sci, Washington, DC USA. RP Baird, DD (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Dept Hlth & Human SErv, NIH, A3-05,111 TW Alexander Dr,Bldg 101,Room 308,POB 1, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS NR 29 TC 33 Z9 36 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 15 PY 2007 VL 165 IS 2 BP 157 EP 163 DI 10.1093/aje/kwj363 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 126EQ UT WOS:000243495400006 PM 17090618 ER PT J AU Sivertsen, A Lie, RT Wilcox, AJ Abyholm, F Vindenes, H Haukanes, BI Houge, G AF Sivertsen, Ase Lie, Rolv Terje Wilcox, Allen J. Abyholm, Frank Vindenes, Hallvard Haukanes, Bjorn Ivar Houge, Gunnar TI Prevalence of duplications and deletions of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE cleft palate; DiGeorge syndrome; del22q11; syndrome; 22q11.2 deletions; 22q11.2 duplications ID DISCORDANT PHENOTYPES; MONOZYGOTIC TWINS; CHROMOSOME 22Q11; MICRODUPLICATION; MALFORMATIONS; DISORDERS; SPECTRUM; FEATURES AB The prevalence of duplications and deletions of the 22q11.2 (DiGeorge syndrome) region was Studied among babies born in Norway with open cleft palate Without cleft lip (cleft palate only, CPO). During a 5-year period (1996-2001), there were 245 live births with CPO that were referred for surgery. DNA was available from 174 cases with overt cleft palate. DNA copy number was analyzed with the Multiplex ligation-dependent probe amplification (MLPA) technique, and an unambiguous result was obtained in 169 (97%) of the samples. We found no 22q11.2 duplications, and one known. and two previously undiagnosed cases with 22q11.2 deletions. All three del22q11-syndrorne cases also had heart malformations, which represent one-third of the 10 babies with heart malformations in our study population, The prevalence of del22q11-syndrome among babies with cleft palate with or without additional malformations Was I of 57 (1.8%). Because the prevalence of CPO in the 35 22q11.2 duplication cases published was 20%, we also investigated if dup22q11-testing was warranted in this group. However, no 22q11.2 duplications were found, indicating that the duplication cases ascertained so far might not be representative of the dup22q11-group as a whole. We conclude that neither del22q11 nor dup22q11 testing is warranted in babies with overt cleft palate as the only finding. (c) 2006 Wiley-Liss, Inc. C1 Univ Bergen, Dept Publ Hlth & Primary Hth Care, NO-5018 Bergen, Norway. Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Durham, NC USA. Univ Oslo, Rikshosp, Dept Plast Surg, N-0027 Oslo, Norway. Haukeland Hosp, Dept Plast Surg, N-5021 Bergen, Norway. Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway. RP Sivertsen, A (reprint author), Univ Bergen, Dept Publ Hlth & Primary Hth Care, Kalfarveien 31, NO-5018 Bergen, Norway. EM ase.sivertsen@isf.uib.no OI Haukanes, Bjorn Ivar/0000-0003-1559-3366; Wilcox, Allen/0000-0002-3376-1311 NR 30 TC 20 Z9 24 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN 15 PY 2007 VL 143A IS 2 BP 129 EP 134 DI 10.1002/ajmg.a.31445 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 124GZ UT WOS:000243357600005 PM 17163526 ER PT J AU Carey, MA Card, JW Bradbury, JA Moorman, MP Haykal-Coates, N Gavett, SH Graves, LP Walker, VR Flake, GP Voltz, JW Zhu, DL Jacobs, ER Dakhama, A Larsen, GL Loader, JE Gelfand, EW Germolec, DR Korach, KS Zeldin, DC AF Carey, Michelle A. Card, Jeffrey W. Bradbury, J. Alyce Moorman, Michael P. Haykal-Coates, Najwa Gavett, Stephen H. Graves, Loan P. Walker, Vickie R. Flake, Gordon P. Voltz, James W. Zhu, Daling Jacobs, Elizabeth R. Dakhama, Azzeddine Larsen, Gary L. Loader, Joan E. Gelfand, Erwin W. Germolec, Dori R. Korach, Kenneth S. Zeldin, Darryl C. TI Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE lung function; asthma; hype rreactivity; M2 muscarinic receptor; estrogen receptor ID PULMONARY PARASYMPATHETIC NERVES; HORMONE REPLACEMENT THERAPY; ER-ALPHA; REFLEX BRONCHOCONSTRICTION; MURINE MODEL; BRONCHIAL HYPERRESPONSIVENESS; MUSCARINIC RECEPTORS; TISSUE DISTRIBUTION; LUNG PARENCHYMA; SMOOTH-MUSCLE AB Rationale: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. Objectives: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice. Methods: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure. Measurements and Main Results: Estrogen receptor-a knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge. Conclusions: These data suggest that estrogen receptor-a is a critical regulator of airway hyperresponsiveness in mice. C1 NIH, NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. US EPA, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. Med Coll Wisconsin, Cardiovasc Res Ctr, Dept Med, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Cardiovasc Res Ctr, Dept Physiol, Milwaukee, WI 53226 USA. Natl Jewish Med & Res Ctr, Dept Pediat, Div Cell Biol, Denver, CO USA. RP Zeldin, DC (reprint author), NIH, NIEHS, Div Intramural Res, 111 TW Alexander Dr,Bldg 101,Room D236, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [Z01 ES101885-03]; NHLBI NIH HHS [P01 HL036577, P01 HL036577-21A15977] NR 65 TC 58 Z9 59 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JAN 15 PY 2007 VL 175 IS 2 BP 126 EP 135 DI 10.1164/rccm.200509-1493OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 126JF UT WOS:000243508500006 PM 17095746 ER PT J AU Ichioka, F Takaya, E Suzuki, H Kajigaya, S Buchman, VL Shibata, H Maki, M AF Ichioka, Fumitaka Takaya, Emi Suzuki, Hironori Kajigaya, Sachiko Buchman, Vladimir L. Shibata, Hideki Maki, Masatoshi TI HD-PTP and Alix share some membrane-traffic related proteins that interact with their Bro1 domains or proline-rich regions SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE ALG-2; Alix; Bro1 domain; charged multivesicular body protein (CHMP); endosomal sorting complex required for transport (ESCRT); HD-PTP; proline-rich region; protein-protein interaction; TSG101 ID ALG-2 INTERACTS; DOWN-REGULATION; CA2+-DEPENDENT MANNER; BINDING PARTNER; NEURONAL DEATH; ANNEXIN-XI; APOPTOSIS; GENE; ALIX/AIP1; COMPLEX AB Mammalian Alix is a multifunctional adaptor protein involved in cell death, receptor endocytosis, endosomal protein sorting and cell adhesion by associating with various proteins such as ALG-2, CIN85/Ruk(1)/SETA, endophilins, CHMP4s and TSG101 HD-PTP is a paralog of Alix and a putative protein tyrosine phosphatase (PTP) that contains a Brol domain, coiled-coils, a proline-rich region (PRR) in addition to a PTP domain. We investigated interactions between HD-PTP and Alix-binding proteins. In the yeast two-hybrid assay, HD-PTP showed positive interactions with CHMP4b/Shax1, TSG101, endophilin A1 and ALG-2 but not with either RabGAPLP or CIN85. We confirmed the interactions in a mammalian system by Strep-pulldown assays in which pulldown products from the lysates of HEK293T cells expressing either Strep-tagged HD-PTP alone or co-expressing with epitope-tagged proteins were analyzed by Western blotting using specific antibodies. While Alix associated with both ALG-2 and TSG101 in a Ca(2+)-dependent manner, HD-PTP interacted with ALG-2 Ca(2+)-dependently but with TSG101 Ca(2+)-independently. (c) 2006 Elsevier Inc. All rights reserved. C1 Nagoya Univ, Grad Sch Bioagr Sci, Dept Appl Mol Biosci, Chikusa Ku, Nagoya, Aichi 4648601, Japan. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Cardiff Univ, Sch Biosci, Cardiff CF10 3US, S Glam, Wales. RP Maki, M (reprint author), Nagoya Univ, Grad Sch Bioagr Sci, Dept Appl Mol Biosci, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648601, Japan. EM mmaki@agr.nagoya-u.ac.jp RI Buchman, Vladimir/A-4814-2010 OI Buchman, Vladimir/0000-0002-7631-8352 NR 46 TC 36 Z9 37 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2007 VL 457 IS 2 BP 142 EP 149 DI 10.1016/j.abb.2006.11.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 127GG UT WOS:000243572800003 PM 17174262 ER PT J AU Rao, JS Bazinet, RP Rapoport, SI Lee, HJ AF Rao, Jagadeesh S. Bazinet, Richard P. Rapoport, Stanley I. Lee, Ho-Joo TI Chronic administration of carbamazepine down-regulates AP-2 DNA-binding activity and AP-2 alpha protein expression in rat frontal cortex SO BIOLOGICAL PSYCHIATRY LA English DT Article DE AP-2; AP-2 alpha; arachidonic acid; bipolar disorder; brain; carbamazepine; NF-kappa B; PKA; PKC; phospholipase A(2); transcription factors ID BIPOLAR AFFECTIVE-DISORDER; ARACHIDONIC-ACID; BRAIN PHOSPHOLIPIDS; CHRONIC LITHIUM; KINASE-A; DOCOSAHEXAENOIC ACID; SIGNAL-TRANSDUCTION; TREATMENT DECREASES; UNANESTHETIZED RAT; MOOD STABILIZERS AB Background: Despite being approved for treating bipolar disorder, carbamazepine's (CBZ) mechanism of action is not fully understood. Carbamazepine and lithium, when administered chronically to rats, decrease brain messenger ribonucleic acid (mRNA), lprotein, and activity levels of the arachidonic acid-selective cytosolic phospholipase A(2) (cPLA(2)). The ability of lithium to decrease cPLA(2) mRNA was ascribed to its ability to down-regulate the cPLA(2) transcription factor, AP-2. The present study was Undertaken to see whether chronic CBZ treatment also would down-regulate the AP-2 transcription factor. Methods. Male CDF-344 rats received (intraperitonally for 30 days) 25 mg/kg per day or vehicle. Transcription factors regulating cPLA(2) were measured by gelshift assay in the frontal cortex. Results: Chronic CBZ decreased AP-2 transciption/factors binding activity, cyclic adenosine monopbosphate (cAMP)-dependent protein kinase A (PKA) activity, nuclear phospho AP-2 alpha and the protein but not mRNA level of AP-2 alpha in rat frontal cortex. There was no significant change in activator protein (AP) 1, nuclear factor kappa B (NF-kappa B), glucocorticoid response element, or polyoma enhancer activator 3 (PEA3). Conclusions. These results support the hypothesis that, like lithium, CBZs down-regulation of AP-2 transcription factor activity may be responsible for down-regulating cPLA2 gene transcription. Chronically administered CBZ appears to decrease AP-2 DNA-binding activity by decreasing cAMP-dependent PKA activity, phospborylation of AP-2 protein, and the protein level of its AP-2 alpha subunit in rat frontal cortex. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S-128, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov RI Rao, Jagadeesh/C-1250-2009 FU Intramural NIH HHS NR 39 TC 29 Z9 29 U1 0 U2 0 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 JAN 15 PY 2007 VL 61 IS 2 BP 154 EP 161 DI 10.1016/j.biopsych.2006.03.029 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 125PS UT WOS:000243454900005 PM 16806101 ER PT J AU Frye, MA Tsai, GCE Huggins, T Coyle, JT Post, RM AF Frye, Mark A. Tsai, Guochuan E. Huggins, Teresa Coyle, Joseph T. Post, Robert M. TI Low cerebrospinal fluid glutamate and glycine in refractory affective disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE glutamate; glycine; mood disorders ID DORSOLATERAL PREFRONTAL CORTEX; BIPOLAR DISORDER; MOOD DISORDERS; GABAPENTIN MONOTHERAPY; PSYCHIATRIC-DISORDERS; DEPRESSED-PATIENTS; D-CYCLOSERINE; AMINO-ACIDS; D-SERINE; SCHIZOPHRENIA AB Background: Glutamatergic dysregulation has been documented in schizophrenia but has received less systematic study in affective illness. Methods: Cerebrospinal fluid (CSF) levels of the excitatory amino acids glutamate (Glu) and aspartate (Asp) and the N-metbyl-D-aspartate (NAIDA) receptor modulator, glycine (GLY) were measured by high performance liquid chromatography in 32 patients with refractory affective disorder (16 female/16 male, 12 bipolar 1, 12 bipolar H, and 8 unipolar) and in 14 age-matched controls. Results: There was a significant reduction in CSF glutamate and glycine in patients versus controls. A diagnosis by sex interaction was present for CSF glycine with lower levels in female patients compared to female controls. Levels of the excitatory amino acids were highly inter-correlated in patients, but not in controls. In patients studied after 6 weeks of lamotrigine, there was a trend for CSF glutamate levels to increase. Conclusions: These data suggest that in patients with refractory affective disorder, excitatory amino acids are dysregulated, as exemplified both by the decreased CSF glutamate and glycine and their high intercorrelation compared to controls. Further controlled study of glutamatergic dysregulation and its relationship to the pathophysiology of affective disorders and potential mechanism of action of mood stabilizers appears indicated. C1 Univ Calif Los Angeles, Dept Psychiat, Los Angeles Neuropsychiat Inst, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Harbor UCLA Med Ctr, Dept Psychiat, Sch Med, Torrance, CA USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Frye, MA (reprint author), 300 UCLA Med Plaza,Suite 1544, Los Angeles, CA 90095 USA. EM mfrye@mednet.ucla.edu FU Intramural NIH HHS; NIMH NIH HHS [R01 MH079261] NR 45 TC 55 Z9 60 U1 1 U2 1 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 JAN 15 PY 2007 VL 61 IS 2 BP 162 EP 166 DI 10.1016/j.biopsych.2006.01.024 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 125PS UT WOS:000243454900006 PM 16735030 ER PT J AU Lopez, VA Detera-Wadleigh, S Cardona, I Kassem, L McMahon, FJ AF Lopez, Victor A. Detera-Wadleigh, Sevilla Cardona, Imer Kassem, Layla McMahon, Francis J. CA Natl Inst Mental Hlth Genetics Ini TI Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts SO BIOLOGICAL PSYCHIATRY LA English DT Article DE TPH2; attempt suicide; bipolar disorder; Genetics; Genetic Variation; polymorphism ID SEROTONIN TRANSPORTER GENE; ISOFORM TPH2 GENE; HAPLOTYPE ANALYSIS; MAJOR DEPRESSION; POLYMORPHISM; BEHAVIOR; LINKAGE; VICTIMS; SCHIZOPHRENIA; POPULATION AB Background: Bipolar affective disorder (BPAD) is a common mental illness that is strongly associated with suicide. Suicidal behavior is thought to result from an interaction of genetic, neurobiological, and pychosocial factors and tends to cluster in families, suggesting specific familial factors distinct from those that underlie BPAD itself Serotonin signaling has long been implicated in both BPAD and suicide, and the gene encoding the brain-expressed isoform typtopban hydroxlyase (TPH2) has been described. Markers in TPH2 have been implicated in suicide and major depressive disorder. but the results across studies are inconsistent. No studies have examined TPH2 in large samples of subjects with BPAD and suicide attempts (SA). We tested for a relationship between genetic variation in TPH2 and risk for BPAD and SA in a large family sample. Methods: The sample consisted of 2018 members of 670 families, ascertained through a sibling pair affected with bipolar I, bipolar II, or scbizoaffective-bipolar disorder and diagnosed under DSM-III/IV criteria. Three single nucleotide polymorphisms representing the common hoplotypes spanning TPH2 were analyzed. Results: Single-marker analysis failed to detect significant genetic association with BPAD or SA, but the number of informative families was small. Haplotype analysis showed significant association with both BPAD and SA, and the same haplotype was significantly associated with both BPAD and SA in a replication sample. Case-only analysis, stratified by SA, suggested that TPH2 was not an independent genetic riskf factor SA in this sample. Conclusions: The TPH2 might contribute to the risk of both BPAD and SA in families with BPAD. Further studies are needed to uncover the functional genetic variation that accounts for the observed associations. C1 NIMH, NIH, Genet Basis Mood & Anx Disorders Mood & Anxiety, US Dept Hlth & Human Serv, Bethesda, MD USA. RP Lopez, VA (reprint author), NIMH, NIH, Genet Basis Mood & Anx Disorders Mood & Anxiety, US Dept Hlth & Human Serv, 35 Covent Dr,Room 1A-202, Bethesda, MD USA. EM victorlopez1@gmail.com RI McMahon, Francis/A-7290-2009; OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS NR 47 TC 64 Z9 66 U1 2 U2 3 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 JAN 15 PY 2007 VL 61 IS 2 BP 181 EP 186 DI 10.1016/j.biopsych.2006.03.028 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 125PS UT WOS:000243454900009 PM 16806105 ER PT J AU Ertley, RN Bazinet, RP Lee, HJ Rapoport, SI Rao, JS AF Ertley, Renee N. Bazinet, Richard P. Lee, Ho-Joo Rapoport, Stanley I. Rao, Jagadeesh S. TI Chronic treatment with mood stabilizers increases membrane GRK3 in rat frontal cortex SO BIOLOGICAL PSYCHIATRY LA English DT Article DE GRK3; GRK2; lithium; carbamazepine; valproate; brain ID BIPOLAR AFFECTIVE-DISORDER; PROTEIN-COUPLED RECEPTORS; POSITRON EMISSION TOMOGRAPHY; BETA-GAMMA-SUBUNITS; ARACHIDONIC-ACID; CHRONIC LITHIUM; BRAIN PHOSPHOLIPIDS; DOCOSAHEXAENOIC ACID; SIGNAL-TRANSDUCTION; UNANESTHETIZED RAT AB Background: G-protein receptor kinases (GRKs) are a family of serine/threonine kinases involved in the homologous desensitization of agonist activated G-protein coupled receptors (GPCRs). G-protein coupled receptor supersensitivity, possibly as a result of decreased in affective disorders. GRK, has been suggested in Methods: We used immunobloting to determine if chronic, therapeutically relevant doses of lithium (Li+), carbamazepine (CBZ), and valproate (VPA), would increase GRK2/3 protein levels in rat frontal cortex. Results: Chronic Li+ (24%) and CBZ (44%) signficantly increased GRK3 in the membrane but not cytosol fractions. Chronic VPA bad no effect on GRK3. G-protein receptor kinase 2 protein levels were unchanged by all treatments. The GRK3 membrane to cytosol ratio was increased significantly in Li+ and CBZ treated rats. Conclusions: These results show that chronically administered Li+ and CBZ, but not VPA, increase the translocation of GRK3 from cytosol to membrane, possibly correcting supersensitivity of GPCRs in bipolar disorder. C1 NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Rao, JS (reprint author), NIA, NIH, Brain Physiol & Metab Sect, 9000 Rockville Pike,Bldg 9,1S-128, Bethesda, MD 20892 USA. EM jrao@grc.nia.nih.gov RI Rao, Jagadeesh/C-1250-2009 FU Intramural NIH HHS NR 57 TC 21 Z9 21 U1 1 U2 3 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 JAN 15 PY 2007 VL 61 IS 2 BP 246 EP 249 DI 10.1016/j.biopsych.2006.03.022 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 125PS UT WOS:000243454900017 PM 16697355 ER PT J AU Schou, M Pike, VW Sovago, J Gulyas, B Gallagher, PT Dobson, DR Walter, MW Rudyk, H Farde, L Halldin, C AF Schou, Magnus Pike, Victor W. Sovago, Judit Gulyas, Balazs Gallagher, Peter T. Dobson, David R. Walter, Magnus W. Rudyk, Helene Farde, Lars Halldin, Christer TI Synthesis of C-11-labelled (R)-OHDMI and CFMME and their evaluation as candidate radioligands for imaging central norepinephrine transporters with PET SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE NET; radioligand; PET; brain ID UPTAKE INHIBITOR; REBOXETINE ANALOGS; LOCUS-COERULEUS; H-3 NISOXETINE; UPTAKE SITES; HUMAN BRAIN; BINDING; AUTORADIOGRAPHY; NORADRENALINE; RADIOTRACERS AB (R)-1-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-3-methylamino-propan-2-ol ((R)-OHDM1) and (S,S)-1-cyclopentyl-2-(5-fluoro-2-methoxy-phenyl)-1-morpholin-2-yl-ethanol (CFMME) were synthesized and found to be potent inhibitors of norepinephrine reuptake. Each was labelled efficiently in its methyl group with carbon-11 (t(1/2) = 20.4 min) as a prospective radioligand for imaging brain norepinephrine transporters (NET) with positron emission tomography (PET). The uptake and distribution of radioactivity in brain following intravenous injection of each radioligand into cynomolgus monkey was examined in vivo with PET. After injection of (R)-[C-11]OHDMI, the maximal whole brain uptake of radioactivity was very low (1.1% of injected dose; I.D.). For occipital cortex, thalamus, lower brainstem, mesencephalon and cerebellum, radioactivity ratios to striatum at 93 min after radioligand injection were 1.35, 1.35, 1.2, 1.2 and 1.0, respectively. After injection of [C-11]UMME, radioactivity readily entered brain (3.5% I.D.). Ratios of radioactivity to cerebellum at 93 min for thalamus, occipital cortex, region of locus coeruleus, mesencephalon and striatum were 1.35, 1.3, 1.3, 1.2 and 1.2, respectively. Radioactive metabolites in plasma were measured by radio-HPLC. (R)[C-11]OHDMI represented 75% of plasma radioactivity at 4 min after injection and 6% at 30 min. After injection of [C-11]UMME, 84% of the radioactivity in plasma represented parent at 4 min and 20% at 30 min. Since the two new hydroxylated radioligands provide only modest regional differentiation in brain uptake and form potentially troublesome lipophilic radioactive metabolites, they are concluded to be inferior to existing radioligands, such as (S,S)-[C-11]MeNER, (S,S)-[F-18]FMeNER-D-2 and (S,S)[F-18]FRB-D-4, for the study of brain NETs with PET in vivo. (c) 2006 Elsevier Ltd. All rights reserved. C1 Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Windlesham GU20 6PH, Surrey, England. RP Schou, M (reprint author), Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. EM magnus.schou@ki.se RI Sovago, Judit/G-7961-2011; Gulyas, Balazs/F-9508-2015 FU NIMH NIH HHS [N01MH32004] NR 43 TC 11 Z9 11 U1 0 U2 5 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 JAN 15 PY 2007 VL 15 IS 2 BP 616 EP 625 DI 10.1016/j.bmc.2006.10.065 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 123SG UT WOS:000243315300002 PM 17123820 ER PT J AU Gilbert, KM Boos, TL Dersch, CM Greiner, E Jacobson, AE Lewis, D Matecka, D Prisinzano, TE Zhang, Y Rothman, RB Rice, KC Venanzi, CA AF Gilbert, Kathleen M. Boos, Terrence L. Dersch, Christina M. Greiner, Elisabeth Jacobson, Arthur E. Lewis, David Matecka, Dorota Prisinzano, Thomas E. Zhang, Ying Rothman, Richard B. Rice, Kenner C. Venanzi, Carol A. TI DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 3D-QSAR; GBR 12909; cocaine addiction; dopamine transporter; DAT/SERT selectivity; validation ID MOLECULAR-FIELD ANALYSIS; CONFORMATIONALLY SAMPLED PHARMACOPHORE; DOPAMINE REUPTAKE INHIBITOR; HIV-1 PROTEASE INHIBITORS; CYCLIC UREA DERIVATIVES; PARTIAL LEAST-SQUARES; ACID METHYL-ESTERS; PIPERIDINE ANALOGS; MONOAMINE TRANSPORTERS; SEROTONIN TRANSPORTER AB The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pKi (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q(2) = 0.508, standard error of prediction = 0.601, two components, r(2) = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pK(i) (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. (c) 2006 Elsevier Ltd. All rights reserved. C1 New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. NIDDKD, Med Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Venanzi, CA (reprint author), New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. EM venanzi@adm.njit.edu RI Prisinzano, Thomas/B-7877-2010 FU NIDA NIH HHS [F31 DA015555, DA01853, DA15555, R15 DA018153, R15 DA018153-01] NR 63 TC 10 Z9 10 U1 2 U2 10 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 JAN 15 PY 2007 VL 15 IS 2 BP 1146 EP 1159 DI 10.1016/j.bmc.2006.09.070 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 123SG UT WOS:000243315300052 PM 17127069 ER PT J AU Metaferia, BB Ray, S Smith, JA Bewley, CA AF Metaferia, Belhu B. Ray, Satyajit Smith, Jeremy A. Bewley, Carole A. TI Design and synthesis of substrate-mimic inhibitors of mycothiol-S-conjugate amidase from Mycobacterium tuberculosis SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE quinic acid; mycothiol bimane; myo-D-inositol; polymer-supported triphenyl phosphine; pseudodisaccharide; mycobacteria ID DISULFIDE; ANALOGS; BIMANE; THIOLS; ACID AB The Staudinger reaction between a polymer-supported triphenylphosphine reagent and pseudo-disaccharide azides is successfully applied to synthesize a variety of substrate-mimic mycothiol analogs. Screening of this new group of analogs against the mycobacterial detoxification enzyme mycothiol-S-conjugate amidase (MCA) yielded several modest inhibitors (IC50 values around 50 mu M) and provided additional structure-activity relationships for future optimization of inhibitors of MCA and its homologs. (c) 2006 Published by Elsevier Ltd. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov FU Intramural NIH HHS NR 24 TC 15 Z9 18 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD JAN 15 PY 2007 VL 17 IS 2 BP 444 EP 447 DI 10.1016/j.bmcl.2006.10.031 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 133KQ UT WOS:000244012200030 PM 17084627 ER PT J AU Byrd, JC Lin, TS Dalton, JT Wu, D Phelps, MA Fischer, B Moran, M Blum, KA Rovin, B Brooker-McEldowney, M Broering, S Schaaf, LJ Johnson, AJ Lucas, DM Heerema, NA Lozanski, G Young, DC Suarez, JR Colevas, AD Grever, MR AF Byrd, John C. Lin, Thomas S. Dalton, James T. Wu, Di Phelps, Mitch A. Fischer, Beth Moran, Mollie Blum, Kristie A. Rovin, Brad Brooker-McEldowney, Michelle Broering, Sarah Schaaf, Larry J. Johnson, Amy J. Lucas, David M. Heerema, Nyla A. Lozanski, Gerard Young, Donn C. Suarez, Jose-Ramon Colevas, A. Dimitrios Grever, Michael R. TI Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia SO BLOOD LA English DT Article ID DEPENDENT KINASE INHIBITOR; TUMOR LYSIS SYNDROME; PHASE-II TRIAL; CONTINUOUS-INFUSION; ALEMTUZUMAB CAMPATH-1H; P53 MUTATIONS; P-TEFB; CANCER; THERAPY; APOPTOSIS AB Despite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m(2) loading dose followed by 30 mg/m(2) 4-hour infusion; cohort 2, 40 mg/m(2) loading dose followed by 40 mg/m(2) 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m(2) loading dose followed by a 50 mg/m(2) 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200 x 10(9)/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases. C1 Ohio State Univ, Div Hematol Oncol, Dept Internal Med, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Dept Med Chem, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Dept Med, Div Nephrol, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. Sanofi Aventis Pharmaceut, Bridgewater, NJ USA. NCI, Canc Therapy & Evaluat Program, Bethesda, MD 20892 USA. RP Byrd, JC (reprint author), Ohio State Univ, Div Hematol Oncol, Dept Internal Med, Starling Loving Hall,Rm B302, Columbus, OH 43210 USA. EM john.byrd@osumc.edu RI Johnson, Amy/A-5662-2009; Phelps, Mitch/H-3941-2013; Blum, Kristie/E-2768-2011; Lucas, David/E-3555-2011; OI Phelps, Mitch/0000-0002-1615-5280; dalton, James T/0000-0002-3915-7326 FU NCI NIH HHS [U01CA 76576, P30 CA 16058, P30 CA016058, R21 CA112947, R21 CA112947-01A1, U01 CA076576] NR 40 TC 270 Z9 276 U1 0 U2 6 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 JAN 15 PY 2007 VL 109 IS 2 BP 399 EP 404 DI 10.1182/blood-2006-05-020735 PG 6 WC Hematology SC Hematology GA 125BN UT WOS:000243416600008 PM 17003373 ER PT J AU Engel, BC Podsakoff, GM Ireland, JL Smogorzewska, EM Carbonaro, DA Wilson, K Shah, A Kapoor, N Sweeney, M Borchert, M Crooks, GM Weinberg, KI Parkman, R Rosenblatt, HM Wu, SQ Hershfield, MS Candotti, F Kohn, DB AF Engel, Barbara C. Podsakoff, Greg M. Ireland, Joanna L. Smogorzewska, E. Monika Carbonaro, Denise A. Wilson, Kathy Shah, Ami Kapoor, Neena Sweeney, Mirna Borchert, Mark Crooks, Gay M. Weinberg, Kenneth I. Parkman, Robertson Rosenblatt, Howard M. Wu, Shi-Qi Hershfield, Michael S. Candotti, Fabio Kohn, Donald B. TI Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report SO BLOOD LA English DT Article ID RETROVIRAL VECTORS; ABNORMALITIES AB A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hernatopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m(2)) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34(+) cells. The expected myelo-suppression developed after busulfan but then persisted, necessitating the administration of untranscluced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoetic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoetic stem cells. C1 Childrens Hosp Los Angeles, Div Res Immunol Bone Marrow Transplantat, Los Angeles, CA 90027 USA. Childrens Hosp Los Angeles, Gen Clin Res Ctr, Los Angeles, CA 90027 USA. Childrens Hosp Los Angeles, Dept Pathol, Los Angeles, CA 90027 USA. Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Kohn, DB (reprint author), Div Res Immunol Bone Marrow Transplantat, 4650 W Sunset Blvd, Los Angeles, CA 90027 USA. EM dkohn@chla.usc.edu RI Kohn, Donald/N-5085-2016 OI Kohn, Donald/0000-0003-1840-6087 FU Intramural NIH HHS; NCRR NIH HHS [M01 RR-43]; NHLBI NIH HHS [HL54850, P50 HL054850]; NIDDK NIH HHS [DK20902, R01 DK020902] NR 14 TC 21 Z9 23 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 JAN 15 PY 2007 VL 109 IS 2 BP 503 EP 506 DI 10.1182/blood-2006-06-031476 PG 4 WC Hematology SC Hematology GA 125BN UT WOS:000243416600023 PM 16973956 ER PT J AU Xin, ZT Beauchamp, AD Calado, RT Bradford, JW Regal, JA Shenoy, A Liang, YY Lansdorp, PM Young, NS Ly, H AF Xin, Zhong-Tao Beauchamp, Adam D. Calado, Rodrigo T. Bradford, Jennifer W. Regal, Joshua A. Shenoy, Aarthi Liang, Yuying Lansdorp, Peter M. Young, Neal S. Ly, Hinh TI Functional characterization of natural telomerase mutations found in patients with hematologic disorders SO BLOOD LA English DT Article ID DOMINANT DYSKERATOSIS-CONGENITA; REVERSE-TRANSCRIPTASE MOTIFS; N-TERMINAL REGION; APLASTIC-ANEMIA; CATALYTIC SUBUNIT; FLOW-CYTOMETRY; GENE TERC; IN-VIVO; RNA; TEMPLATE AB Human telomerase hTERC RNA serves as a template for the catalytic hTERT protein to synthesize telomere repeats at chromosome ends. We have recently shown that some patients with bone marrow failure syndromes are heterozygous carriers for hTERC or hTERT mutations. These sequence variations usually lead to a compromised telomerase function by haploinsufficiency. Here, we provide functional characterization of an additional 8 distinct hTERT sequence variants and 5 hTERC variants that have recently been identified in patients with dyskeratosis congenita (DC) or aplastic anemia (AA). Among the mutations, 2 are novel telomerase variants that were identified in our cohort of patients. Whereas most of the sequence variants modulate telomerase function by haploinsufficiency, 2 hTERC variants with sequence changes located within the template region appear to act in a dominant-negative fashion. Inherited telomerase gene mutations, therefore, operate by various mechanisms to shorten telomere lengths, leading to limited marrow stem cell reserve and renewal capacity in patients with hematologic disorders. C1 Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. RP Ly, H (reprint author), Emory Univ, Dept Pathol & Lab Med, 105L Whitehead Biomed Res Bldg,615 Michael St, Atlanta, GA 30322 USA. EM hly@emory.edu RI Calado, Rodrigo/G-2619-2011 FU NIAID NIH HHS [P30 AI050409]; NIDDK NIH HHS [DK64399] NR 48 TC 60 Z9 67 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 JAN 15 PY 2007 VL 109 IS 2 BP 524 EP 532 DI 10.1182/blood-2006-07-035089 PG 9 WC Hematology SC Hematology GA 125BN UT WOS:000243416600026 PM 16990594 ER PT J AU Arbiser, JL Kau, T Konar, M Narra, K Ramchandran, R Summers, SA Vlahos, CJ Ye, KQ Perry, BN Matter, W Fischl, A Cook, J Silver, PA Bain, J Cohen, P Whitmire, D Furness, S Govindarajan, B Bowen, JP AF Arbiser, Jack L. Kau, Tweeny Konar, Martha Narra, Krishna Ramchandran, Ramani Summers, Scott A. Vlahos, Chris J. Ye, Keqiang Perry, Betsy N. Matter, William Fischl, Anthony Cook, James Silver, Pamela A. Bain, Jenny Cohen, Philip Whitmire, David Furness, Scott Govindarajan, Baskaran Bowen, J. Phillip TI Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis SO BLOOD LA English DT Article ID PROTEIN-KINASE INHIBITORS; IN-VIVO; AKT; GROWTH; ACTIVATION; 3-KINASE; ZEBRAFISH; PATHWAYS; TUMORIGENESIS; ANGIOSARCOMA AB Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Bet (PKB alpha), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase-activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent anglogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Aid: and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested. C1 Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. NCI, Pathol Lab, NIH, Rockville, MD USA. Univ Utah, Dept Internal Med, Div Endocrinol Metab & Diabet, Salt Lake City, UT 84112 USA. Lilly Res Labs, Indianapolis, IN USA. Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. Univ Dundee, Coll Life Sci, MRC, Prot Phosphorylat Unit, Dundee DD1 4HN, Scotland. Univ Georgia, Dept Chem, Athens, GA 30602 USA. Univ N Carolina, Dept Chem & Biochem, Greensboro, NC 27412 USA. RP Arbiser, JL (reprint author), Emory Univ, Sch Med, Dept Dermatol, WMB 5309,101 Woodruff Circle, Atlanta, GA 30322 USA. EM jarbise@emory.edu FU Medical Research Council [MC_U127084348]; NCI NIH HHS [K22 CA095325, K22 CA095325-01, K22 CA095325-02]; NIAMS NIH HHS [R01 AR047901, R01 AR47901] NR 41 TC 34 Z9 35 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2007 VL 109 IS 2 BP 560 EP 565 DI 10.1182/blood-2006-06-029934 PG 6 WC Hematology SC Hematology GA 125BN UT WOS:000243416600031 PM 16990598 ER PT J AU Kharas, MG Yusuf, I Scarfone, VM Yang, VW Segre, JA Huettner, CS Fruman, DA AF Kharas, Michael G. Yusuf, Isharat Scarfone, Vanessa M. Yang, Vincent W. Segre, Julia A. Huettner, Claudia S. Fruman, David A. TI KLF4 suppresses transformation of pre-B cells by ABL oncogenes SO BLOOD LA English DT Article ID KRUPPEL-LIKE FACTOR; GENE-EXPRESSION PROFILES; PHOSPHOINOSITIDE 3-KINASE; TRANSCRIPTION FACTORS; TUMOR-SUPPRESSOR; DOWN-REGULATION; BONE-MARROW; DNA-DAMAGE; CANCER; PROLIFERATION AB Genes that are strongly repressed after B-cell activation are candidates for being inactivated, mutated, or repressed in B-cell malignancies. Kruppel-like factor 4 (Klf4), a gene down-regulated in activated murine B cells, is expressed at low levels in several types of human B-cell lineage lymphomas and leukemias. The human KLF4 gene has been identified as a tumor suppressor gene in colon and gastric cancer; in concordance with this, overexpression of KLF4 can suppress proliferation in several epithelial cell types. Here we investigate the effects of KLF4 on pro/pre-B-cell transformation by v-Abl and BCR-ABL, oncogenes that cause leukemia in mice and humans. We show that overexpression of KLF4 induces arrest and apoptosis in the G, phase of the cell cycle. KLF4-mediated death, but not cell-cycle arrest, can be rescued by Bcl-X-L overexpression. Transformed pro/pre-B cells expressing KLF4 display increased expression of p21(CIP) and decreased expression of c-Myc and cyclin D2. Tetracycline-inducible expression of KLF4 in B-cell progenitors of transgenic mice blocks transformation by BCR-ABL and depletes leukemic pre-B cells in vivo. Collectively, our work identifies KLF4 as a putative tumor suppressor in B-cell malignancies. (c) 2007 by The American Society of Hematology C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Emory Univ, Dept Med, Atlanta, GA 30322 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Blood Ctr SE Wisconsin Inc, Milwaukee, WI 53233 USA. Univ Calif Irvine, Ctr Immunol, Irvine, CA 92717 USA. RP Fruman, DA (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, 3242 McGaugh Hall, Irvine, CA 92697 USA. EM dfruman@uci.edu FU NCI NIH HHS [T32 CA009054, T32 CA9054]; NIAID NIH HHS [R01 AI050831, AI50831] NR 53 TC 42 Z9 45 U1 0 U2 3 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 JAN 15 PY 2007 VL 109 IS 2 BP 747 EP 755 DI 10.1182/blood-2006-03-011106 PG 9 WC Hematology SC Hematology GA 125BN UT WOS:000243416600055 PM 16954505 ER PT J AU Yao, YG Ogasawara, Y Kajigaya, S Molldrem, JJ Falcao, RP Pintao, MC McCoy, JP Rizzatti, EG Young, NS AF Yao, Yong-Gang Ogasawara, Yoji Kajigaya, Sachiko Molldrem, Jeffrey J. Falcao, Roberto P. Pintao, Maria-Carolina McCoy, J. Philip, Jr. Rizzatti, Edgar Gil Young, Neal S. TI Mitochondrial DNA sequence variation in single cells from leukemia patients SO BLOOD LA English DT Article ID MTDNA CONTROL-REGION; POINT MUTATIONS; STEM-CELLS; REPLICATION; CANCER; TUMORS; IDENTIFICATION; PROLIFERATION; HETEROGENEITY; GRANULOCYTES AB A high frequency of mtDNA somatic mutation has been observed in many tumors as well as in aging tissues. In this study, we analyzed the mtDNA control region sequence variation in 3534 single normal cells and individual blasts from 18 patients with leukemia and 10 healthy donors, to address the mutation process in leukemic cells. We found significant differences in mtDNA sequence, as represented by the number of haplotypes and the mean number of cells with each nonaggregate haplotype in a population of cells, in patients compared to controls. Patients with similar clinical leukemia types, particularly acute myeloid leukemia (AML), did not show a uniform pattern of sequence variation in single blasts. Some patients at relapse presented a complex shift of major haplotypes in single cells. Four patients showed high frequencies of cells containing mutations 189, 260, 16150, and 16488, respectively, as a result of clonal expansion and could be considered as potential markers for their respective disease progression. To our knowledge, this is the first large-scale study of mtDNA variation in single malignant cells. Our results suggest that the somatic mutation process in leukemia is complex, leading to diverse levels of genetic alterations due to either intrinsic aspects of leukemia pathophysiology or chemotherapy effects. (c) 2007 by The American Society of Hematology C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA. Univ Sao Paulo, Ribeirao Preto Med Sch, Div Hematol, BR-14049 Ribeirao Preto, Brazil. RP Yao, YG (reprint author), NHLBI, Hematol Branch, NIH, NIH Bldg 10 CRC,Rm 3E-5216,1 Ctr Dr, Bethesda, MD 20892 USA. EM yaoy3@nhlbi.nih.gov; youngns@nhlbi.nih.gov NR 44 TC 30 Z9 31 U1 0 U2 4 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 JAN 15 PY 2007 VL 109 IS 2 BP 756 EP 762 DI 10.1182/blood-2006-01-011007 PG 7 WC Hematology SC Hematology GA 125BN UT WOS:000243416600056 PM 16946307 ER PT J AU Kamangar, F Qiao, YL Blaser, MJ Sun, XD Katki, H Fan, JH Perez-Perez, GI Abnet, CC Zhao, P D Mark, S Taylor, PR Dawsey, SM AF Kamangar, F. Qiao, Y-L Blaser, M. J. Sun, X-D Katki, H. Fan, J-H Perez-Perez, G. I. Abnet, C. C. Zhao, P. D Mark, S. Taylor, P. R. Dawsey, S. M. TI Helicobacter pylori and oesophageal and gastric cancers in a prospective study in China SO BRITISH JOURNAL OF CANCER LA English DT Article DE Helicobacter pylori; oesophageal cancer; gastric cancer; China ID SQUAMOUS-CELL CARCINOMA; GENERAL-POPULATION; RISK-FACTORS; INFECTION; ADENOCARCINOMA; SEROPOSITIVITY; CAGA; METAANALYSIS; LINXIAN; CARDIA AB In a cohort of 29 584 residents of Linxian, China, followed from 1985 to 2001, we conducted a case - cohort study of the magnitude of the association of Helicobacter pylori seropositivity with cancer risk in a random sample of 300 oesophageal squamous cell carcinomas, 600 gastric cardia adenocarcinomas, all 363 diagnosed gastric non-cardia adenocarcinomas, and a random sample of the entire cohort (N = 1050). Baseline serum was evaluated for IgG antibodies to whole-cell and CagA H. pylori antigens by enzyme-linked immunosorbent assay. Risks of both gastric cardia and non-cardia cancers were increased in individuals exposed to H. pylori ( Hazard ratios (HRs) and 95% confidence intervals 1.64; 1.26 - 2.14, and 1.60; 1.15 - 2.21, respectively), whereas risk of oesophageal squamous cell cancer was not affected (1.17; 0.88 - 1.57). For both cardia and non-cardia cancers, HRs were higher in younger individuals. With longer time between serum collection to cancer diagnosis, associations became stronger for cardia cancers but weaker for non-cardia cancers. CagA positivity did not modify these associations. The associations between H. pylori exposure and gastric cardia and non-cardia adenocarcinoma development were equally strong, in contrast to Western countries, perhaps due to the absence of Barrett's oesophagus and oesophageal adenocarcinomas in Linxian, making all cardia tumours of gastric origin, rather than a mixture of gastric and oesophageal malignancies. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Dept Canc Epidemiol, Inst Canc, Beijing 100021, Peoples R China. NYU, Sch Med, Dept Med, New York, NY USA. NYU, Sch Med, Dept Microbiol, New York, NY USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80202 USA. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 3034, Bethesda, MD 20892 USA. EM kamangaf@mail.nih.gov; qiaoy@public.bta.net.cn RI Qiao, You-Lin/B-4139-2012; Katki, Hormuzd/B-4003-2015; Abnet, Christian/C-4111-2015; OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843; Perez Perez, Guillermo /0000-0002-0131-5798 FU CCR NIH HHS [N01RC47701]; NCI NIH HHS [N01-SC-91030]; NIGMS NIH HHS [R01 GM063270, R01-GM-63270] NR 27 TC 77 Z9 83 U1 0 U2 5 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 JAN 15 PY 2007 VL 96 IS 1 BP 172 EP 176 DI 10.1038/sj.bjc.6603517 PG 5 WC Oncology SC Oncology GA 125DS UT WOS:000243422800029 PM 17179990 ER PT J AU Quintas-Cardama, A Kantarjian, H Garcia-Manero, G O'Brien, S Faderl, S Estrov, Z Giles, F Murgo, A Ladle, N Verstovsek, S Cortes, J AF Quintas-Cardama, Alfonso Kantarjian, Hagop Garcia-Manero, Guillermo O'Brien, Susan Faderl, Stefan Estrov, Zeev Giles, Francis Murgo, Anthony Ladle, Nakia Verstovsek, Srdan Cortes, Jorge TI Phase I/II study of subcutaneous homoharringtonine in patients with chronic myeloid leukemia who have failed prior therapy SO CANCER LA English DT Article DE homoharringtonine; imatinib; chronic myelogenous leukemia; ABL mutations ID CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB MESYLATE THERAPY; LOW-DOSE CYTARABINE; CYTOGENETIC RESPONSES; INTERFERON-ALPHA; SEMISYNTHETIC HOMOHARRINGTONINE; ST1571 THERAPY; ABL MUTATIONS; BLAST CRISIS; RESISTANCE AB BACKGROUND. Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon. METHODS. A Phase I study was completed of subcutaneous (S.C.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) S.C. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) S.C. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of S.C. HHT RESULTS. Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable. CONCLUSIONS. Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure. C1 MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Cortes, J (reprint author), MD Anderson Canc Ctr, Dept Leukemia, 1515 Holocombe Blvd,Unit 428, Houston, TX 77030 USA. EM jcortes@mdanderson.org NR 33 TC 89 Z9 93 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2007 VL 109 IS 2 BP 248 EP 255 DI 10.1002/cncr.22398 PG 8 WC Oncology SC Oncology GA 126XS UT WOS:000243549500011 PM 17154172 ER PT J AU Adams, EK Breen, N Joski, PJ AF Adams, E. Kathleen Breen, Nancy Joski, Peter J. TI Impact of the National Breast and Cervical Cancer Early Detection Program on mammography and pap test utilization among white, hispanic, and African American women: 1996-2000 SO CANCER LA English DT Article; Proceedings Paper CT Conference on Expliring Models to Eliminate Cancer Disparities among African American and Latino Populations CY APR 21-22, 2005 CL Atlanta, GA SP Amer Canc Soc DE screening; determinants; racial disparities; insurance ID MEDICALLY UNDERSERVED WOMEN; HEALTH INTERVIEW SURVEY; SCREENING PRACTICES; SELF-REPORT; CARE; DISPARITIES; COVERAGE; AUDIT AB Prevention, including routine cancer screening, is key to meeting national goals for the elimination of death and suffering due to cancer. Since 1991, the U.S. government has invested in programs such as the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) to detect breast and cervical cancer early among uninsured low-income women. A concomitant goal is reducing racial disparities in screening and early detection, and the NBCCEDP program targets low income women who are more often racial and ethnic minorities. This paper analyzes data to test for effects of the NBCCEDP and other determinants of screening across racial/ethnic groups. We used data from the Behavioral Risk Factor Surveillance System (BRFSS) for 1996 through 2000. These data indicate that gaps in testing for breast and cervical cancers between African American and non-Hispanic white women aged 40-64 years have closed but remain for Hispanics. Multivariate findings indicate that the longevity of free screening sites through the NBCCEDP significantly increased both tests for non-Hispanic white women. The data do not confirm this effect for other racial and ethnic groups. Analysis did indicate that public insurance, or Medicaid, was equal to private insurance in promoting increased testing for African Americans and Hispanics, but not for non-Hispanic whites. Assuring that Medicaid remains available for women in this nonelderly group and increasing access to free screening sites can lead us closer to national screening goals, yet policies still need to address racial/ethnic disparities in insurance and service delivery. C1 Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. NCI, Hlth Serv & Econ Branch, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Adams, EK (reprint author), Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Room 656,1518 Clifton Rd NE, Atlanta, GA 30322 USA. EM eadam01@sph.emory.edu NR 38 TC 88 Z9 88 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2007 VL 109 IS 2 SU S BP 348 EP 358 DI 10.1002/cncr.22353 PG 11 WC Oncology SC Oncology GA 127TB UT WOS:000243608100002 PM 17136766 ER PT J AU Wetter, DW Mazas, C Daza, P Nguyen, L Fouladi, RT Li, YS Cofta-Woerpel, L AF Wetter, David W. Mazas, Carlos Daza, Patricia Nguyen, Lynne Fouladi, Rachel T. Li, Yisheng Cofta-Woerpel, Ludmila TI Reaching and treating Spanish-speaking smokers through the National Cancer Institute's Cancer Information Service - A randomized controlled trial SO CANCER LA English DT Article; Proceedings Paper CT Conference on Expliring Models to Eliminate Cancer Disparities among African American and Latino Populations CY APR 21-22, 2005 CL Atlanta, GA SP Amer Canc Soc DE smoking cessation; cancer prevention; Hispanics; health promotion; tobacco control ID SMOKING-CESSATION; INTERVENTIONS; LATINOS AB Although the prevalence of smoking is lower among Hispanics than among the general population, smoking still levies a heavy public health burden on this underserved group. The current study, Adios al Fumar (Goodbye to Smoking), was designed to increase the reach of the Spanish-language smoking cessation counseling service provided by the National Cancer Institute's Cancer Information Service (CIS) and to evaluate the efficacy of a culturally sensitive, proactive, behavioral treatment program among Spanish-speaking smokers. Adios was a 2-group randomized clinical trial evaluating a telephone-based smoking cessation intervention. Spanish-speaking smokers (N = 297) were randomized to receive either standard counseling or enhanced counseling (EC). Paid media was used to increase the reach of the Spanish-language smoking cessation services offered by the CIS. The Adios sample was of very low socioeconomic status (SES), and more than 90% were immigrants. Calls to the CIS requesting smoking cessation help in Spanish increased from 0.39 calls to 17.8 calls per month. The unadjusted effect of EC only approached significance (OR = 2.4, P = .077), but became significant after controlling for demographic and tobacco-related variables (OR = 3.8, P = .048). Adios al Fumar demonstrated that it is possible to reach, retain, and deliver an adequate dose of treatment to a very low SES population that has traditionally been viewed as difficult to reach and hard to follow. Moreover, the findings suggest that a proactive, telephone-counseling program, based on the Treating Tobacco Use and Dependence Clinical Practice Guideline and adapted to be culturally appropriate for Hispanics, is effective. C1 Univ Texas, MD Anderson Canc Ctr, Dept Hlth Disparities Res, Houston, TX 77030 USA. Baylor Coll Med, Menninger Clin, Dept Psychiat, Houston, TX 77030 USA. NCI, Canc Informat Serv, Houston, TX USA. Simon Fraser Univ, Dept Psychol, Burnaby, BC V5A 1S6, Canada. Univ Texas, MD Anderson Canc Ctr, Dept Biostat & Appl Math, Houston, TX USA. Univ Texas, MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX USA. RP Wetter, DW (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Hlth Disparities Res, 1515 Holcombe Blvd,Unit 125, Houston, TX 77030 USA. EM dwetter@mdanderson.org OI Wetter, David/0000-0002-6366-0108 FU NCI NIH HHS [R01 CA94826, R25 CA57730, R01 CA89350, R01 CA089350] NR 27 TC 48 Z9 48 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2007 VL 109 IS 2 SU S BP 406 EP 413 DI 10.1002/cncr.22360 PG 8 WC Oncology SC Oncology GA 127TB UT WOS:000243608100008 PM 17149758 ER PT J AU Campbell, LC Keefe, FJ Scipio, C McKee, DC Edwards, CL Herman, SH Johnson, LE Colvin, OM McBride, CM Donatucci, C AF Campbell, Lisa C. Keefe, Francis J. Scipio, Cindy McKee, Daphne C. Edwards, Christopher L. Herman, Steven H. Johnson, Lawrence E. Colvin, O. Michael McBride, Colleen M. Donatucci, Craig TI Facilitating research participation and improving quality of life for African American prostate cancer survivors and their intimate partners - A pilot study of telephone-based coping skills training SO CANCER LA English DT Article; Proceedings Paper CT Conference on Expliring Models to Eliminate Cancer Disparities among African American and Latino Populations CY APR 21-22, 2005 CL Atlanta, GA SP Amer Canc Soc DE prostate cancer; African Americans; intimate partners; caregivers; symptoms; side-effects; coping skills training ID CONTROLLED CLINICAL-TRIAL; SELF-EFFICACY; RADICAL PROSTATECTOMY; FAMILY CAREGIVERS; SOCIAL SUPPORT; MEN; HEALTH; PAIN; INTERVENTIONS; VALIDATION AB African American men experience worse prostate cancer outcomes compared with those of Caucasian men, not only in incidence and mortality rates, but also in coping with the side effects of treatment. Unfortunately, African American men have been significantly under-represented in research evaluating the efficacy of psychosocial interventions for improving coping in prostate cancer survivors. This pilot study explored the feasibility and efficacy of coping skills training (CST), an intervention developed to enhance coping with treatment side effects in a sample of African American prostate cancer survivors and their intimate partners. The intervention was delivered in a telephone-based format designed to facilitate research participation. A total of 40 couples were randomized to either 6 sessions of CST or usual care. Survivors completed measures of disease-specific quality of life (QOL) related to urinary, sexual, bowel, and hormonal symptom domains, as well as measures of global QOL (i.e., physical functioning and mental health). Partners completed measures of caregiver strain, mood, and vigor. Analysis of data from 30 couples (12 couples in CST, 18 couples in usual care) indicated that CST produced moderate to large treatment effects for QOL related to bowel, urinary, sexual, and hormonal symptoms. Partners who underwent CST reported less caregiver strain, depression, and fatigue, and more vigor, with moderate effect sizes observed that approached conventional levels of statistical significance. These preliminary findings suggest that telephone-based CST is a feasible approach that can successfully enhance coping in African American prostate cancer survivors and their intimate partners. C1 Duke Univ, Med Ctr, Pain Prevent & Treatment Res Program, Dept Psychiat & Behav Med, Durham, NC 27704 USA. Duke Univ, Med Ctr, Pain Management Program, Durham, NC USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Med, Div Med Psychol, Durham, NC USA. N Carolina Conference United Methodist Church, Raleigh, NC USA. Duke Univ, Med Ctr, Div Hematol Oncol, Dept Med, Durham, NC USA. NHGRI, Scoial & Behav Res Branch, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Urol, Dept Surg, Durham, NC USA. RP Campbell, LC (reprint author), Duke Univ, Med Ctr, Pain Prevent & Treatment Res Program, Dept Psychiat & Behav Med, 2200 W Main St,Suite 340, Durham, NC 27704 USA. EM campb069@mc.duke.edu FU NCI NIH HHS [CA14236-2853] NR 64 TC 71 Z9 73 U1 1 U2 19 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2007 VL 109 IS 2 SU S BP 414 EP 424 DI 10.1002/cncr.22355 PG 11 WC Oncology SC Oncology GA 127TB UT WOS:000243608100009 PM 17173280 ER PT J AU Bowen, C Stuart, A Ju, JH Tuan, J Blonder, J Conrads, TP Veenstra, TD Gelmann, EP AF Bowen, Cai Stuart, August Ju, Jeong-Ho Tuan, Jenny Blonder, Josip Conrads, Thomas P. Veenstra, Timothy D. Gelmann, Edward P. TI NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity SO CANCER RESEARCH LA English DT Article ID HUMAN PROSTATE CANCERS; LARGE T-ANTIGEN; DNA TOPOISOMERASES; HOMEOBOX GENE; CELL-CYCLE; SUBNUCLEAR DISTRIBUTION; CHROMOSOME 8P12-21; ALLELIC LOSS; EXPRESSION; P53 AB The prostate-specific homeodomain protein NKX3.1 is a tumor suppressor that is commonly down-regulated in human prostate cancer. Using an NKX3.1 affinity column, we isolated topoisomerase I (Topo I) from a PC-3 prostate cancer cell extract. Topo I is a class 113 DNA-resolving enzyme that is ubiquitously expressed in higher organisms and many prokaryotes. NKX3.1 interacts with Topo I to enhance formation of the Topo I-DNA complex and to increase Topo I cleavage of DNA. The two proteins interacted in affinity pull-down experiments in the presence of either DNase or RNase. The NKX3.1 homeodomain was essential, but not sufficient, for the interaction with Topo I. NKX3.1 binding to Topo I occurred independently of the Topo I NH2-terminal domain. The binding of equimolar amounts of Topo I to NKX3.1 caused displacement of NKX3.1 from its cognate DNA recognition sequence. Topo I activity in prostates of Nkx3.1(+/-) and Nkx3.1(-/-) mice was reduced compared with wild-type mice, whereas Topo I activity in livers, where no NKX3.1 is expressed, was independent of Nkx3.1 genotype. Endogenous Topo I and NKX3.1 could be coimmunoprecipitated from LNCaP cells, where NKX3.1 and Topo I were found to colocalize in the nucleus and comigrate within the nucleus in response to either gamma-irradiation or mitomycin C exposure, two DNA-damaging agents. This is the first report that a homeodomain protein can modify the activity of Topo I and may have implications for organ-specific DNA replication, transcription, or DNA repair. C1 Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Georgetown Univ, Dept Med, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Sci Applicat Int Corp, Lab Proteom & Analyt Technol, NCI, Frederick, MD USA. RP Gelmann, EP (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM gelmanne@georgetown.edu FU NIEHS NIH HHS [ES09888] NR 55 TC 26 Z9 27 U1 0 U2 0 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 JAN 15 PY 2007 VL 67 IS 2 BP 455 EP 464 DI 10.1158/0008-5472.CAN-06-1591 PG 10 WC Oncology SC Oncology GA 128TZ UT WOS:000243683000006 PM 17234752 ER PT J AU Atkins, MB Ernstoff, MS Figlin, RA T Flaherty, K George, DJ Kaelin, WG Kwon, ED Libermann, TA Linehan, WM McDermott, DF Ochoa, AC Pantuck, AJ Rini, BI Rosen, MA Sosman, JA Sukhatme, VP Vieweg, JW Wood, CG King, L AF Atkins, Michael B. Ernstoff, Marc S. Figlin, Robert A. T Flaherty, Keith George, Daniel J. Kaelin, William G., Jr. Kwon, Eugene D. Libermann, Towia A. Linehan, W. Marston McDermott, David F. Ochoa, Augusto C. Pantuck, Allan J. Rini, Brian I. Rosen, Mark A. Sosman, Jeffrey A. Sukhatme, Vikas P. Vieweg, Johannes W. Wood, Christopher G. King, Laura TI Innovations and challenges in renal cell carcinoma: Summary statement from the second Cambridge conference SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 2nd International Conference on the Innovations and Challenges in Renal Cancer CY MAR 24-25, 2006 CL Cambridge, MA ID INHIBITOR; SU11248; CANCER AB Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment. C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. Univ Florida, Hlth Sci Ctr, Gainesville, FL USA. Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. Mayo Clin, Rochester, MN USA. NCI, Bethesda, MD 20892 USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. InforMED Commun Inc, Carlisle, MA USA. RP Atkins, MB (reprint author), 330 Brookline Ave, Boston, MA 02215 USA. EM matkins@bidmc.harvard.edu RI Libermann, Towia/F-9866-2010; OI Libermann, Towia/0000-0002-4006-8179 NR 10 TC 20 Z9 20 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2007 VL 13 IS 2 SU S BP 667S EP 670S DI 10.1158/1078-0432.CCR-06-2231 PN 2 PG 4 WC Oncology SC Oncology GA 133WC UT WOS:000244043600001 PM 17255291 ER PT J AU Linehan, WM Pinto, PA Srinivasan, R Merino, M Choyke, P Choyke, L Coleman, J Toro, J Glenn, G Vocke, C Zbar, B Schmidt, LS Bottaro, D Neckers, L AF Linehan, W. Marston Pinto, Peter A. Srinivasan, Ramaprasad Merino, Maria Choyke, Peter Choyke, Lynda Coleman, Jonathan Toro, Jorge Glenn, Gladys Vocke, Cathy Zbar, Bert Schmidt, Laura S. Bottaro, Donald Neckers, Len TI Identification of the genes for kidney cancer: Opportunity for disease-specific targeted therapeutics SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 2nd International Conference on the Innovations and Challenges in Renal Cancer CY MAR 24-25, 2006 CL Cambridge, MA ID TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; HIPPEL-LINDAU-DISEASE; PAPILLARY RENAL-CARCINOMAS; RECEPTOR TYROSINE KINASE; CELL LUNG-CANCER; HEPATOCYTE GROWTH-FACTOR; SOMATIC MUTATIONS; C-MET; SPONTANEOUS PNEUMOTHORAX AB Recent advances in understanding the kidney cancer gene pathways has provided the foundation for the development of targeted therapeutic approaches for patients with this disease. Kidney cancer is not a single disease; it includes a number of different types of renal cancers, each with different histologic features, a different clinical course, a different response to therapy, and different genes causing the defects. Most of what is known about the genetic basis of kidney cancer has been learned from study of the inherited forms of kidney cancer: von Hippel Lindau (VHL gene), hereditary papillary renal carcinoma (c-Met gene), Birt Hogg Dube (BHD gene), and hereditary leiomyomatosis renal cell cancer (fumarate hydratase gene). These Mendelian single-gene syndromes provide a unique opportunity to evaluate the effectiveness of agents that target the VHL, c-Met, BHD, and fumarate hydratase pathways. C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Frederick Inc, Frederick, MD 21701 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Room 1-5940,Bldg 10, Bethesda, MD 20892 USA. EM wml@nih.gov RI Bottaro, Donald/F-8550-2010; OI Bottaro, Donald/0000-0002-5057-5334; Coleman, Jonathan/0000-0002-6428-7835 FU Intramural NIH HHS; NCI NIH HHS [N01 CO 12400] NR 98 TC 70 Z9 70 U1 2 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JAN 15 PY 2007 VL 13 IS 2 SU S BP 671S EP 679S DI 10.1158/1078-0432.CCR-06-1870 PN 2 PG 9 WC Oncology SC Oncology GA 133WC UT WOS:000244043600002 PM 17255292 ER PT J AU Pillai, A Mansouri, A Behringer, R Westphal, H Goulding, M AF Pillai, Andrea Mansouri, Ahmed Behringer, Richard Westphal, Heiner Goulding, Martyn TI Lhx1 and Lhx5 maintain the inhibitory-neurotransmitter status of interneurons in the dorsal spinal cord SO DEVELOPMENT LA English DT Article DE Lhx1; Lhx5; Pax2; inhibitory neurons; spinal cord; mouse ID ASSOCIATION INTERNEURONS; NEURONAL DIFFERENTIATION; MOUSE DEVELOPMENT; MOTOR-NEURONS; THYROID-GLAND; GENE LHX5; CELL FATE; EXPRESSION; PAX8; LIM1 AB Lhx1 and Lhx5 are co-expressed in multiple interneuron cell types in the developing spinal cord. These include early-born dI4 and dl6 inhibitory interneurons, as well as late-born inhibitory dIL(A) neurons (dIL(A)), all of which express the paired-domain transcription factor Pax2. Although it appears that Lhx1 and Lhx5 do not control the initial specification of the neuronal cell types in which they are expressed, we have found a cell-autonomous requirement for either Lhx1 or Lhx5 to maintain the expression of Pax2, Pax5 and Pax8 in dorsal inhibitory neurons at later developmental stages. Lhx1; Lhx5 double-knockout mice exhibit a downregulation of Gad1 and Viaat (Slc32a1) from E13.5 onwards that is closely associated with a decrease in Pax2 expression. Pax2 is a key factor for dorsal GABAergic identity, with the expression of Pax5 and Pax8 being differentially dependent on Pax2 in the dorsal horn. In summary, our findings support a model in which the differentiation of GABAergic interneurons in the dorsal cord depends on Pax2, with Lhx1 and Lhx5 helping to activate and maintain Pax2 expression in these cells. Lhx1 and Lhx5 therefore function together with Pax2, Pax5 and Pax8 to establish a GABAergic inhibitory-neurotransmitter program in dorsal horn interneurons. C1 Salk Inst Biol Studies, Mol Neurobiol Lab, La Jolla, CA 92037 USA. Univ Calif San Diego, Biol Grad Program, La Jolla, CA 92037 USA. Max Planck Inst Biophys Chem, Dept Mol Cell Biol, D-37077 Gottingen, Germany. Univ Texas, MD Anderson Canc Ctr, Dept Mol Genet, Houston, TX 77030 USA. NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Goulding, M (reprint author), Salk Inst Biol Studies, Mol Neurobiol Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM goulding@salk.edu FU NINDS NIH HHS [NS 31249, NS 31978] NR 44 TC 59 Z9 59 U1 2 U2 8 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 JAN 15 PY 2007 VL 134 IS 2 BP 357 EP 366 DI 10.1242/dev.02717 PG 10 WC Developmental Biology SC Developmental Biology GA 119KN UT WOS:000243011300014 PM 17166926 ER PT J AU Yeo, SY Kim, M Kim, HS Huh, TL Chitnis, AB AF Yeo, Sang-Yeob Kim, MinJung Kim, Hyung-Seok Huh, Tae-Lin Chitnis, Ajay B. TI Fluorescent protein expression driven by her4 regulatory elements reveals the spatioternporal pattern of Notch signaling in the nervous system of zebrafish embryos SO DEVELOPMENTAL BIOLOGY LA English DT Article DE notch reporter; transgenic; Su(H); CBF1; CSL; her4; mind bomb; Neurogenin1; zath3; neurogenesis ID SPLIT COMPLEX GENES; BINDING-PROTEIN; EARLY NEUROGENESIS; DROSOPHILA-MELANOGASTER; DEFAULT REPRESSION; LATERAL INHIBITION; CELL-INTERACTIONS; SUPPRESSOR; HAIRLESS; ENHANCER AB Notch activation inhibits neuronal differentiation during development of the nervous system; however, the dynamic role of Notch signaling in individual cell lineages remains poorly understood. We have characterized 3.4 kb 5'-regulatory sequence of a Notch target gene, her4, and used it to drive fluorescent gene expression in transgenic lines where the spatiotemporal pattern of Notch activation can be examined in vivo. The 3.4 kb her4 promoter contains five predicted Su(H) binding sites of which two proximal sites were confirmed to be required for Notch-mediated transcriptional activation. Without Notch, Su(H) effectively represses transcription regulated by the promoter. Analyses of transgenic zebrafish showed that while the expression of proneural genes and Notch activation were both critical for endogenous her4 expression, reporter gene expression was primarily regulated by Notch activity. This study also showed that her4 may be differently regulated in sensory cranial ganglia, where Notch activity is not essential for her4 expression and where Su(H) may repress her4 expression. The establishment of a reporter line with Notch-Su(H)-dependent fluorescent gene expression provides a tool to explore the complex role of Notch signaling in the development of vertebrate nervous system. (c) 2006 Published by Elsevier Inc. C1 Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. EM sangyeobyeo@knu.ac.kr; chitnisa@mail.nih.gov FU Intramural NIH HHS NR 36 TC 63 Z9 63 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JAN 15 PY 2007 VL 301 IS 2 BP 555 EP 567 DI 10.1016/j.ydbio.2006.10.020 PG 13 WC Developmental Biology SC Developmental Biology GA 130DR UT WOS:000243780100019 PM 17134690 ER PT J AU Ueyama, T Lekstrom, K Tsujibe, S Saito, N Leto, TL AF Ueyama, Takehiko Lekstrom, Kristen Tsujibe, Satoshi Saito, Naoaki Leto, Thomas L. TI Subcellular localization and function of alternatively spliced Noxo1 isoforms SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article ID NADPH OXIDASE NOX1; COLON EPITHELIAL-CELLS; PX DOMAIN; NOX1-DEFICIENT MICE; ENDOTHELIAL-CELLS; NAD(P)H OXIDASE-1; MEMBRANE-BINDING; REACTIVE OXYGEN; SH3 DOMAIN; SUPEROXIDE AB Nox organizer 1 (Noxo1), a p47(phox) homolog, is produced as four isoforms with unique N-terminal PX domains derived by alternative mRNA splicing. We compared the subcellular distribution of these isoforms or their isolated PX domains produced as GFP fusion proteins, as well as their ability to support Nox1 activity in several transfected models. Noxo1 alpha, beta, gamma, and delta show different subcellular localization patterns, determined by their PX domains. In HEK293 cells, Noxo1 beta exhibits prominent plasma membrane binding, Noxo1 gamma shows plasma membrane and nuclear associations, and Noxo1 alpha and 6 localize primarily on intracellular vesicles or cytoplasmic aggregates, but not the plasma membrane. Nox1 activity correlates with Noxo1 plasma membrane binding in HEK293 cells, since Noxo1 beta supports the highest activity and Noxo1 gamma and Noxo1 alpha support moderate or low activities, respectively. In COS-7 cells, where Noxo1 alpha localizes on the plasma membrane, the activities supported by the three isoforms (alpha, beta, and gamma) do not differ significantly. The PX domains of beta and gamma bind the same phospholipids, including phosphatidic acid. These results indicate that the variant PX domains are unique determinants of Noxo1 localization and Nox1 function. Finally, the overexpressed Noxo1 isoforms do not affect p22(phox) localization, although Nox1 is needed to transport p22(phox) to the plasma membrane. Published by Elsevier Inc. C1 NIAID, NIH, Mol Def Sect, Lab Host Def, Rockville, MD 20852 USA. Kobe Univ, Mol Pharmacol Lab, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan. RP Ueyama, T (reprint author), NIAID, NIH, Mol Def Sect, Lab Host Def, Twinbrook 11,Room 203,12441 Parklawn Dr, Rockville, MD 20852 USA. EM tueyama@kobe-u.ac.jp; tleto@nih.gov FU Intramural NIH HHS [Z01 AI000614-16] NR 45 TC 23 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2007 VL 42 IS 2 BP 180 EP 190 DI 10.1016/j.freeadbiomed.2006.08.024 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 125AH UT WOS:000243413400004 PM 17189824 ER PT J AU Pietraforte, D Matarrese, P Straface, E Gambardella, L Metere, A Scorza, G Leto, TL Malorni, W Minetti, M AF Pietraforte, Donatella Matarrese, Paola Straface, Elisabetta Gambardella, Lucrezia Metere, Alessio Scorza, Giuseppe Leto, Thomas L. Malorni, Walter Minetti, Maurizio TI Two different pathways are involved in peroxynitrite-induced senescence and apoptosis of human erythrocytes SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE nitric oxide; peroxynitrite; carbon dioxide; red blood cell; aging; apoptosis; glycophorins; band 3; protein 4.1; spin trapping; DMPO; DBNBS; 3-nitrotyrosine; GSH; thiols ID RED-BLOOD-CELLS; CARBONATE RADICAL-ANION; NITRIC-OXIDE; EPR DETECTION; TYROSINE NITRATION; PROTEIN RADICALS; NITROGEN-DIOXIDE; URIC-ACID; OXIDATION; MEMBRANE AB CO, changes the biochemistry of peroxynitrite basically in two ways: (i) nitrating species is the CO3.-/(.)N02 radical pair, and (ii) peroxynitrite diffusion distance is significantly reduced. For peroxynitrite generated extracellularly this last effect is particularly dramatic at low cell density because CO3.- and (NO2)-N-. are short-lived and decay mostly in the extracellular space or at the cell surface/membrane. This study was aimed to distinguish between peroxynitrite-induced extra- and intracellular modifications of red blood cells (RBC). Our results show that at low cell density and in the presence of CO, peroxynitrite induced the oxidation of surface thiols, the formation of 3-nitrotyrosine and DMPO-RBC adducts, and the down-regulation of glycophorins A and C (biomarkers of senescence). Reactivation of glycolysis reversed only the oxidation of surface thiols. Without CO2 peroxynitrite also induced the oxidation of hemoglobin and glutathione, the accumulation of lactate, a decrease in ATP, the clustering of band 3, the externalization of phosphatidylserine, and the activation of caspases 8 and 3 (biomarkers of apoptosis). The latter biomarkers were all reversed by reactivation of glycolysis. We hypothesize that cell senescence could (generally) be derived by irreversible radical-mediated oxidation of membrane targets, while the appearance of apoptotic biomarkers could be bolstered by oxidation of intracellular targets. These results suggest that, depending on extracellular homolysis or diffusion to the intracellular space, peroxynitrite prompts RBCs toward either senescence or apoptosis through different oxidation mechanisms. (c) 2006 Elsevier Inc. All rights reserved. C1 Ist Super Sanita, Dept Cell Biol, I-00161 Rome, Italy. Ist Super Sanita, Dept Neurosci, I-00161 Rome, Italy. NIAID, NIH, Mol Def Sect, Lab Host Def, Bethesda, MD 20892 USA. RP Minetti, M (reprint author), Ist Super Sanita, Dept Cell Biol, Viale Regina Elena 299, I-00161 Rome, Italy. EM mminetti@iss.it RI Malorni, Walter/G-5874-2016; OI Pietraforte, Donatella/0000-0001-6370-912X NR 51 TC 30 Z9 32 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2007 VL 42 IS 2 BP 202 EP 214 DI 10.1016/j.freeadbiomed.2006.10.035 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 125AH UT WOS:000243413400006 PM 17189826 ER PT J AU Brown, KE Mathahs, MM Broadhurst, KA Coleman, MC Ridnour, LA Schmidt, WN Spitz, DR AF Brown, Kyle E. Mathahs, M. Meleah Broadhurst, Kimberly A. Coleman, Mitchell C. Ridnour, Lisa A. Schmidt, Warren N. Spitz, Douglas R. TI Increased hepatic telomerase activity in a rat model of iron overload: A role for altered thiol redox state? SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE glutamate cysteine ligase; glutathione; hemochromatosis; oxidative stress; telomeres; free radicals ID STRESS-INDUCED APOPTOSIS; HUMAN FIBROBLASTS; OXIDATIVE STRESS; LIVER-CIRRHOSIS; DIETARY IRON; EXPRESSION; CELLS; SENESCENCE; RESISTANCE; PROTEIN AB Telomeres are repeated sequences at chromosome ends that are incompletely replicated during mitosis. Telomere shortening caused by proliferation or oxidative damage culminates in replicative arrest and senescence, which may impair regeneration during chronic liver injury. Whereas the effects of experimental liver injury on telomeres have received little attention, prior studies suggest that telomerase, the enzyme complex that catalyzes the addition of telomeric repeats, is protective in some rodent liver injury models. Thus, the aim of this study was to determine the effects of iron overload on telomere length and telomerase activity in rat liver. Mean telomere lengths were similar in iron-loaded and control livers. However, telomerase activity was increased 3-fold by iron loading, with no change in levels of TERT mRNA or protein. Because thiol redox state has been shown to modulate telomerase activity in vitro, hepatic thiols were assessed. Significant increases in GSH (1.5-fold), cysteine (15-fold), and glutamate cysteine ligase activity (1.5-fold) were observed in iron-loaded livers, whereas telomerase activity was inhibited by treatment with N-ethylmaleimide. This is the first demonstration of increased telomerase activity associated with thiol alterations in vivo. Enhanced telomerase activity may be an important factor contributing to the resistance of rodent liver to iron-induced damage. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Iowa, Roy J & Lucille A Carver Coll Med, Div Gastroenterol Hepatol, Iowa City, IA 52242 USA. Iowa City VA Med Ctr, Iowa City, IA USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Program Free Rad & Radiat Biol, Iowa City, IA 52242 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Brown, KE (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Div Gastroenterol Hepatol, 4553 JCP,200 Hawkins Dr, Iowa City, IA 52242 USA. EM kyle-brown@uiowa.edu FU NCI NIH HHS [P30-CA086862, R01 CA100045, P30 CA086862, R01-CA100045]; NHLBI NIH HHS [R01 HL051469]; NIDDK NIH HHS [R21-DK068453-01A1, R21 DK068453] NR 41 TC 14 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2007 VL 42 IS 2 BP 228 EP 235 DI 10.1016/j.freeadbiomed.2006.10.039 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 125AH UT WOS:000243413400008 PM 17189828 ER PT J AU Chen, KH Miyazaki, T Tsai, HF Bennett, JE AF Chen, Kuang-Hua Miyazaki, Taiga Tsai, Huei-Fung Bennett, John E. TI The blip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata SO GENE LA English DT Article DE YAP1; FLR1; stress responsc; Benomyl; yeast ID OXIDATIVE STRESS-RESPONSE; SACCHAROMYCES-CEREVISIAE; ANTIFUNGAL SUSCEPTIBILITY; DRUG-RESISTANCE; FLUCONAZOLE RESISTANCE; JUN FAMILY; FLR1 GENE; YEAST; YAP1; SITES AB Transcriptional regulation in response to environmental challenges is crucial for survival of many organisms. In this study, we characterized structural and functional properties of CgAP1, a Saccharomyccs cerevisiae YAP1 ortholog, which encodes a transcription factor involved in various stress responses. Deletion of CgAP1 led to decreased resistance to hydrogen peroxide, 4-nitroquinoline-N-oxide (4-NQO), benomyl, and cadmium chloride, which could be fully recovered by reintroduction of an intact CgAP1. CgAP1 was shown to function in S. cerevisiae as it restored the drug resistance of the yap1 mutant. Moreover, overexpression of CgAP1 in a S. cerevisiae wild-type strain increased its resistance to cycloheximide, 1,10-phenanthroline, 4-NQO, and fluconazole. Overexpression of CgAP1 also phenotypically suppressed the drug sensitivity of two Yap1p-regulated transporter mutants, Delta atr1 and Delta flr1, to diamide, 4-NQO, and cadmium. Northern blot analysis indicated that Cgap1p regulates the benomyl-induced expression of CgFLR1, a homolog of S. cerevisiae FLR1, which encodes a transporter of the major facilitator superfamily. In contrast to the S. cerevisiae flr1 mutant, deletion of CgFLR1 in C. glabrata only resulted in increased sensitivity to benomyl, diamide, and menadione, but not 4-NQO, cycloheximide, or fluconazole. Taken together, this report demonstrated that CgAP1 plays a critical role in response to various stresses in C. glabrata and reduces the stress through transcriptional activation of its target genes including CgFLR1. Published by Elsevier B.V. C1 NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Lab Clin Infect Dis, NIH, Clin Ctr Room 11C304, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU Intramural NIH HHS NR 46 TC 44 Z9 49 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 15 PY 2007 VL 386 IS 1-2 BP 63 EP 72 DI 10.1016/j.gene.2006.08.010 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 129NU UT WOS:000243737000007 PM 17046176 ER PT J AU Buetow, KH AF Buetow, Kenneth H. TI Uniting efforts in molecular medicine SO GENETIC ENGINEERING NEWS LA English DT Article C1 NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. RP Buetow, KH (reprint author), NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. EM buetowke@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0270-6377 J9 GENET ENG NEWS JI Genet. Eng. News PD JAN 15 PY 2007 VL 27 IS 2 BP 44 EP 45 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 129VS UT WOS:000243758800014 ER PT J AU Toews, JC Schram, V Weerth, SH Mignery, GA Russell, JT AF Toews, Joanna C. Schram, Vincent Weerth, Susanna H. Mignery, Gregory A. Russell, James T. TI Signaling proteins in the axoglial apparatus of sciatic nerve nodes of Ranvier SO GLIA LA English DT Article DE sciatic nerve; IP(3)Rs; Schwann cells; nodes of Ranvier ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; MYELINATING SCHWANN-CELLS; SINGLE-CHANNEL FUNCTION; MOLECULAR-ORGANIZATION; NEUROMUSCULAR-JUNCTION; CALCIUM TRANSIENTS; GAP-JUNCTIONS; RAT-BRAIN; AXONS; GLIA AB During action potential conduction, the axonal specializations at the node, together with the adjacent paranodal terminations of the myelin sheath, interact with glial processes that invest the nodal gap. The nature of the mutual signals between axons and myelinating glia, however, are not well understood. Here we have characterized the distribution of inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in the axoglial apparatus by immunohistochemistry, using known myelin domain-specific markers. While IP(3)R1 is not expressed in the Schwann cells or the axon, IP(3)R2 and IP(3)R3 are expressed in distinct cellular domains, suggesting distinct signaling roles for the two receptors. IP(3)R3 is the most predominant isoform in Schwann cells, and is expressed in particularly dense patches in the paranodal region. In addition to IP(3)Rs, two other members of the metabotropic Ca2+ signaling pathway, G(alpha)q, and P(2)Y1 type of purinoceptors were also found in Schwann cells. Their pattern of expression matches the expression of their signaling partners, the IP(3)Rs. One interesting finding to emerge from this study is the expression of connexin 32 (Cx32) in close proximity with IP(3)R3. Although IP(3)R3 and Cx32 are not colocalized, their expression in the same membrane areas raises the question whether Schwann cell Ca2+ signals either control the function of the gap junctions, or whether the gap junctional channels serve as conduits for rapid radial spread of Ca2+ signals initiated during action potential propagation. Published 2006 Wiley-Liss, Inc. C1 NICHD, Lab Cellular & Mol Neurophysiol, Sect Cell Biol & Signal Transduct, NIH, Bethesda, MD 20892 USA. Loyola Univ, Dept Physiol, Maywood, IL 60153 USA. RP Russell, JT (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Sect Cell Biol & Signal Transduct, NIH, Bldg 49,Room 5A-22,49 Convent Dr,MSC 4480, Bethesda, MD 20892 USA. EM james@helix.nih.gov NR 41 TC 14 Z9 15 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD JAN 15 PY 2007 VL 55 IS 2 BP 202 EP 213 DI 10.1002/glia.20448 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 113WP UT WOS:000242629000008 PM 17091480 ER PT J AU Law, AJ Kleinman, JE Weinberger, DR Weickert, CS AF Law, Amanda J. Kleinman, Joel E. Weinberger, Daniel R. Weickert, Cynthia Shannon TI Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia SO HUMAN MOLECULAR GENETICS LA English DT Article ID RECEPTOR TYROSINE KINASE; NEUREGULIN-1; CELLS; MIGRATION; CLEAVAGE; PROTEIN; AKT1; SUSCEPTIBILITY; LOCALIZATION; TRANSCRIPTS AB The neuregulin 1 (NRG1) receptor, ErbB4, has been identified as a potential risk gene for schizophrenia. HER4/ErbB4 is a receptor tyrosine kinase whose transcript undergoes alternative splicing in the brain. Exon 16 encodes isoforms containing a metalloprotease cleavable extracellular domain (JM-a), exon 15 for a cleavage resistant form (JM-b) and exon 26 for a cytoplasmic domain (CYT-1) with a phosphotidylinositol-3 kinase (PI3K) binding site. Disease-associated variants in the ErbB4 gene are intronic and implicate altered splicing of the gene. We examined ErbB4 splice-variant gene expression in the hippocampus and dorsolateral prefrontal cortex (DLPFC) in schizophrenia using qPCR and investigated whether expression levels are associated with previously reported genomic risk variants in ErbB4 in a large cohort of human brains. In the DLPFC, we confirmed previous observations, in a separate cohort, that mRNA for ErbB4 splice isoforms containing exon 16 (JM-a) and exon 26 (CYT-1) are significantly elevated in patients with schizophrenia. A main effect of genotype was observed in the DLPFC and hippocampus at a single risk SNP located in intron 12 (rs4673628) on isoforms containing exon 16 (JM-a). We also found that three intronic risk SNPs (rs7598440, rs707284, rs839523) and a core-risk haplotype surrounding exon 3 are strongly associated with elevated expression of splice variants containing exon 26 (CYT-1). These findings suggest that dysregulation of splice-variant specific expression of ErbB4 in the brain underlies the genetic association of the gene with schizophrenia and that the NRG1/ErbB4 signaling pathway may be an important genetic network involved in the pathogenesis of the disease. C1 Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Law, AJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. EM amanda.law@psych.ox.ac.uk RI Shannon Weickert, Cynthia/G-3171-2011; Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU Intramural NIH HHS; Medical Research Council [G120/997] NR 45 TC 172 Z9 177 U1 2 U2 9 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 JAN 15 PY 2007 VL 16 IS 2 BP 129 EP 141 DI 10.1093/hmg/ddl449 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 130NP UT WOS:000243806600002 PM 17164265 ER PT J AU Whitby, D Marshall, VA Bagni, RK Miley, WJ McCloud, TG Hines-Boykin, R Goedert, JJ Conde, BA Nagashima, K Mikovits, J Dittmer, DP Newman, DJ AF Whitby, Denise Marshall, Vickie A. Bagni, Rachel K. Miley, Wendell J. McCloud, Thomas G. Hines-Boykin, Rebecca Goedert, James J. Conde, Betty A. Nagashima, Kunio Mikovits, Judy Dittmer, Dirk P. Newman, David J. TI Reactivation of Kaposi's sarcoma-associated herpesvirus by natural products from Kaposi's sarcoma endemic regions SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Kaposi's sarcoma associated hetpesvirus; natural products; reactivation ID HUMAN-HERPESVIRUS-8 HHV-8; EUPHORBIA-TIRUCALLI; BURKITTS-LYMPHOMA; PLANT; INFECTION; AIDS; QUANTIFICATION; TRANSMISSION; POPULATION; ANTIBODIES AB Kaposi's sarcoma (KS) and its causative agent, Kaposi's sarcoma associated herpesvirus (KSHV/HHV-8), a gamma2 herpesvirus, have distinctive geographical distributions that are largely unexplained. We propose the "oncoweed" hypothesis to explain these differences, namely that environmental cofactors present in KS endemic regions cause frequent reactivation of KSHV in infected subjects, leading to increased viral shedding and transmission leading to increased prevalence of KSHV infection as well as high viral load levels and antibody titers. Reactivation also plays a role in the pathogenesis of KSHV-associated malignancies. To test this hypothesis, we employed an in vitro KSHV reactivation assay that measured increases in KSHV viral load in KSHV infected primary effusion lymphoma (PEL) cells and screened aqueous natural product extracts from KS endemic regions. Of 4,842 extracts from 38 countries, 184 (5%) caused KSHV reactivation. Extracts that caused reactivation came from a wide variety of plant families, and extracts from Africa, where KSHV is highly prevalent, caused the greatest level of reactivation. Time course experiments were performed using 28 extracts that caused the highest levels of reactivation. The specificity of the effects on viral replication was examined using transcriptional profiling of all viral mRNAs. The array data indicated that the natural extracts caused an ordered cascade of lytic replication similar to that seen after induction with synthetic activators. These in vitro data provide support for the "oncoweed" hypothesis by demonstrating basic biological plausibility. (c) 2006 Wiley-Liss, Inc. C1 NCI Frederick, SAIC Frederick, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD 21702 USA. NCI Frederick, SAIC Frederick, Nat Prod Support Grp, Frederick, MD 21702 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73190 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI Frederick, SAIC Frederick, Image Anal Lab, Res Technol Program, Frederick, MD 21702 USA. NCI Frederick, SAIC Frederick, Lab Antiviral Drug Mechanisms, Frederick, MD 21702 USA. Univ N Carolina, Dept Microbiol & Immunol, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA. NCI Frederick, Nat Prod Branch, Frederick, MD 21702 USA. RP Whitby, D (reprint author), NCI Frederick, SAIC Frederick, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD 21702 USA. EM whitbyd@ncifcrf.gov FU NCI NIH HHS [R01 CA163217, N01-CO-12400, N01CO12400, R01 CA109232]; NIDCR NIH HHS [R01 DE018304-02, R01 DE018304, R01 DE018304-01, R01 DE018304-03] NR 39 TC 35 Z9 37 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 15 PY 2007 VL 120 IS 2 BP 321 EP 328 DI 10.1002/ijc.22205 PG 8 WC Oncology SC Oncology GA 117JH UT WOS:000242868800013 PM 17066452 ER PT J AU Ellis, J Gow, S West, K Waldner, C Rhodes, C Mutwiri, G Rosenberg, H AF Ellis, John Gow, Sheryl West, Keith Waldner, Cheryl Rhodes, Carrie Mutwiri, George Rosenberg, Helene TI Response of calves to challenge exposure with virulent bovine respiratory syncytial virus following intranasal administration of vaccines formulated for parenteral administration SO JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION LA English DT Article ID VIRAL CHALLENGE; EFFICACY; DISEASE; CATTLE; INFECTIONS; ANTIBODIES AB Objective-To determine whether single-fraction and combination modified-live bovine respiratory syncytial virus (BRSV) vaccines commercially licensed for parenteral administration could stimulate protective immunity in calves after intranasal administration. Design-Randomized controlled trial. Animals-39 calves. Procedures-Calves were separated from dams at birth, fed colostrum with a minimal concentration of antibodies against BRSV, and maintained in isolation. In 2 preliminary experiments, 9-week-old calves received 1 (n=3) or 2 (3) doses of a single-component, modified-live BRSV vaccine or no vaccine (8 control calves in each experiment), and were challenged with BRSV 21 days after vaccination. In a third experiment, 2-week-old calves received combination modified-live virus (MLV) vaccines with or without BRSV and calves were challenged with BRSV 8 days later. Calves were euthanized, and lung lesions were measured. Immune responses, including serum and nasal antibody and nasal interferon-alpha concentrations, were assessed. Results-BRSV challenge induced signs of severe clinical respiratory tract disease, including death and pulmonary lesions in unvaccinated calves and in calves that received a combination viral vaccine without BRSV Pulmonary lesions were significantly less severe in BRSV-challenged calves that received single or combination BRSV vaccines. The proportion of calves that shed virus and the peak virus titer was decreased, compared with control calves. Protection was associated with mucosal IgA antibody responses after challenge. Conclusions and Clinical Relevance-Single and combination BRSV vaccines administered intranasally provided clinical protection and sparing of pulmonary tissue similar to that detected in response to parenteral delivery of combination MLV and inactivated BRSV vaccines previously assessed in the same challenge model. C1 Univ Saskatchewan, Coll Vet Med, Dept Vet Microbiol, Saskatoon, SK S7N 5B4, Canada. Univ Saskatchewan, Coll Vet Med, Dept Large Anim Clin Sci, Saskatoon, SK S7N 5B4, Canada. Vaccine & Infect Dis Org, Saskatoon, SK S7N 5E3, Canada. NIAID, NIH, Bethesda, MD 20892 USA. RP Ellis, J (reprint author), Univ Saskatchewan, Coll Vet Med, Dept Vet Microbiol, Saskatoon, SK S7N 5B4, Canada. NR 24 TC 24 Z9 24 U1 0 U2 1 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0003-1488 J9 JAVMA-J AM VET MED A JI JAVMA-J. Am. Vet. Med. Assoc. PD JAN 15 PY 2007 VL 230 IS 2 BP 233 EP 243 DI 10.2460/javma.230.2.233 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA 126CT UT WOS:000243490500021 PM 17223757 ER PT J AU Castellino, F Germain, RN AF Castellino, Flora Germain, Ronald N. TI Chemokine-guided CD4(+) T cell help enhances generation of IL-6R alpha(IL)-I-high-7R alpha(high) prememory CD8(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SELECTIVE EXPRESSION; SECONDARY EXPANSION; VACCINE DEVELOPMENT; CD8-T-CELL MEMORY; CD4-T-CELL HELP; DENDRITIC CELLS; IL-7 RECEPTOR; IN-VIVO; SURVIVAL; DIFFERENTIATION AB CD4(+) T cells promote effective CD8(+) T cell-mediated immunity, but the timing and mechanistic details of such help remain controversial. Furthermore, the extent to which innate stimuli act independently of help in enhancing CD8(+) T cell responses is also unresolved. Using a noninfectious vaccine model in immunocompetent mice, we show that even in the presence of innate stimuli, CD4(+) T cell help early after priming is required for generating an optimal pool of functional memory CD8(+) T cells. CD4(+) T cell help increased the size of a previously unreported population of IL-6R alpha(IL)-I-high-7R alpha(high) prememory CD8(+) T cells shortly after priming that showed a survival advantage in vivo and contributed to the majority of functional memory CD8(+) T cells after the contraction phase. In accord with our recent demonstration of chemokine-guided recruitment of naive CD8(+) T cells to sites of CD4(+) T cell-dendritic cell interactions, the generation of IL-6R alpha(IL)-I-high-7R alpha(high) prememory as well as functional memory CD8(+) T cells depended on the early postvaccination action of the inflammatory chemokines CCL3 and CCL4. Together, these findings support a model of CD8(+) T cell memory cell differentiation involving the delivery of key signals early in the priming process based on chemokine-guided attraction of naive CD8(+) T cells to sites of Ag-driven interactions between TLR-activated dendritic cells and CD4(+) T cells. They also reveal that elevated IL-6R alpha expression by a subset of CD8(+) T cells represents an early imprint of CD4(+) T cell helper function that actively contributes to the survival of activated CD8(+) T cells. C1 NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. RP Germain, RN (reprint author), NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bldg 10,Room 11N-311,10 Ctr Dr, Bethesda, MD 20892 USA. EM rgermain@nih.gov FU Intramural NIH HHS NR 51 TC 58 Z9 58 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2007 VL 178 IS 2 BP 778 EP 787 PG 10 WC Immunology SC Immunology GA 123UB UT WOS:000243320400018 PM 17202339 ER PT J AU Younes, SA Trautmann, L Yassine-Diab, B Kalfayan, LH Kernaleguen, AE Cameron, TO Boulassel, R Stern, LJ Routy, JP Grossman, Z Dumont, AR Sekaly, RP AF Younes, Souheil-Antoine Trautmann, Lydie Yassine-Diab, Bader Kalfayan, Lena H. Kernaleguen, Anne-Elen Cameron, Thomas O. Boulassel, Rachid Stern, Lawrence J. Routy, Jean-Pierre Grossman, Zvi Dumont, Alain R. Sekaly, Rafick-Pierre TI The duration of exposure to HIV modulates the breadth and the magnitude of HIV-specific memory CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; LYMPHOCYTE-PROLIFERATIVE RESPONSES; CELLULAR IMMUNE-RESPONSES; VIRUS LOAD; HIV-1-INFECTED SUBJECTS; ANTIGEN PERSISTENCE; INFECTED SUBJECTS; TYPE-1 INFECTION; VIRAL-INFECTIONS; HELPER-CELLS AB The impact of exposure to Ag on the development and maintenance of human CD4(+) memory T cells in general and HIV infection in particular is partially understood. In this study, we measured HIV-specific CD4(+) T cell proliferative responses against HIV proteins and derived peptides one year after highly active antiretroviral therapy initiation in 39 HIV-infected patients who initiated therapy at different times following infection. We show that a brief exposure to HIV of < 1 month does not allow the generation of significant detectable frequencies of HIV-specific CD4(+) memory T cells. Patients having prolonged cumulative exposure to high viral load due to therapy failures also demonstrated limited HIV-specific CD4(+) T cell responses. In contrast, patients exposed to significant levels of virus for periods ranging from 3 to 18 mo showed brisk and broad HIV-specific CD4(+) T cell responses 2 year following the onset of therapy intervention. We also demonstrate that the nadir CD4(+) T cell count before therapy initiation correlated positively with the breadth and magnitude of these responses. Our findings indicate that the loss of proliferative HIV-specific CD4(+) T cell responses is associated with the systemic progression of the disease and that a brief exposure to HIV does not allow the establishment of detectable frequencies of HIV-specific memory CD4(+) T cells. C1 Univ Montreal, Res Ctr, Ctr Hosp, Lab Immunol,Dept Microbiol & Immunol, Montreal, PQ H2X 1P1, Canada. McGill Univ, Immundeficiency Serv, Ctr Hlth, Royal Victoria Hosp,Div Haematol, Montreal, PQ H3A 2T5, Canada. NYU, Sch Med, Skirball Inst Biomol Med, Mol Pathogenesis Program, New York, NY 10016 USA. Univ Massachusetts, Sch Med, Dept Pathol, Amherst, MA 01605 USA. Tel Aviv Univ, Dept Physiol & Pharmacol, Tel Aviv, Israel. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Sekaly, RP (reprint author), Univ Montreal, Res Ctr, Ctr Hosp, Lab Immunol,Dept Microbiol & Immunol, 264 Rene Levesque Blvd E, Montreal, PQ H2X 1P1, Canada. EM rafick-pierre.sekaly@umontreal.ca RI Grossman, Zvi/A-9643-2008; younes, souheil-antoine/G-4503-2014 OI younes, souheil-antoine/0000-0003-2186-7140 FU NIAID NIH HHS [R37 AI038996-11A1, R37 AI038996] NR 62 TC 23 Z9 24 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2007 VL 178 IS 2 BP 788 EP 797 PG 10 WC Immunology SC Immunology GA 123UB UT WOS:000243320400019 PM 17202340 ER PT J AU Song, HF Zhang, J Chiang, YJ Siraganian, RP Hodes, RJ AF Song, Haifeng Zhang, Juan Chiang, Y. Jeffrey Siraganian, Reuben P. Hodes, Richard J. TI Redundancy in B cell developmental pathways: c-Cbl inactivation rescues early B cell development through a B cell linker protein-independent pathway SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PHOSPHOTYROSINE-BINDING DOMAIN; SYK TYROSINE KINASE; ANTIGEN RECEPTOR; PROTOONCOGENE PRODUCT; PRE-BCR; SIGNAL-TRANSDUCTION; NEGATIVE REGULATION; POSITIVE SELECTION; ALLELIC EXCLUSION; TUMOR-SUPPRESSOR AB Deficiency in the adaptor protein B cell linker protein (BLNK) results in a substantial but incomplete block in B cell development, suggesting that alternative pathways exist for B lineage differentiation. Another adaptor protein, c-Cbl, plays a negative regulatory role in several BCR-signaling pathways. We therefore investigated the role of c-Cbl during B cell development and addressed the possibility that redundancies in pathways for B cell differentiation could be further revealed by eliminating negative effects mediated by c-Cbl. Strikingly, c-Cbl inactivation reversed a number of the critical defects in early B cell differentiation that are seen in BLNK-deficient mice. c-Cbl(-/-)BLNK(-/-) mice exhibited normalized down-regulation of pre-BCR and CD43, up-regulation of MHC class II, and augmented L chain rearrangement, resulting in a successful transition from pre-B cells to immature B cells. c-Cbl inactivation also reversed the potentially tumor-predisposing hyperproliferative response of BLNK-/- pre-B cells to IL-7. Pre-BCR cross-linking induced enhanced and prolonged tyrosine phosphorylation in c-Cbl(-/-)BLNK(-/-) pre-BCR+ pre-B cells compared with c-Cbl(+/-)BLNK(-/-) cells, including elevated phosphorylation of Lyn, Syk, Btk, and phospholipase G-gamma 2. Our studies suggest that some, but not all, pre-BCR-triggered developmental events can be mediated by BLNK-independent pathways that are negatively regulated by c-Cbl, and further suggest that different events during early B cell development require different strength or duration of pre-BCR signaling. C1 NIA, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Oral Infect & Immun Branch, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Hodes, RJ (reprint author), NIA, NIH, Bldg 10,Room 4B10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hodesr@31.nia.nih.gov FU Intramural NIH HHS NR 51 TC 3 Z9 4 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 JAN 15 PY 2007 VL 178 IS 2 BP 926 EP 935 PG 10 WC Immunology SC Immunology GA 123UB UT WOS:000243320400033 PM 17202354 ER PT J AU Yang, XH Hinnebusch, BJ Trunkle, T Bosio, CM Suo, ZY Tighe, M Harmsen, A Becker, T Crist, K Walters, N Avci, R Pascual, DW AF Yang, Xinghong Hinnebusch, B. Joseph Trunkle, Theresa Bosio, Catharine M. Suo, Zhiyong Tighe, Mike Harmsen, Ann Becker, Todd Crist, Kathryn Walters, Nancy Avci, Recep Pascual, David W. TI Oral vaccination with Salmonella simultaneously expressing Yersinia pestis F1 and V antigens protects against bubonic and pneumonic plague SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ENTERICA SEROVAR TYPHI; ENTEROTOXIGENIC ESCHERICHIA-COLI; MACROPHAGE-INDUCIBLE EXPRESSION; FLEA-BORNE PLAGUE; ATTENUATED SALMONELLA; IMMUNE-RESPONSES; CHROMOSOMAL INTEGRATION; MONOCLONAL-ANTIBODIES; TYPHIMURIUM VACCINE; CAPSULAR ANTIGEN AB The gut provides a large area for immunization enabling the development of mucosal and systemic Ab responses. To test whether the protective Ags to Yersinia pestis can be orally delivered, the Y. pestis caf1 operon, encoding the F1-Ag and virulence Ag (V-Ag) were cloned into attenuated Salmonella vaccine vectors. F1-Ag expression was controlled under a promoter from the caf1 operon; two different promoters (P), PtetA in pV3, PphoP in pV4, as well as a chimera of the two in pV55 were tested. F1-Ag was amply expressed; the chimera in the pV55 showed the best V-Ag expression. Oral immunization with Salmonella-F1 elicited elevated secretory (S)-IgA and serum IgG titers, and Salmonella-V-Ag(pV55) elicited much greater S-IgA and serum IgG Ab titers than Salmonella-V-Ag(pV3) or Salmonella-V-Ag(pV4). Hence, a new Salmonella vaccine, Salmonella-(F1+V)Ags, made with a single plasmid containing the caf1 operon and the chimeric promoter for V-Ag allowed the simultaneous expression of F1 capsule and V-Ag. Salmonella-(F1+V)Ags elicited elevated Ab titers similar to their monotypic derivatives. For bubonic plague, mice dosed with Salmonella-(F1+V)Ags and Salmonella-Fl-Ag showed similar efficacy (> 83% survival) against similar to 1000 LD50 Y. pestis. For pneumonic plague, immunized mice required immunity to both F1- and V-Ags because the mice vaccinated with Salmonella-(F1+V)Ags protected against 100 LD50 Y. pestis. These results show that a single Salmonella vaccine can deliver both F1- and V-Ags to effect both systemic and mucosal immune protection against Y. pestis. C1 Montana State Univ, Bozeman, MT 59717 USA. NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80521 USA. Montana State Univ, Dept Phys, Bozeman, MT 59717 USA. RP Pascual, DW (reprint author), Montana State Univ, POB 173610, Bozeman, MT 59717 USA. EM dpascual@montana.edu RI Yang, Xinghong/A-5473-2012; Bosio, Catharine/D-7456-2015 FU NCRR NIH HHS [P20 RR 020185]; NIAID NIH HHS [AI 56286, U54 AI 06537] NR 57 TC 62 Z9 65 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2007 VL 178 IS 2 BP 1059 EP 1067 PG 9 WC Immunology SC Immunology GA 123UB UT WOS:000243320400048 PM 17202369 ER PT J AU Saul, A AF Saul, Allan TI Malaria vaccines based on the Plasmodium falciparum merozoite surface protein 3 - Should we avoid amino acid sequence polymorphisms or embrace them? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID APICAL MEMBRANE ANTIGEN-1; GLUTAMATE-RICH PROTEIN; PROTECTION; ANTIBODIES; ASSOCIATION; IMMUNITY; MONKEYS; TRIAL C1 NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Saul, A (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, 5640 Fishers Ln,Twinbrook 1 Room 1113, Rockville, MD 20852 USA. EM asaul@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU Intramural NIH HHS NR 18 TC 7 Z9 7 U1 1 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 JAN 15 PY 2007 VL 195 IS 2 BP 171 EP 173 DI 10.1086/509813 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 122OW UT WOS:000243237300004 PM 17191161 ER PT J AU Scanga, CA Bafica, A Sher, A AF Scanga, Charles A. Bafica, Andre Sher, Alan TI Viral gene expression in HIV Transgenic mice is activated by Mycobacterium tuberculosis and suppressed after antimycobacterial chemotherapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Keystone Symposium on the Pathogen-Host Standoff - Persistent and Latent Infection CY MAR 25, 2004 CL Taos, NM ID IMMUNODEFICIENCY-VIRUS TYPE-1; NECROSIS-FACTOR-ALPHA; LONG TERMINAL REPEAT; TOLL-LIKE RECEPTOR-2; IMMUNE ACTIVATION; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; INFECTIOUS VIRUS; RHESUS-MONKEYS; MOUSE MODEL AB We used human immunodeficiency virus (HIV) transgenic (Tg) mice incorporating the entire viral genome to study the effect of Mycobacterium tuberculosis infection on the induction of integrated HIV gene expression. When aerogenically infected with M. tuberculosis, these mice displayed a progressive increase in pulmonary gag and env mRNA levels and of p24 antigen production by cultured splenocytes. In situ hybridization of lungs revealed increased viral transcription associated with areas of inflammation and acid-fast bacilli. By neutralizing tumor necrosis factor (TNF) in vivo after M. tuberculosis exposure, we found that, although initially TNF independent, the increased HIV expression triggered by M. tuberculosis was highly dependent on this cytokine by 4 weeks after infection. Furthermore, treatment with antimycobacterial drugs markedly reduced HIV transgene expression. These studies establish an animal model for investigating the influence of M. tuberculosis on latent HIV expression and for testing therapeutic regimens for reducing the disease burden in patients with acquired immunodeficiency syndrome-associated tuberculosis. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 50 South Dr,MSC 8003, Bethesda, MD 20892 USA. EM asher@niaid.nih.gov FU Intramural NIH HHS NR 51 TC 3 Z9 4 U1 0 U2 2 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 JAN 15 PY 2007 VL 195 IS 2 BP 246 EP 254 DI 10.1086/510244 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 122OW UT WOS:000243237300013 PM 17191170 ER PT J AU Clarimon, J Brancati, F Peckham, E Valente, EM Dallapiccola, B Abruzzese, G Girlanda, P Defazio, G Berardelli, A Hallett, M Singleton, AB AF Clarimon, Jordi Brancati, Francesco Peckham, Elizabeth Valente, Enza Maria Dallapiccola, Bruno Abruzzese, Giovanni Girlanda, Paolo Defazio, Giovanni Berardelli, Alfredo Hallett, Mark Singleton, Andrew B. TI Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm SO MOVEMENT DISORDERS LA English DT Article DE genetics; blepharospasm; DRD5; DYT1; association; case-control ID ONSET TORSION DYSTONIA; CERVICAL DYSTONIA; RECEPTOR DRD5; GENE; HAPLOTYPE; POLYMORPHISM; FAMILY AB Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYTI) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYTI as previously described in an Icelandic population. We have also found global significant DYTI haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia. (C) 2006 Movement Disorder Society. C1 NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Mendel Inst Med Genet & Twin Res, IRCCS, CSS, Rome, Italy. Univ G dAnnunzio, Dept Biomed Sci, Chieti, Italy. Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy. NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Genoa, Dept Neurosci Ophthalmol & Genet, Genoa, Italy. Univ Messina, Dept Neurosci Psychiat & Anesthesiol, Messina, Italy. Univ Bari, Dept Neurol & Psychiat Sci, Bari, Italy. Univ Roma La Sapienza, Dept Neurol Sci, Rome, Italy. Univ Roma La Sapienza, Inst NEUROMED IRCCS Pozzilli IS, Rome, Italy. Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. RP Clarimon, J (reprint author), Hosp Santa Creu & Sant Pau, Unidad Memoria, Lab Alzheimer, Neurol Serv, Sant Antoni Ma Claret 167, Barcelona 08025, Spain. EM jclarimon@santpau.es RI Singleton, Andrew/C-3010-2009; Dallapiccola, Bruno/K-8692-2016; OI Dallapiccola, Bruno/0000-0002-5031-1013; Clarimon, Jordi/0000-0002-6824-6942; GIRLANDA, Paolo/0000-0002-7152-2290 NR 17 TC 29 Z9 31 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JAN 15 PY 2007 VL 22 IS 2 BP 162 EP 166 DI 10.1002/mds.21182 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 132LR UT WOS:000243944800002 PM 17133500 ER PT J AU Bodurka, J Ye, F Petridou, N Murphy, K Bandettini, PA AF Bodurka, J. Ye, F. Petridou, N. Murphy, K. Bandettini, P. A. TI Mapping the MRI voxel volume in which thermal noise matches physiological noise-Implications for fMRI SO NEUROIMAGE LA English DT Article DE physiological noise; imaging volume; T-1; mapping; image segmentation; fMRI ID SIGNAL-TO-NOISE; HUMAN-BRAIN; DATA-ACQUISITION; FUNCTIONAL MRI; 3.0 TESLA; EPI; CORTEX; RATIO AB This work addresses the choice of the imaging voxel volume in blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Noise of physiological origin that is present in the voxel time course is a prohibitive factor in the detection of small activation-induced BOLD signal changes. If the physiological noise contribution dominates over the temporal fluctuation contribution in the imaging voxel, further increases in the voxel signal-to-noise ratio (SNR) will have diminished corresponding increases in temporal signal-to-noise (TSNR), resulting in reduced corresponding increases in the ability to detect activation induced signal changes. On the other hand, if the thermal and system noise dominate (suggesting a relatively low SNR) further decreases in SNR can prohibit detection of activation-induced signal changes. Here we have proposed and called the "suggested" voxel volume for fMRI the volume where thermal plus system-related and physiological noise variances are equal. Based on this condition we have created maps of fMRI suggested voxel volume from our experimental data at 3T, since this value will spatially vary depending on the contribution of physiologic noise in each voxel. Based on our fast EPI segmentation technique we have found that for gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF) brain compartments the mean suggested cubical voxel volume is: (1.8 mm)(3), (2.1 MM)(3) and (1.4 MM)(3), respectively. Serendipitously, (1.8 MM)3 cubical voxel volume for GM approximately matches the cortical thickness, thus optimizing BOLD contrast by minimizing partial volume averaging. The introduced suggested fMRI voxel volume can be a useful parameter for choice of imaging volume for functional studies. Published by Elsevier Inc. C1 NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. NIMH, Neurophysiol Imaging Facil, NIH, Bethesda, MD 20892 USA. NIMH, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. RP Bodurka, J (reprint author), NIMH, Funct MRI Facil, NIH, 10 Ctr Dr,Bldg 10,Room 1D80, Bethesda, MD 20892 USA. EM bodurkaj@mail.nih.gov RI Murphy, Kevin/A-1581-2010; Bandettini, Peter/F-5871-2012 OI Murphy, Kevin/0000-0002-6516-313X; FU Intramural NIH HHS [Z01 MH002783-05] NR 30 TC 76 Z9 77 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JAN 15 PY 2007 VL 34 IS 2 BP 542 EP 549 DI 10.1016/j.neuroimage.2006.09.039 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 117VJ UT WOS:000242901100006 PM 17101280 ER PT J AU Murphy, K Bodurka, J Bandettini, PA AF Murphy, Kevin Bodurka, Jerzy Bandettini, Peter A. TI How long to scan? The relationship between fMRI temporal signal to noise ratio and necessary scan duration SO NEUROIMAGE LA English DT Article ID EVENT-RELATED FMRI; HIGH-RESOLUTION FMRI; PHYSIOLOGICAL NOISE; SPATIAL EXTENT; OCULAR DOMINANCE; FUNCTIONAL MRI; BOLD RESPONSE; HUMAN BRAIN; ORIENTATION; ACTIVATION AB Recent advances in MRt receiver and coil technologies have significantly improved image signal-to-noise ratios (SNR) and thus temporal SNR (TSNR). These gains in SNR and TSNR have allowed the detection of fMRI signal changes at higher spatial resolution and therefore have increased the potential to localize small brain structures such as cortical layers and columns. The majority of current fMRI processing strategies employ multi-subject averaging and therefore require spatial smoothing and normalization, effectively negating these gains in spatial resolution higher than about 10 mm(3). Reliable detection of activation in single subjects at high resolution is becoming a more common desire among fMRI researchers who are interested in comparing individuals rather than populations. Since TSNR decreases with voxel volume, detection of activation at higher resolutions requires longer scan durations. The relationship between TSNR, voxel volume and delectability is highly non-linear. In this study, the relationship between TSNR and the necessary fMRI scan duration required to obtain significant results at varying P values is determined both experimentally and theoretically. The results demonstrate that, with a TSNR of 50, detection of activation of above 2% requires at most 350 scan volumes (when steps are taken to remove the influence of physiological noise from the data). Importantly, these results also demonstrate that, for activation magnitude on the order of 1%, the scan duration required is more sensitive to the TSNR level than at 2%. This study showed that with voxel volumes of similar to 10 mm(3) at 3 T, and a corresponding TSNR of similar to 50, the required number of time points that guarantees detection of signal changes of 1% is about 860, but if TSNR increases by only 20%, the time for detection decreases by more than 30%. More than just being an exercise in numbers, these results imply that imaging of columnar resolution (effect size = 1% and assuming a TR of I s) at 3 Twill require either 10 min for a TSNR of 60 or 40 min for a TSNR of 30. The implication is that at these resolutions, TSNR is likely to be critical for determining success or failure of an experiment. Published by Elsevier Inc. C1 NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, NIH, Bethesda, MD 20892 USA. NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Bandettini, PA (reprint author), NIMH, Lab Brain & Cognit, Sect Funct Imaging Methods, NIH, Bldg 10,Room 1D80B,10 Ctr Dr MSC 1148, Bethesda, MD 20892 USA. EM bandettimi@nih.gov RI Murphy, Kevin/A-1581-2010 OI Murphy, Kevin/0000-0002-6516-313X FU Intramural NIH HHS [Z01 MH002783-05] NR 40 TC 116 Z9 117 U1 0 U2 7 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 JAN 15 PY 2007 VL 34 IS 2 BP 565 EP 574 DI 10.1016/j.neuroimage.2006.09.032 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 117VJ UT WOS:000242901100008 PM 17126038 ER PT J AU Luo, Q Holroyd, T Jones, M Hendler, T Blair, J AF Luo, Qian Holroyd, Tom Jones, Matthew Hendler, Talma Blair, James TI Neural dynamics for facial threat processing as revealed by gamma band synchronization using MEG SO NEUROIMAGE LA English DT Article ID TASK-RELATED CHANGES; VISUAL-CORTEX; CORTICAL SYNCHRONIZATION; RIGHT AMYGDALA; BOLD RESPONSE; EXPRESSIONS; EMOTION; FEAR; RECOGNITION; FACES AB Facial threat conveys important information about imminent environmental danger. The rapid detection of this information is critical for survival and social interaction. However, due to technical and methodological difficulties, the spatiotemporal profile for facial threat processing is unknown. By utilizing magnetoencephalography (MEG), a brain-imaging technique with superb temporal resolution and fairly good spatial resolution, Synthetic Aperture Magnetometry (SAM), a recently developed source analysis technique, and a sliding window analysis, we identified the spatiotemporal development of facial threat processing in the gamma frequency band. We also tested the dual-route hypothesis by LeDoux who proposed, based on animal research, that there are two routes to the amygdala: a quick subcortical route and a slower and cortical route. Direct evidence with humans supporting this model has been lacking. Moreover, it has been unclear whether the subcortical route responds specifically to fearful expressions or to threatening expressions in general. We found early event-related synchronizations (ERS) in response to fearful faces in the hypothalamus/thalamus area (10-20 ms) and then the amygdala (2030 ms). This was even earlier than the ERS response seen to fearful faces in visual cortex (40-50 ms). These data support LeDoux's suggestion of a quick, subcortical thamalo-amygdala route. Moreover, this route was specific for fear expressions; the ERS response in the amygdala to angry expressions had a late onset (150-160 ms). The ERS onset in prefrontal cortex followed that seen within the amygdala (around 160-210 ms). This is consistent with its role in higher-level emotional/cognitive processing. C1 NIMH, Mood & Ansiety Disorders Program, NIH, Bethesda, MD 20892 USA. NIMH, MEG Core Facil, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. Tel Aviv Sourasky Med Ctr, Wohl Inst Adv Imaging, IL-64239 Tel Aviv, Israel. RP Luo, Q (reprint author), NIMH, Mood & Ansiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM luoj@mail.nih.gov RI hendler, talma/C-7677-2012 FU Intramural NIH HHS [Z99 MH999999] NR 60 TC 102 Z9 109 U1 1 U2 14 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 JAN 15 PY 2007 VL 34 IS 2 BP 839 EP 847 DI 10.1016/j.neuroimage.2006.09.023 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 117VJ UT WOS:000242901100031 PM 17095252 ER PT J AU Ramjanee, S Robertson, JS Franke-Fayard, B Sinha, R Waters, AP Janse, CJ Wu, Y Blagborough, AM Saul, A Sinden, RE AF Ramjanee, Souraya Robertson, James S. Franke-Fayard, Blandine Sinha, Ria Waters, Andrew P. Janse, Chris J. Wu, Yimin Blagborough, Andrew M. Saul, Allan Sinden, Robert E. TI The use of transgenic Plasmodium berghei expressing the Plasmodium vivax antigen P25 to determine the transmission-blocking activity of sera from malaria vaccine trials SO VACCINE LA English DT Article DE Plasmodium berghei; P. vivax; transgenic; Pvs25; transmission-blocking assay ID ANTIBODIES; MOSQUITO; GALLINACEUM; COMPLEMENT; FALCIPARUM; OOKINETE; IMMUNITY; SURFACE; PVS28; ASSAY AB P25 is a major surface protein of Plasmodium ookinetes. Antibodies against P25 prevent the formation of oocysts in the mosquito and thereby block transmission of the parasite through an endemic population. Plasmodium vivax transmission-blocking vaccines based on Pv25 have undergone human trials and inhibit transmission significantly. The current assay to determine transmission-blocking activity (TBA) of these sera, the 'standard membrane feeding assay', is complex and can be performed by few groups worldwide that require both mosquito breeding facilities and access to volunteers naturally infected with P.vivax-a costly, and uncontrolled source of parasites. Here we report the development of novel assays to determine TBA using two clones (Pv25DR and Pv25DR3) of transgenic rodent parasites (Plasmodium berghei) expressing Pv25. We show that oocyst development of the transgenic parasites is inhibited by monoclonal antibody against Pv25 with the same kinetics exhibited by wild type parasites when exposed to mouse monoclonal antibodies targeted to a paralogous protein P28. Human transmission-blocking sera from a clinical vaccine trial of Pv25 inhibited oocyst development of Pv25DR and Pv25DR3, whereas non-blocking sera did not. We further show transmission-blocking activity can be determined in a simple assays of ookinete development in vitro, assays that obviate the need for mosquito colonies. These results demonstrate that transgenic rodent malarias expressing proteins from human Plasmodium species can be cheap, safe, and simple tools for testing TBA from sera. To this end the cloned lines have been deposited with, and are freely available from, MR4. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, London SW7 2AZ, England. Leiden Univ, Med Ctr, Dept Parasitol, NL-9600 RC Leiden, Netherlands. NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Sinden, RE (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Cell & Mol Biol, Imperial Coll Rd, London SW7 2AZ, England. EM r.sinden@imperial.ac.uk RI Waters, Andy/C-9377-2009; Saul, Allan/I-6968-2013 OI Waters, Andy/0000-0001-8900-2982; Saul, Allan/0000-0003-0665-4091 FU Wellcome Trust NR 21 TC 30 Z9 31 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 15 PY 2007 VL 25 IS 5 BP 886 EP 894 DI 10.1016/j.vaccine.2006.09.035 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 133MF UT WOS:000244016300013 PM 17049690 ER PT J AU Honjo, Y Nagineni, CN Larsson, J Nandula, SR Hooks, JJ Chan, CC Karlsson, S Kulkarni, AB AF Honjo, Yasuyuki Nagineni, Chandrasekharam N. Larsson, Jonas Nandula, Seshagiri R. Hooks, John J. Chan, Chi-Chao Karlsson, Stefan Kulkarni, Ashok B. TI Neuron-specific TGF-beta signaling deficiency results in retinal detachment and cataracts in mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE TGF-beta receptor I; retinal detachment; extracellular matrix; chondroitin-6-sulfate; Cre-lox P system; cataracts; TGF-beta; retina; retinal pigment epithelium ID INTERPHOTORECEPTOR MATRIX; EXPRESSION; PROTEOGLYCANS; LENS; ADHESION; SULFATE AB We generated a mouse model (cKO) with a conditional deletion of TGF-beta signaling in the retinal neurons by crossing TGF-beta receptor I (TGF-beta RI) floxed mice with nestin-Cre mice. Almost all of the newborn cKO mice had retinal detachment at the retinal pigment epithelium (RPE)/photoreceptor layer junction of the neurosensory retina (NSR). The immunostaining for chondroitin-6-sulfate showed a very weak reaction in cKO mice in contrast to intense staining in the photoreceptor layer in wild-type mice. Macroscopic cataracts, in one or both eyes, were observed in 50% of the mice by 6 months of age, starting as early as the first month after birth. The cKO mouse model demonstrates that the TGF-beta signaling deficiency in retinal cells leads to decreased levels of chondroitin sulfate proteoglycan in the retinal interpho to receptor matrix. This in turn causes retinal detachment due to the loss of adhesion of the NSR to RPE. (c) 2006 Elsevier Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Lund Univ, Lund Strateg Ctr Stem Cell Biol & Cell Therapy, S-22100 Lund, Sweden. RP Kulkarni, AB (reprint author), Natl Inst Dent & Craniofacial Res, Funct Genom Sect, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. EM ak40m@nih.gov FU Intramural NIH HHS; NIDCR NIH HHS [Z01 DE000664-10] NR 24 TC 8 Z9 8 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 12 PY 2007 VL 352 IS 2 BP 418 EP 422 DI 10.1016/j.bbrc.2006.11.033 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 121ZU UT WOS:000243196300022 PM 17126294 ER PT J AU Trotman, LC Wang, XJ Alimonti, A Chen, ZB Teruya-Feldstein, J Yang, HJ Pavletich, NP Carver, BS Cordon-Cardo, C Erdjument-Bromage, H Tempst, P Chi, SG Kim, HJ Misteli, T Jiang, XJ Pandolfi, PP AF Trotman, Lloyd C. Wang, Xinjiang Alimonti, Andrea Chen, Zhenbang Teruya-Feldstein, Julie Yang, Haijuan Pavletich, Nikola P. Carver, Brett S. Cordon-Cardo, Carlos Erdjument-Bromage, Hediye Tempst, Paul Chi, Sung-Gil Kim, Hyo-Jong Misteli, Tom Jiang, Xuejun Pandolfi, Pier Paolo TI Ubiquitination regulates PTEN nuclear import and tumor suppression SO CELL LA English DT Article ID PTEN/MMAC1 GENE; PROSTATE-CANCER; COWDEN-DISEASE; P53; MUTATIONS; PATHWAY; IDENTIFICATION; EXPRESSION; SYSTEM; ROLES AB The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of IPTEN. C1 Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Pathol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Cell Biol Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Struct Biol Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Howard Hughes Med Inst, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Dept Urol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Program Mol Biol, New York, NY 10021 USA. Korea Univ, Sch Life Sci & Biotechnol, Seoul 136701, South Korea. Kyung Hee Univ, Sch Med, Seoul 130701, South Korea. NCI, NIH, Bethesda, MD 20892 USA. RP Pandolfi, PP (reprint author), Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, 1275 York Ave, New York, NY 10021 USA. EM p-pandolfi@ski.mskcc.org OI Tempst, Paul/0000-0002-6680-3987 FU Intramural NIH HHS; NCI NIH HHS [P30 CA008748, P30-CA-08748, R01 CA082328, R01 CA137050, R01-CA-82328] NR 43 TC 353 Z9 375 U1 1 U2 30 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 12 PY 2007 VL 128 IS 1 BP 141 EP 156 DI 10.1016/j.cell.2006.11.040 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 139GN UT WOS:000244420400019 PM 17218261 ER PT J AU Grant, BF Harford, TC Muthen, BO Yi, HY Hasin, DS Stinson, FS AF Grant, Bridget F. Harford, Thomas C. Muthen, Bengt O. Yi, Hsiao-Ye Hasin, Deborah S. Stinson, Frederick S. TI DSM-IV alcohol dependence and abuse: Further evidence of validity in the general population SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE DSM-IV; alcohol dependence; alcohol abuse; MIMIC model; validity ID HEALTH INTERVIEW SURVEY; NATIONAL EPIDEMIOLOGIC SURVEY; USE DISORDER CRITERIA; AUDADIS-ADR; MAJOR DEPRESSION; MENTAL-DISORDERS; SCHEDULE AUDADIS; UNITED-STATES; DRUG MODULES; SAMPLE AB Background: In order to understand the validity of the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) alcohol abuse and dependence diagnoses, studies are needed in both clinical and general population samples. The purpose of this study was to examine the construct and criterion-oriented validity of DSM-IV alcohol dependence and abuse in the general population with respect to factor structure and their relationship to family history of alcoholism, treatment utilization, and psychiatric comorbidity. Methods: This analysis is based on data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), in which nationally representative data were collected in personal interviews conducted with one randomly selected adult in each sample household or group quarters. A subset (n=26,946) of the NESARC sample (total n=43,093) who reported drinking one or more drinks during the year preceding the interview formed the basis of analyses. Latent variable modeling was used to assess the concurrent validity of DSM-IV alcohol abuse and dependence symptom items. Results: The latent variable modeling yielded one major factor related to alcohol dependence, a second factor related to alcohol abuse and a third smaller factor defined by tolerance. The validity of alcohol dependence in general population samples was further supported by statistically significant associations with family history of alcoholism, treatment utilization, and psychiatric and medical comorbidities. Conclusions: The factor structure and relationship to external criterion variables observed in the study provide support for the further validity of DSM-IV alcohol dependence in the general population, whereas support for the validity of DSM-IV abuse was equivocal. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA USA. Univ Calif Los Angeles, Grad Sch Educ & Informat, Los Angeles, CA USA. Columbia Univ, Dept Epidemiol, New York, NY USA. Columbia Univ, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Room 3077,MS 9304,5635 Fishers Lane, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov FU Intramural NIH HHS; NIAAA NIH HHS [N0AA32001, N01AA82014] NR 53 TC 80 Z9 80 U1 5 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 12 PY 2007 VL 86 IS 2-3 BP 154 EP 166 DI 10.1016/j.drugalcdep.2006.05.019 PG 13 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 129TU UT WOS:000243753800008 PM 16814489 ER PT J AU Ghitza, UE Rothman, RB Gorelick, DA Henningfield, JE Baumann, MH AF Ghitza, Udi E. Rothman, Richard B. Gorelick, David A. Henningfield, Jack E. Baumann, Michael H. TI Serotonergic responsiveness in human cocaine users SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE abstinence; cocaine; cortisol; fenfluramine; prolactin; serotonin ID D-FENFLURAMINE; NUCLEUS-ACCUMBENS; ADRENOCORTICOTROPIC HORMONE; NEUROENDOCRINE RESPONSES; PROLACTIN RESPONSES; INTRAVENOUS COCAINE; RETEST RELIABILITY; CORTISOL RESPONSES; MAJOR DEPRESSION; SMOKED COCAINE AB Background: Animal experiments show that repeated cocaine injections induce changes in brain serotonin (5-hydroxytryptamine, or 5-HT) function which can be detected by altered neuroendocrine responsiveness to serotonergic drug challenge. Studies of human cocaine users given a serotonergic challenge have produced inconsistent results. Methods: Hormone responses evoked by the 5-HT releaser D,L-fenflurainine (FEN) were examined in eight human cocaine users who resided on a closed research ward. FEN (60 rug oral) was given after a 7-day cocaine-free period and 3 days after a 5-day period of daily double-blind administration of intranasal cocaine (96 mg) and active placebo (4 mg cocaine). Plasma cortisol and prolactin levels were measured after FEN challenges, and after cocaine and placebo administration. Results: Cocaine significantly elevated plasma cortisol levels to a similar clearee, on the first and fifth days of administration, but did not alter prolactin levels on either day. The first FEN challenge significantly increased plasma prolactin and cortisol, whereas the second challenge increased only prolactin. Conclusions: Intranasal cocaine increases plasma cortisol without affecting prolactin, with no evidence for tolerance. The reduction in FEN-induced cortisol secretion after cocaine exposure suggests that deficits in 5-HT transmission during early cocaine abstinence might contribute to the maintenance of drug dependence. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NIDA, Clin Psychopharmacol Sect, Medicat Discovery Res Branch, IRP,NIH, Baltimore, MD 21224 USA. NIDA, Clin Psychopharmacol Sect, Clin Pharmacol & Therapeut Res Branch, IRP,NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Pinney Assoc, Baltimore, MD USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, Medicat Discovery Res Branch, IRP,NIH, 333 Cassell Dr,Triad Suite 4500, Baltimore, MD 21224 USA. EM mbaumann@intra.nida.nih.gov FU Intramural NIH HHS NR 56 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JAN 12 PY 2007 VL 86 IS 2-3 BP 207 EP 213 DI 10.1016/j.drugalcdep.2006.06.007 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 129TU UT WOS:000243753800014 PM 16930852 ER PT J AU Kitazawa, T Hashiba, K Cao, JS Unno, T Komori, S Yamada, M Wess, J Taneike, T AF Kitazawa, Takio Hashiba, Kano Cao, Jinshan Unno, Toshihiro Komori, Sei-ichi Yamada, Masahisa Wess, Jurgen Taneike, Tetsuro TI Functional roles of muscarinic M-2 and M-3 receptors in mouse stomach motility: Studies with muscarinic receptor knockout mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE muscarinic M-2 receptor; muscarinic M-3 receptor; knockout mouse; stomach; motility ID SMOOTH-MUSCLE; ACETYLCHOLINE-RECEPTORS; IN-VITRO; SUBTYPES; LACKING; CONTRACTIONS; FUNDUS; ILEUM; VIVO; RAT AB Functional roles of muscarinic acetylcholine receptors in the regulation of mouse stomach motility were examined using mice genetically lacking muscarinic M-2 receptor and/or M-3 receptor and their corresponding wild-type (WT) mice. Single application of carbachol (1 nM-30 mu M) produced concentration-dependent contraction in antral and fundus strips from muscarinic M-2 receptor knockout (M2R-KO) and M-3 receptor knockout (M3R-KO) mice but not in those from M-2 and M-3 receptors double knockout (M-2/M3R-KO) mice. A comparison of the concentration-response curves with those for WT mice showed a significant decrease in the negative logarithm of EC50 (pEC(50)) value (M2R-KO) or amplitude of maximum contraction M3R-KO in the muscarinic receptor-deficient mice. The tonic phase of carbachol-induced contraction was decreased in gastric strips from M3R-KO mice. Antagonistic affinity for 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) or 11-([2-[(diethylamino)methyl]-1-piperdinyl]acetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX116) indicated that the contractile responses in M2R-KO and M3R-KO mice were mediated by muscarinic M3 and M, receptors, respectively. Electrical field stimulation (EFS, 0.5-32 Hz) elicited frequency-dependent contraction in physostigmine- and N-omega-nitro-L-arginine methylester (L-NAME)-treated fundic and antral strips from M2R-KO and M3R-KO mice, but the cholinergic contractile components decreased significantly compared with those in WT mice. In gastric strips from M-2/M3R-KO mice, cholinergic contractions elicited by EFS were not observed but atropine-resistant contractions were more conspicuous than those in gastric strips from WT mice. Gastric emptying in WT mice and that in M-2/M3R-KO mice were comparable, suggesting that motor function of the stomach in the KO mice did not differ from that in the WT mice. The results indicate that both muscarinic M-2 and M-3 receptors but not other subtypes mediate carbachol- or EFS-induced contraction in the mouse stomach but that the contribution of each receptor to concentration-response relationships is distinguishable. Although there was impairment of nerve-mediated cholinergic responses in the stomach of KO mice, gastric emptying in KO mice was the same as that in WT mice probably due to the compensatory enhancement of the non-cholinergic contraction pathway. (c) 2006 Elsevier B.V. All rights reserved. C1 Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 069, Japan. Gifu Univ, Fac Appl Biol Sci, Pharmacol Lab, Gifu 5011193, Japan. RIKEN, Brain Sci Inst, Mol Neuropathol Grpo, Neurogenet Lab, Wako, Saitama 3510198, Japan. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Kitazawa, T (reprint author), Rakuno Gakuen Univ, Sch Vet Med, Dept Pharmacol, Ebetsu, Hokkaido 069, Japan. EM tko-kita@rakuno.ac.jp NR 28 TC 16 Z9 19 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 12 PY 2007 VL 554 IS 2-3 BP 212 EP 222 DI 10.1016/j.ejphar.2006.10.013 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 134HE UT WOS:000244073300018 PM 17113073 ER PT J AU Zhang, JH Wang, SB Kern, S Cui, XL Danner, RL AF Zhang, Jianhua Wang, Shuibang Kern, Steven Cui, Xiaolin Danner, Robert L. TI Nitric oxide down-regulates polo-like kinase 1 through a proximal promoter cell cycle gene homology region SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLO-LIKE KINASE; ACTIVATED-PROTEIN-KINASE; CANCER-CELLS; MITOSIS; PROLIFERATION; TRANSCRIPTION; REPRESSION; EXPRESSION; APOPTOSIS; DEPLETION AB Polo-like kinase 1 (PLK1) is an evolutionarily conserved serine/threonine kinase essential for cell mitosis. As a master cell cycle regulator, p21/Waf1 plays a critical role in cell cycle progression. Nitric oxide (NO center dot) has been shown to down-regulate PLK1 and up-regulate p21/Waf1 independent of cGMP. Here, the respective roles of p38 MAPK and p21/Waf1 in NO center dot-mediated PLK1 repression were investigated using differentiated U937 cells that lack soluble guanylate cyclase. NO center dot was shown to down-regulate both PLK1 mRNA and protein. Nuclear run-on assays and mRNA stability studies demonstrated that the effect of NO center dot on PLK1 expression was associated with decreased transcription without changes in transcript stability. SB202190, a p38 MAPK inhibitor, prevented transcriptional repression of PLK1 by NO center dot. Transfection with dominant-negative p38 MAPK mutant eliminated the NO center dot effect on both p21/Waf1 and PLK1 gene expression. Knockdown of p21/Waf1 with siRNA also substantially reduced the regulatory effect of NO center dot on PLK1. Reporter gene experiments showed that NO center dot decreased activity of the PLK1 proximal promoter, an effect that was blocked by p38 MAPK inhibitor. Deletion or mutation of the CDE/CHR promoter site, an element regulated by p21/Waf1, increased base-line promoter activity and abolished NO center dot repression of the PLK1 promoter. Likewise, electrophoretic mobility shift assays with CDE/CHR probe revealed a NO center dot-mediated change in protein-probe complex formation. Competition with various unlabeled CDE/CHR mutant sequences showed that NO center dot increased nuclear protein binding to intact CHR. These results demonstrate that a NO center dot-p38 MAPK-p21/Waf1 signal transduction pathway represses PLK1 through a canonical CDE/CHR promoter element. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Danner, RL (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM rdanner@nih.gov FU Intramural NIH HHS NR 40 TC 9 Z9 10 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 12 PY 2007 VL 282 IS 2 BP 1003 EP 1009 DI 10.1074/jbc.M607609200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 123KQ UT WOS:000243295200023 PM 17121839 ER PT J AU Nossal, NG Makhov, AM Chastain, PD Jones, CE Griffith, JD AF Nossal, Nancy G. Makhov, Alexander M. Chastain, Paul D., II Jones, Charles E. Griffith, Jack D. TI Architecture of the bacteriophage T4 replication complex revealed with nanoscale biopointers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HELICASE ASSEMBLY PROTEIN; STRAND DNA-SYNTHESIS; LEADING-STRAND; LOADING PROTEIN; RNA PRIMERS; POLYMERASE GP43; LOADER PROTEIN; FORK DNA; IN-VITRO; T4 AB Our previous electron microscopy of DNA replicated by the bacteriophage T4 proteins showed a single complex at the fork, thought to contain the leading and lagging strand proteins, as well as the protein-covered single-stranded DNA on the lagging strand folded into a compact structure. "Trombone" loops formed from nascent lagging strand fragments were present on a majority of the replicating molecules (Chastain, P., Makhov, A. M., Nossal, N. G., and Griffith, J. D. (2003) J. Biol. Chem. 278, 21276 - 21285). Here we probe the composition of this replication complex using nanoscale DNA biopointers to show the location of biotin-tagged replication proteins. We find that a large fraction of the molecules with a trombone loop had two pointers to polymerase, providing strong evidence that the leading and lagging strand polymerases are together in the replication complex. 6% of the molecules had two loops, and 31% of these had three pointers to biotin-tagged polymerase, suggesting that the two loops result from two fragments that are being extended simultaneously. Under fixation conditions that extend the lagging strand, occasional molecules show two nascent lagging strand fragments, each being elongated by a biotin-tagged polymerase. T4 41 helicase is present in the complex on a large fraction of actively replicating molecules but on a smaller fraction of molecules with a stalled polymerase. Unexpectedly, we found that 59 helicase-loading protein remains on the fork after loading the helicase and is present on molecules with extensive replication. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Griffith, JD (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, Mason Farm Rd, Chapel Hill, NC 27599 USA. EM jdg@med.unc.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM31819] NR 47 TC 39 Z9 39 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 12 PY 2007 VL 282 IS 2 BP 1098 EP 1108 DI 10.1074/jbc.M606772200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 123KQ UT WOS:000243295200034 PM 17105722 ER PT J AU Govind, CK Zhang, F Qiu, HF Hofmeyer, K Hinnebusch, AG AF Govind, Chhabi K. Zhang, Fan Qiu, Hongfang Hofmeyer, Kimberly Hinnebusch, Alan G. TI Gcn5 promotes acetylation, eviction, and methylation of nucleosomes in transcribed coding regions SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTIONAL ACTIVATOR GCN4P; GLOBAL HISTONE ACETYLATION; TATA-BINDING-PROTEIN; IN-VIVO TARGET; SACCHAROMYCES-CEREVISIAE; ACETYLTRANSFERASE COMPLEX; GENE-EXPRESSION; PHO5 PROMOTER; SRB MEDIATOR AB We report that coactivator SAGA, containing the HAT Gcn5p, occupies the GAL land ARG1 coding sequences during transcriptional induction, dependent on PIC assembly and Ser5 phosphorylation of the Pol II CTD. Induction of GAL1 increases H3 acetylation per nucleosome in the ORF, dependent on SAGA integrity but not the alternative Gcn5p-HAT complex ADA. Unexpectedly, H3 acetylation in ARG1 coding sequences does not increase during induction due to the opposing activities of multiple HDAs associated with the ORE Remarkably, inactivation of Gcn5p decreases nucleosome eviction from both GAL1 and a long (similar to 8 kb) ORF transcribed from the GAL1 promoter. This is associated with reduced Pol II occupancy at the 3' end and decreased mRNA production, selectively, for the long ORF. Gcn5p also enhances H3-K4 trimethylation in the ARG1 ORF and bulk histones. Thus, Gcn5p, most likely in SAGA, stimulates modification and eviction of nucleosomes in transcribed coding sequences and promotes Pol II elongation. C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU Intramural NIH HHS NR 55 TC 146 Z9 147 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 12 PY 2007 VL 25 IS 1 BP 31 EP 42 DI 10.1016/j.molcel.2006.11.020 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 127DY UT WOS:000243566700003 PM 17218269 ER PT J AU Geng, Y Lee, YM Welcker, M Swanger, J Zagozdzon, A Winer, JD Roberts, JM Kaldis, P Clurman, BE Sicinski, P AF Geng, Yan Lee, Young-Mi Welcker, Markus Swanger, Jherek Zagozdzon, Agnieszka Winer, Joel D. Roberts, James M. Kaldis, Philipp Clurman, Bruce E. Sicinski, Piotr TI Kinase-independent function of cyclin E SO MOLECULAR CELL LA English DT Article ID DNA-REPLICATION; S-PHASE; HUMAN-CELLS; PREREPLICATION COMPLEX; G1 CYCLIN; CDK2; CDC6; ACTIVATION; CHROMATIN; E-CDK2 AB E-type cyclins are thought to drive cell-cycle progression by activating cyclin-dependent kinases, primarily CDK2. We previously found that cyclin E-null cells failed to incorporate MCM helicase into DNA prereplication complex during G(0) -> S phase progression. We now report that a kinase-deficient cyclin E mutant can partially restore MCM loading and S phase entry in cyclin E-null cells. We found that cyclin E is loaded onto chromatin during G(0) -> S progression. In the absence of cyclin E, CDT1 is normally loaded onto chromatin, whereas MCM is not, indicating that cyclin E acts between CDT1 and MCM loading. We observed a physical association of cyclin E with CDT1 and with MCMs. We propose that cyclin E facilitates MCM loading in a kinase-independent fashion, through physical interaction with CDT1 and MCM. Our work indicates that-in addition to their function as CDK activators-E cyclins play kinase-independent functions in cell-cycle progression. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Howard Hughes Med Inst, Seattle, WA 98109 USA. Harvard Univ, Sch Med, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Clurman, BE (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. EM bclurman@fhcrc.org; peter_sicinski@dfci.harvard.edu RI Kaldis, Philipp/G-2714-2010 OI Kaldis, Philipp/0000-0002-7247-7591 FU NCI NIH HHS [CA102742, CA108950, CA84069] NR 45 TC 114 Z9 116 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 12 PY 2007 VL 25 IS 1 BP 127 EP 139 DI 10.1016/j.molcel.2006.11.029 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 127DY UT WOS:000243566700010 PM 17218276 ER PT J AU Scroggins, BT Robzyk, K Wang, DX Marcu, MG Tsutsumi, S Beebe, K Cotter, RJ Felts, S Toft, D Karnitz, L Rosen, N Neckers, L AF Scroggins, Bradley T. Robzyk, Kenneth Wang, Dongxia Marcu, Monica G. Tsutsumi, Shinji Beebe, Kristin Cotter, Robert J. Felts, Sara Toft, David Karnitz, Larry Rosen, Neal Neckers, Len TI An acetylation site in the middle domain of Hsp90 regulates chaperone function SO MOLECULAR CELL LA English DT Article ID HEAT-SHOCK-PROTEIN; HISTONE DEACETYLASE INHIBITORS; GLUCOCORTICOID-RECEPTOR; HETEROPROTEIN COMPLEX; STEROID-RECEPTOR; TERMINAL DOMAIN; CANCER CELLS; YEAST; EXPRESSION; KINASE AB Heat-shock protein 90 (Hsp90) chaperones a key subset of signaling proteins and is necessary for malignant transformation. Hsp90 is subject to an array of posttranslational modifications that affect its function, including acetylation. Histone deacetylase (HDAC) inhibitors and knockdown of HDAC6 induce Hsp90 acetylation and inhibit its activity. However, direct determination of the functional consequences of Hsp90 acetylation has awaited mapping of specific sites. We now demonstrate that Hsp90 K294 is acetylated. Mutational analysis of K294 shows that its acetylation status is a strong determinant of client protein and cochaperone binding. In yeast, Hsp90 mutants that cannot be acetylated at K294 have reduced viability and chaperone function compared to WT or to mutants that mimic constitutive acetylation. These data suggest that acetylation/deacetylation of K294 plays an important role in regulating the Hsp90 chaperone cycle. C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY 10021 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Mayo Clin, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. EM len@helix.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 SC010074-10] NR 36 TC 224 Z9 238 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JAN 12 PY 2007 VL 25 IS 1 BP 151 EP 159 DI 10.1016/j.molcel.2006.12.008 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 127DY UT WOS:000243566700012 PM 17218278 ER PT J AU Duran, AS Losso, MH Salomon, H Harris, DR Pampuro, S Soto-Ramirez, LE Duarte, G de Souza, RS Read, JS AF Duran, Adriana S. Losso, Marcelo H. Salomon, Horacio Harris, D. Robert Pampuro, Sandra Soto-Ramirez, Luis E. Duarte, Geraldo de Souza, Ricardo S. Read, Jennifer S. CA NISDI Study Grp TI Drug resistance among HIV-infected pregnant women receiving antiretrovirals for prophylaxis SO AIDS LA English DT Article DE mother-to-child transmission; antiretroviral drug resistance; HIV-1 mutations; HIV-1 and pregnancy ID TO-CHILD TRANSMISSION; IMMUNODEFICIENCY-VIRUS TYPE-1; MATERNAL-INFANT TRANSMISSION; ZIDOVUDINE TREATMENT; COMBINATION; PREVENTION; LAMIVUDINE; THERAPY AB Objective: To quantify primary resistance mutations (PRMs) among HIV-1-infected women receiving antiretroviral therapy (ART) for prevention of mother-to-child transmission (MTCT). Methods: Peripheral blood mononuclear cell samples from HIV-1-infected women enrolled in a prospective cohort study in Argentina, the Bahamas, Brazil, and Mexico (NISDI Perinatal Study) were assayed for PRMs. Eligible women were those enrolled by March 2005 and diagnosed with HIV-1 infection during the current pregnancy, and who received ART for MTCT prophylaxis and were followed for 6-12 weeks postpartum. Results: Of 819 women, 198 met the eligibility criteria. At enrollment, 98% were asymptomatic, 62% had plasma viral load < 1000copies/ml, 53% had CD4+ cell count >= 500 cells/mu l, and 78% were ART-exposed (mean duration, 8.0 weeks; 95% confidence interval, 7.1-8.9). The most complex ART regimen during pregnancy was usually (81%) a three-drug regimen [two nucleoside reverse transcriptase inhibitors (NRTIs) + one protease inhibitor or two NRTIs + one non-nucleoside reverse transcriptase inhibitor). PRMs were observed in samples from 19 (16%) of 118 women that were amplifiable at one or both time points [11/76 (14%) at enrollment; 14/97 (14%) at 6-12 weeks]. The occurrence of PRMs was not associated with clinical, immunological, or virological disease stage at either time point, whether ART-naive versus exposed at enrollment, or the most complex or number of antiretroviral drug regimens received during pregnancy (P > 0.1). Of 55 women with amplifiable samples at both time points, PRMs were detected in I I samples (20%). Conclusions: PRMs occurred among 16.1% of relatively healthy HIV-1-infected mothers from Latin American and Caribbean countries receiving MTCT prophylaxis. (c) 2007 Lippincott Williams & Wilkins. C1 Hosp JM Ramos Mejia, Serv Inmunocomprometidos, Buenos Aires, DF, Argentina. Univ Buenos Aires, Sch Med, Dept Microbiol, Natl Reference Ctr AIDS, Buenos Aires, DF, Argentina. Westat Corp, Rockville, MD USA. Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Infect Dis, Mexico City, DF, Mexico. Univ Sao Paulo, BR-14049 Ribeirao Preto, Brazil. Univ Caxias do Sul, Lab Perquisa HIV AIDS, Caxias do Sul, Brazil. NICHD, CRMC, Pediat Adolescent & maternal AIDS Branch, Bethesda, MD USA. RP Duran, AS (reprint author), Hosp JM Ramos Mejia, Serv Inmunocomprometidos, Urquiza 609, Buenos Aires, DF, Argentina. EM aduran@hivramos.org.ar RI Mussi-Pinhata, Marisa/G-6568-2012; Duarte, Geraldo/J-7906-2012 FU NICHD NIH HHS [N01-HD-3-3345] NR 19 TC 18 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 11 PY 2007 VL 21 IS 2 BP 199 EP 205 DI 10.1097/QAD.0b013e328011770b PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 127FQ UT WOS:000243571100010 PM 17197811 ER PT J AU Chaturvedi, AK Pfeiffer, RM Chang, L Goedert, JJ Biggar, RJ Engels, EA AF Chaturvedi, Anil K. Pfeiffer, Ruth M. Chang, Leonard Goedert, James J. Biggar, Robert J. Engels, Eric A. TI Elevated risk of lung cancer among people with AIDS SO AIDS LA English DT Article DE HIV/AIDS; immunosuppression; CD4; lung cancer; smoking; epidemiology ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; UNITED-STATES; HIV; SMOKING; COHORT; INFECTION; EMPHYSEMA; WOMEN; ERA AB Background and objectives: Lung cancer is a common malignancy among people with AIDS (PWA). Lung cancer risk was compared between PWA and the general population and its relationship with immunosuppression was assessed. The likelihood that excess risk is explained by a high prevalence of smoking was also investigated. Methods: Records on adolescent and adult PWA (N=397927) were linked with cancer registries in 11 US regions. Cancer risk was assessed for the period 60 months before to 60 months after AIDS onset, with specific emphasis on the period 4-27 months after onset. Observed incidence was compared with general population rates and rates from a lung cancer prediction model for smokers. Results: Compared with the general population, lung cancer risk among PWA was elevated overall [n = 1489 cases; standardized incidence ratio (SIR), 3.8; 95% confidence interval (CI), 3.6-4.1] and in the 4-27 months afterAIDS (n = 393 cases; SIR, 2.9; 95% Cl, 2.6-3.2). In the 4-27 months after AIDS, risk was significantly elevated for all demographic subgroups, and was especially high among young PWA (SIRs for ages 1529 years, 10.4; 30-39 years, 6.3; 40-49 years, 3.7). Lung cancers generally presented at an advanced stage. Risk was not associated with CD4 cell counts at AIDS (P-trend = 0.36). Under plausible smoking assumptions, observed incidence was significantly higher than predicted among 40-49 and 50-59-year-old men with AIDS (observed/predicted =5.03 and 1.43, respectively) and 40-49-year-old women with AIDS (observed/predicted = 1.88), but not among older PWA. Conclusion: Lung cancer risk was substantially elevated among PWA. Smoking could not entirely account for the observed elevation, especially among younger adults, suggesting a role for additional co-factors. (c) 2007 Lippincott Williams & Wilkins. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Chaturvedi, AK (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7072, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov RI Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural NIH HHS NR 27 TC 98 Z9 100 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 11 PY 2007 VL 21 IS 2 BP 207 EP 213 DI 10.1097/QAD.0b013e3280118fca PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 127FQ UT WOS:000243571100011 PM 17197812 ER PT J AU Welzel, TM Gao, XJ Pfeiffer, RM Martin, MP O'Brien, SJ Goedert, JJ Carrington, M O'Brien, TR AF Welzel, Tania M. Gao, Xiaojiang Pfeiffer, Ruth M. Martin, Maureen P. O'Brien, Stephen J. Goedert, James J. Carrington, Mary O'Brien, Thomas R. TI HLA-B Bw4 alleles and HIV-1 transmission in heterosexual couples SO AIDS LA English DT Article DE AIDS; Bw4; ethnicity; HIV-1; human leukocyte antigen; infectivity; sexual transmission ID IMMUNODEFICIENCY-VIRUS TYPE-1; TRANSFUSION RECIPIENTS; HLA-B; AIDS; INFECTION; HEMOPHILIA AB Background: Genetic factors may play a role in the transmission of HIV-1. Because HLA-B alleles influence HIV-1 disease progression and viral levels, they might also influence HIV-1 transmission. Objective: To investigate if the presence of HLA-B alleles with the Bw4 epitope in HIV-1-infected men decreased the risk of transmission to their female sex partners. Methods: The study comprised 304 HIV-1-infected men with hemophilia and 325 female sex partners. HLA class I genes were amplified using sequence-specific primers. Products of the polymerase chain reaction were blotted on nylon membranes and hybridized with sequence-specific oligonucleoticle probes. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for HIV-1 infection among the women. Results: Among the 325 women, 44 (13.5%) were infected with HIV-1. HIV-1 infection in the women was associated with the HLA-B genotype of their male partner [Bw6/Bw6, 22/118 (18.6%); Bw4/Bw6, 18/154 (11.7%); Bw4/Bw4, 4/53 (7.6%)]. Compared with men who were homozygous for Bw6, men who carried Bw4 were about half as likely to have transmitted HIV-1 to their female partner (OR, 0.52; 95% Cl, 0.27-0.98; P=0.04). Transmission was higher among couples in which the man's ethnicity was other than White (OR, 2.60; 95% Cl, 1.25-5.40; P=0.01), but the association between HIV-1 transmission and HLA-B genotype was not confounded by race. Conclusion: The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission, which suggests that these alleles reduce infectivity for HIV-1. (c) 2007 Lippincott Williams & Wilkins. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Lab Genom Divers, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, EPS 7082,MSC 7234,6120 Execut Blvd, Bethesda, MD 20892 USA. EM obrient@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 16 TC 17 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 11 PY 2007 VL 21 IS 2 BP 225 EP 229 DI 10.1097/QAD.0b013e3280123840 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 127FQ UT WOS:000243571100013 PM 17197814 ER PT J AU Hassan, SA AF Hassan, Sergio A. TI Liquid-structure forces and electrostatic modulation of biomolecular interactions in solution SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Review ID SOLVENT-INDUCED FORCES; MOLECULAR-DYNAMICS SIMULATIONS; PROTEIN-FOLDING THERMODYNAMICS; SCREENED COULOMB POTENTIALS; SIDE-CHAIN INTERACTIONS; AQUEOUS IONIC-SOLUTIONS; FREE-ENERGY DIFFERENCES; SCALED PARTICLE THEORY; DIELECTRIC-CONSTANT; POLAR LIQUIDS AB Molecular interactions in solution are controlled by the bulk medium and by the forces originating in the structured region of the solvent close to the solutes. In this paper, a model of electrostatic and liquid-structure forces for dynamics simulations of biomolecules is presented. The model introduces information on the microscopic nature of the liquid in the vicinity of polar and charged groups and the associated non-pairwise character of the forces, thus improving upon conventional continuum representations. The solvent is treated as a polar and polarizable medium, with dielectric properties described by an inhomogeneous version of the Onsager theory. This treatment leads to an effective position-dependent dielectric permittivity that incorporates saturation effects of the electric field and the spatial variation of the liquid density. The non-pairwise additivity of the liquid-structure forces is represented by centers of force located at specific points in the liquid phase. These out-of-the-solute centers are positioned at the peaks of liquid density and exert local, external forces on the atoms of the solute. The density is calculated from a barometric law, using a Lennard-Jones-type solute-liquid effective interaction potential. The conceptual aspects of the model and its exact numerical solutions are discussed for single alkali and halide ions and for ion-pair interactions. The practical aspects of the model and the simplifications introduced for efficient computation of forces in molecular solutes are discussed in the context of polar and charged amino acid dimers. The model reproduces the contact and solvent-separated minima and the desolvation barriers of intermolecular potentials of mean force of amino acid dimers, as observed in atomistic dynamics simulations. Possible refinements based on an improved treatment of molecular correlations are discussed. C1 NIH, Ctr Mol Modeling, DCB, CIT,US DHHS, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, Ctr Mol Modeling, DCB, CIT,US DHHS, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CT999999] NR 121 TC 22 Z9 23 U1 1 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD JAN 11 PY 2007 VL 111 IS 1 BP 227 EP 241 DI 10.1021/jp0647479 PG 15 WC Chemistry, Physical SC Chemistry GA 122LV UT WOS:000243229400027 PM 17201447 ER PT J AU Drazen, JM Zarin, DA AF Drazen, Jeffrey M. Zarin, Deborah A. TI Salvation by registration SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIH, ClinicalTrials Gov, Natl Lib Med, Bethesda, MD 20892 USA. RP Zarin, DA (reprint author), NIH, ClinicalTrials Gov, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. OI Drazen, Jeffrey/0000-0003-2715-9890 NR 3 TC 15 Z9 15 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 11 PY 2007 VL 356 IS 2 BP 184 EP 185 DI 10.1056/NEJMe068291 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 124NE UT WOS:000243373700013 PM 17215537 ER PT J AU Hohmann, CF Crawley, JN AF Hohmann, Christine F. Crawley, Jacque N. TI Special issue: Animal models for autism - Foreword SO BEHAVIOURAL BRAIN RESEARCH LA English DT Editorial Material C1 Morgan State Univ, Baltimore, MD 21251 USA. NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Hohmann, CF (reprint author), Morgan State Univ, Cold Spring Ln & Hillen Rd, Baltimore, MD 21251 USA. EM chohmann@morgan.edu; crawleyj@intra.nimh.nih.gov 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 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 10 PY 2007 VL 176 IS 1 BP 1 EP 3 DI 10.1016/j.bbr.2006.10.010 PG 3 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 125QK UT WOS:000243456800001 ER PT J AU Moy, SS Nadler, JJ Young, NB Perez, A Holloway, LP Barbaro, RP Barbaro, JR Wilson, LM Threadgill, DW Lauder, JM Magnuson, TR Crawley, JN AF Moy, Sheryl S. Nadler, Jessica J. Young, Nancy B. Perez, Antonio Holloway, L. Paige Barbaro, Ryan P. Barbaro, Justin R. Wilson, Lindsay M. Threadgill, David W. Lauder, Jean M. Magnuson, Terry R. Crawley, Jacqueline N. TI Mouse behavioral tasks relevant to autism: Phenotypes of 10 inbred strains SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the International-Behavioral-Neuroscience-Society CY MAR, 2005 CL Santa Fe, MEXICO SP Int Behav Neurosci Soc DE autism; locomotion; sociability; social preference; social approach; T-maze; Morris water mazes; reversal tasks ID ANXIETY-RELATED BEHAVIORS; QUANTITATIVE TRAIT LOCI; FRAGILE-X-SYNDROME; DOPAMINE-RECEPTOR MEDIATION; CORPUS-CALLOSUM; RETT-SYNDROME; MICE LACKING; GENETIC-ANALYSIS; KNOCKOUT MICE; EMOTIONAL REACTIVITY AB Three defining clinical symptoms of autism are aberrant reciprocal social interactions, deficits in social communication, and repetitive behaviors, including motor stereotypies and insistence on sameness. We developed a set of behavioral tasks designed to model components of these core symptoms in mice. Male mice from 10 inbred strains were characterized in assays for sociability, preference for social novelty, and reversal of the spatial location of the reinforcer in T-maze and Morris water maze tasks. Six strains, C57BL/6J, C57L/J, DBA/2J, FVB/NJ, C3H/HeJ, and AKR/J, showed significant levels of sociability, while A/J, BALB/cByJ, BTBR T(+)tflJ, and 129S1/SvImJ mice did not. C57BL/6J, C57L/J, DBA/2J, FVB/NJ, BALB/cByJ, and BTBR T(+)tflJ showed significant preference for social novelty, while C3H/HeJ, AKR/J, A/J, and 129S1/SvImJ did not. Normal scores on relevant control measures confirmed general health and physical abilities in all strains, ruling out artifactual explanations for social deficits. Elevated plus maze scores confirmed high anxiety-like behaviors in A/J, BALB/cByJ, and 129S1/SvImJ, which could underlie components of their low social approach. Strains that showed high levels of performance on acquisition of a T-maze task were also able to reach criterion for reversal learning. On the Morris water maze task, DBA/2J, AKR/J, BTBR T(+)tflJ, and 129S1/SvImJ failed to show significant quadrant preference during the reversal probe trial. These results highlight a dissociation between social task performance and reversal learning. BTBR T(+)tflJ is a particularly interesting strain, displaying both low social approach and resistance to change in routine on the water maze, consistent with an autism-like phenotype. Our multitask strategy for modeling symptoms of autism will be useful for investigating targeted and random gene mutations, QTLs, and microarray analyses. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ N Carolina, Neurodev Disorders Res Ctr, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Psychiat, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell & Dev Biol, Sch Med, Chapel Hill, NC 27599 USA. Univ N Carolina, N Carolina STAART Ctr Autism Res, Sch Med, Chapel Hill, NC 27599 USA. NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20893 USA. RP Moy, SS (reprint author), Univ N Carolina, Neurodev Disorders Res Ctr, Sch Med, CB 7146, Chapel Hill, NC 27599 USA. EM ssmoy@med.unc.edu RI Threadgill, David/N-4425-2013 OI Threadgill, David/0000-0003-3538-1635 FU Intramural NIH HHS; NICHD NIH HHS [P30 HD03110, P30 HD003110]; NIMH NIH HHS [U54 MH066418, U54 MH66418] NR 131 TC 358 Z9 364 U1 19 U2 50 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 10 PY 2007 VL 176 IS 1 BP 4 EP 20 DI 10.1016/j.bbr.2006.07.030 PG 17 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 125QK UT WOS:000243456800002 PM 16971002 ER PT J AU Ricceri, L Moles, A Crawley, J AF Ricceri, Laura Moles, Anna Crawley, Jacqueline TI Behavioral phenotyping of mouse models of neurodevelopmental disorders: Relevant social behavior patterns across the life span SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the International-Behavioral-Neuroscience-Society CY JUN, 2005 CL Santa Fe, NM SP Int Behav Neurosci Soc DE ultrasonic vocalizations; maternal potentiation; homing; ontogeny of agonistic behavior; social interactions ID MICE MUS-MUSCULUS; ESTROGEN-RECEPTOR-ALPHA; RAT RATTUS-NORVEGICUS; AUTISM SPECTRUM DISORDERS; ANXIETY-LIKE BEHAVIOR; FEMALE HOUSE MICE; BETA-ERKO MALE; ULTRASONIC VOCALIZATIONS; DOWN-SYNDROME; AGGRESSIVE-BEHAVIOR AB Social responses are a key element for behavioral phenotyping of mouse models of neurodevelopmental disorders associated with social deficits. Here we describe selected behavioral responses that can be measured in developing and adult mice, with special emphasis on ultrasonic vocalizations, a behavioral response not yet systematically characterized in most of the genetic mouse models of social abnormalities. A recently developed task to measure social approach relevant to the first core symptom of autism is highlighted. We also focus on those developmental factors, including litter size, litter composition, and early social milieu, that are often underestimated when measuring adult social behavior in mouse models of neurodevelopmental disorders. We present a summary of available data concerning social behavioral responses in mice with targeted gene mutations. We conclude by suggesting that assessment of early behavioral traits, and corresponding relationships with adult behavioral profiles, could be a useful strategy to investigate mouse models of neurodevelopmental disorders associated with social deficits. Published by Elsevier B.V. C1 Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, I-00161 Rome, Italy. CNR, CERC, Inst Neurosci, I-00143 Rome, Italy. NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Ricceri, L (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM laura.ricceri@iss.it OI Moles, Anna/0000-0002-5805-5763; Ricceri, Laura/0000-0001-9850-2284 NR 179 TC 47 Z9 47 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 10 PY 2007 VL 176 IS 1 BP 40 EP 52 DI 10.1016/j.bbr.2006.08.024 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 125QK UT WOS:000243456800005 PM 16996147 ER PT J AU Low, NCP Hardy, J AF Low, Nancy C. P. Hardy, John TI Psychiatric disorder criteria and their application to research in different racial groups SO BMC PSYCHIATRY LA English DT Letter ID AFRICAN-AMERICAN FAMILY; ETHNIC-DIFFERENCES; DISEASE AB Background: The advent of standardized classification and assessment of psychiatric disorders, and considerable joint efforts among many countries has led to the reporting of international rates of psychiatric disorders, and inevitably, their comparison between different racial groups. Results: In neurologic diseases with defined genetic etiologies, the same genetic cause has different phenotypes in different racial groups. Conclusion: We suggest that genetic differences between races mean that diagnostic criteria refined in one racial group, may not be directly and simply applicable to other racial groups and thus more effort needs to be expended on defining diseases in other groups. Cross-racial confounds (in addition to cultural confounds) make the interpretation of rates in different groups even more hazardous than seems to have been appreciated. C1 NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. NIMH, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, Intramural Res Program, Porter Neurosci Bldg,NIH Main Campus, Bethesda, MD 20892 USA. EM lown@mail.nih.gov; hardyj@mail.nih.gov RI Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 16 TC 1 Z9 1 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-244X J9 BMC PSYCHIATRY JI BMC Psychiatry PD JAN 10 PY 2007 VL 7 AR 1 DI 10.1186/1471-244X-7-1 PG 3 WC Psychiatry SC Psychiatry GA 174AW UT WOS:000246914600001 PM 17214899 ER PT J AU Weber, HA Hodges, AE Guthrie, JR O'Brien, BM Robaugh, D Clark, AP Harris, RK Algaier, JW Smith, CS AF Weber, Holly A. Hodges, Andrew E. Guthrie, Jill R. O'Brien, Brandon M. Robaugh, David Clark, Alice P. Harris, Roger K. Algaier, Joseph W. Smith, Cynthia S. TI Comparison of proanthocyanidins in commercial antioxidants: Grape seed and pine bark extracts SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE grape seed extract; pine bark extract; proanthocyanidin; catechin; epicatechin; HPLC; LC/MS; GC/MS; GPC; MALDI-TOF MS ID PROCYANIDIN-RICH EXTRACT; FLIGHT MASS-SPECTROMETRY; VITIS-VINIFERA; PYCNOGENOL; CELLS; RATS; POLYMERIZATION; CHROMATOGRAPHY; POLYPHENOLS; INHIBITION AB The major constituents in grape seed and pine bark extracts are proanthocyanidins. To evaluate material available to consumers, select lots were analyzed using high-performance liquid chromatography, gas chromatography/mass spectrometry (GC/MS), liquid chromatography/mass spectrometry (LC/MS), gel permeation chromatography (GPC), and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Atmospheric pressure chemical ionization (APCI) LC/MS was used to identify monomers, dimers, and trimers present. GC/MS analyses led to the identification of ethyl esters of hexadecanoic acid, linoleic acid, and oleic acid, as well as smaller phenolic and terpene components. The GPC molecular weight (MW) distribution indicated components ranging from similar to 162 to similar to 5500 MW (pine bark less than 1180 MW and grape seed similar to 1180 to similar to 5000 MW). MALDI-TOF MS analyses showed that pine bark did not contain oligomers with odd numbers of gallate units and grape seed contained oligomers with both odd and even numbers of gallate. Reflectron MALDI-TOF MS identified oligomers up to a pentamer and heptamer, and linear MALDI-TOF MS showed a mass range nearly double that of reflectron analyses. C1 Midwest Res Inst, Kansas City, MO 64110 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Algaier, JW (reprint author), Midwest Res Inst, 425 Volker Blvd, Kansas City, MO 64110 USA. EM jalgaier@mriresearch.org FU NIEHS NIH HHS [N01-ES-05457] NR 45 TC 74 Z9 75 U1 0 U2 33 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD JAN 10 PY 2007 VL 55 IS 1 BP 148 EP 156 DI 10.1021/jf063150n PG 9 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 121ZH UT WOS:000243195000020 PM 17199326 ER PT J AU Hofer, T Tangkeangsirisin, W Kennedy, MG Mage, RG Raiker, SJ Venkatesh, K Lee, H Giger, RJ Rader, C AF Hofer, Thomas Tangkeangsirisin, Wisit Kennedy, Michael G. Mage, Rose G. Raiker, Stephen J. Venkatesh, Karthik Lee, Hakjoo Giger, Roman J. Rader, Christoph TI Chimeric rabbit/human Fab and IgG specific for members of the Nogo-66 receptor family selected for species cross-reactivity with an improved phage display vector SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE rabbit monoclonal antibodies; b9 allotype; phage display; nogo-66 receptor family; RTN4R; RTN4RL2 ID COMBINATORIAL ANTIBODY LIBRARIES; MONOCLONAL-ANTIBODIES; GENERATION; REGENERATION; INHIBITION; PROTEINS; REPERTOIRE; FRAGMENTS AB NgR1, NgR2, and NgR3 which constitute the Nogo-66 receptor family are primarily expressed by neurons in the central nervous system (CNS) and believed to limit axonal growth and sprouting following CNS injury. In an attempt to define the expression and decipher the function of individual members of the Nogo-66 receptor family, we previously reported the generation of selective rabbit polyclonal antibodies. Here we exploit the same immune repertoires by phage display technology to generate rabbit monoclonal antibodies (mAbs) with nanomolar affinity to epitopes that are specific for NgR1 and NgR2, respectively, but at the same time conserved between mouse, rat, and human orthologs. Employing phage display vector pC3C, a newly designed phagemid optimized for the generation and selection of Fab libraries with human constant domains, rabbit mAbs were selected from chimeric rabbit/human Fab libraries, characterized in terms of specificity, affinity, and amino acid sequence, and finally converted to chimeric rabbit/human IgG. Using immunofluorescence microscopy and immunoprecipitation, we demonstrate strong and specific recognition of cell surface bound Nogo-66 receptor family members by chimeric rabbit/human IgG. The rabbit mAbs reported here together with their amino acid sequences constitute a defined panel of species cross-reactive reagents in infinite supply which will aid investigations toward a functional role of the Nogo-66 receptor family in and beyond the CNS. Published by Elsevier B.V. C1 NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Rochester, Sch Med & Dent, Ctr Aging & Dev Biol, Rochester, NY 14642 USA. RP Rader, C (reprint author), NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM raderc@mail.nih.gov FU Intramural NIH HHS [Z01 BC010647-01]; NINDS NIH HHS [F31 NS049870, NS047333, R01 NS047333, R56 NS047333] NR 24 TC 17 Z9 18 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 JAN 10 PY 2007 VL 318 IS 1-2 BP 75 EP 87 DI 10.1016/j.jim.2006.10.007 PG 13 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 131HE UT WOS:000243858800009 PM 17140598 ER PT J AU Giacobini, P Messina, A Wray, S Giampietro, C Crepaldi, T Carmeliet, P Fasolo, A AF Giacobini, Paolo Messina, Andrea Wray, Susan Giampietro, Costanza Crepaldi, Tiziana Carmeliet, Peter Fasolo, Aldo TI Hepatocyte growth factor acts as a motogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration SO JOURNAL OF NEUROSCIENCE LA English DT Article DE GnRH-1; LHRH; HGF; migration; olfactory system; development ID FACTOR-SCATTER FACTOR; MESENCHYMAL STEM-CELLS; RECEPTOR C-MET; PLASMINOGEN-ACTIVATOR; FACTOR/SCATTER FACTOR; GNRH NEURONS; LHRH NEURONS; IN-VITRO; NEUROTROPHIC FACTOR; OLFACTORY SYSTEM AB Reproduction in mammals is under the control of the hypothalamic neuropeptide gonadotropin hormone-releasing hormone-1 (GnRH1). GnRH-1-secreting neurons originate during embryonic development in the nasal placode and migrate into the forebrain along olfactory nerves. Gradients of secreted molecules may play a role in this migratory process. In this context, hepatocyte growth factor (HGF) is a potential candidate, because it promotes cell motility in developing brain and has been shown previously to act as a motogen on immortalized GnRH-1 neurons (GN11). In this study, the role of HGF and its receptor Met during development of the GnRH-1 system was examined. GnRH-1 cells express Met during their migration and downregulate its expression once they complete this process. Tissue-type plasminogen activator (tPA), a known HGF activator, is also detected in migratory GnRH-1 neurons. Consistent with in vivo expression, HGF is present in nasal explants, and GnRH-1 neurons express Met. HGF-neutralizing antibody was applied to explants to examine the role of the endogenous growth factor. Migration of GnRH-1 cells and olfactory axon outgrowth were significantly reduced, in line with disruption of a guidance gradient. Exogenous application of HGF to explants increased the distance that GnRH-1 cells migrated, suggesting that HGF also acts as a motogen to GnRH-1 neurons. Functional experiments, performed on organotypic slice cultures, show that creation of an opposing HGF gradient inhibits GnRH-1 neuronal migration. Finally, tPA(-/-):uPA(-/-) (urokinase-type plasminogen activator(-/-)) knock-out mice exhibit strong reduction of the GnRH-1 cell population. Together, these data indicate that HGF signaling via Met receptor influences the development of GnRH-1. C1 Univ Turin, Dept Human & Anim Biol, I-10123 Turin, Italy. Natl Inst Neurol Disorders & Stroke, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Canc Res Inst Mol Oncol, Italian Fdn, I-20139 Milan, Italy. Univ Turin, Dept Anat Pharmacol & Forens Med, I-10125 Turin, Italy. Katholieke Univ Leuven VIB, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium. RP Giacobini, P (reprint author), Univ Turin, Dept Human & Anim Biol, Via Accademia Albertina 13, I-10123 Turin, Italy. EM paolo.giacobini@unito.it RI Giampietro, Costanza/D-4643-2016; Giacobini, Paolo/P-5451-2015; OI Giampietro, Costanza/0000-0001-5229-3835; Giacobini, Paolo/0000-0002-3075-1441; wray, susan/0000-0001-7670-3915 NR 73 TC 46 Z9 47 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 10 PY 2007 VL 27 IS 2 BP 431 EP 445 DI 10.1523/JNEUROSCI.4979-06.2007 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 124VY UT WOS:000243400100021 PM 17215404 ER PT J AU Papaconstantinou, AD Snyderwine, EG AF Papaconstantinou, Andriana D. Snyderwine, Elizabeth G. TI Proliferation and apoptosis in PhIP-induced rat mammary gland carcinomas with elevated phosphotyrosine-STAT5a SO FEBS LETTERS LA English DT Article DE 2-animo-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); rat mammary glands; breast cancers STAT5a; proliferation; apoptosis ID PROLACTIN PRL RECEPTOR; BREAST-CANCER CELLS; CYCLIN D1 PROMOTER; SIGNAL TRANSDUCER; GENE-EXPRESSION; TRANSCRIPTION FACTORS; HEMATOPOIETIC-CELLS; SHORT FORMS; STAT5; DIFFERENTIATION AB In the present study we addressed whether proliferation and apoptosis in 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine-induced rat mammary gland carcinomas were different between carcinomas with high and low expression of phosphotyrosine (pY)-STAT5a. We determined that carcinomas with high pY-STAT5a were more proliferative (MIB5 immunostaining) and had a higher expression of cyclin D1 and estrogen receptor alpha. Furthermore, carcinomas with elevated pY-STAT5a demonstrated lower apoptosis as measured by the TUNEL assay and the Bcl-2 to Bax ratio, and showed increased expression of the long and short isoforms of the prolactin receptor. The results of this study are consistent with the notion that activated STAT5a may provide a growth advantage in some types of mammary gland cancers. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, NIH, Bethesda, MD 20892 USA. EM elizabeth_snyderwine@nih.gov NR 40 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JAN 9 PY 2007 VL 581 IS 1 BP 29 EP 33 DI 10.1016/j.febslet.2006.11.071 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 128JB UT WOS:000243652900005 PM 17173897 ER PT J AU Koike, C Uddin, M Wildman, DE Gray, EA Trucco, M Starzl, TE Goodman, M AF Koike, Chihiro Uddin, Monica Wildman, Derek E. Gray, Edward A. Trucco, Massimo Starzl, Thomas E. Goodman, Morris TI Functionally important glycosyltransferase gain and loss during catarrhine primate emergence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adaptive evolution; glycobiology; pseudogene ID MOLECULAR EVOLUTION; ALPHA-1,3-GALACTOSYLTRANSFERASE GENE; PORCINE ALPHA-1,3-GALACTOSYLTRANSFERASE; ALPHA-1,3 GALACTOSYLTRANSFERASE; PHEROMONE TRANSDUCTION; GENOMIC ORGANIZATION; TRICHROMATIC VISION; HOMINOID SLOWDOWN; WORLD MONKEYS; COLOR-VISION AB A glycosyltransferase, alpha 1,3galactosyltransferase, catalyzes the terminal step in biosynthesis of Gal alpha 1,3Gal beta 1-4GlcNAc-R (alpha Gal), an oligosaccharide cell surface epitope. This epitope or antigenically similar epitopes are widely distributed among the different forms of life. Although abundant in most mammals, aGal is not normally found in catarrhine primates (Old World monkeys and apes, including humans), all of which produce anti-alpha Gal antibodies from infancy onward. Natural selection favoring enhanced resistance to alpha Gal-positive pathogens has been the primary reason offered to account for the loss of aGal in catarrhines. Here, we question the primacy of this immune defense hypothesis with results that elucidate the evolutionary history of GGTA1 gene and pseudogene loci. One such locus, GGTA1P, a processed (intronless) pseudogene (PPG), is present in platyrrhines, i.e., New World monkeys, and catarrhines but not in prosimians. PPG arose in an early ancestor of anthropoids (catarrhines and platyrrhines), and GGTA1 itself became an unprocessed pseudogene in the late catarrhine stem lineage. Strong purifying selection, denoted by low nonsynonymous substitutions per nonsynonymous site/synonymous substitutions per synonymous site values, preserved GGTA1 in noncatarrhine mammals, indicating that the functional gene product is subjected to considerable physiological constraint. Thus, we propose that a pattern of alternative and/or more beneficial glycosyltransferase activity had to first evolve in the stem catarrhines before GGTA1 inactivation could occur. Enhanced defense against aGal-positive pathogens could then have accelerated the replacement of aGal-positive catarrhines by alpha Gal-negative catarrhines. However, we emphasize that positively selected regulatory changes in sugar chain metabolism might well have contributed in a major way to catarrhine origins. C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Dept Anat & Cell Biol, Detroit, MI 48201 USA. Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Thomas E Starzl Transplantat Inst, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Div Immunogenet, Pittsburgh, PA 15213 USA. Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Gynecol & Obstet, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Goodman, M (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Dept Anat & Cell Biol, 540 E Cranfield Ave, Detroit, MI 48201 USA. EM mgoodwayne@aol.com FU Intramural NIH HHS; NIDDK NIH HHS [R01DK64207, R01 DK064207] NR 69 TC 41 Z9 44 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 9 PY 2007 VL 104 IS 2 BP 559 EP 564 DI 10.1073/pnas.0610012104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125MG UT WOS:000243445400030 PM 17194757 ER PT J AU Milner, JD Ward, JM Keane-Myers, A Paul, WE AF Milner, Joshua D. Ward, Jerrold M. Keane-Myers, Andrea Paul, William E. TI Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE eosinophils; IgE; IL-4; macrophages; pneumonia ID IN-VIVO; DIFFERENTIATION; PROLIFERATION; HOMEOSTASIS; EXPRESSION; LYMPHOMA; GENERATE; MUTATION; FOXP3; IL-2 AB Lymphopenia and restricted T cell repertoires in humans are often associated with severe eosinophilic disease and a T cell Th2 bias. To examine the pathogenesis of this phenomenon, C57BL/6 Rag2-/- mice received limited (3 x 10(4)) or large (2 x 10(6)) numbers of CD4 T cells. Three to 5 months after transfer, mice that had received 3 x 10(4) T cells, but not those that received 2 x 10(6), developed fulminant macrophage pneumonia with eosinophilia, Ym1 deposition, and methacholine-induced airway hyperresponsiveness, as well as eosinophilic gastritis; esophagitis and other organ damage occurred in some cases. Donor cells were enriched for IL-4, IL-5, and IL-13 producers. When 3 x 10(4) cells were transferred into CD3 epsilon-/- hosts, the mice developed strikingly elevated serum IgE. Prior transfer of 3 x 10(5) CD25+ CD4 T cells into Rag2-/- recipients prevented disease upon subsequent transfer of CD25- CD4 T cells, whereas 3 x 10(4) regulatory T cells (Tregs) did not, despite the fact that there were equal total numbers of Tregs in the host at the time of transfer of CD25- CD4 T cells. Limited repertoire complexity of Tregs may lead to a failure to control induction of immunopathologic responses, and limitation in repertoire complexity of conventional cells may be responsible for the Th2 phenotype. C1 Natl Inst Allergy & Infect Dis, Immunol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Infect Dis Pathogenesis Sect, NIH, Comparat Med Branch, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), Natl Inst Allergy & Infect Dis, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [K12 HD000850, K12 HD00850] NR 25 TC 63 Z9 63 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 9 PY 2007 VL 104 IS 2 BP 576 EP 581 DI 10.1073/pnas.0610289104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125MG UT WOS:000243445400033 PM 17202252 ER PT J AU Sato, N Patel, HJ Waldmann, TA Tagaya, Y AF Sato, Noriko Patel, Hirai J. Waldmann, Thomas A. Tagaya, Yutaka TI The IL-15/IL-15R alpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokine retention in vivo; memory CD8 homing ID NATURAL-KILLER-CELLS; MARROW-DERIVED CELLS; GROWTH-FACTOR; CUTTING EDGE; INTERLEUKIN-2 RECEPTOR; LYMPHOID HOMEOSTASIS; TRANS-PRESENTATION; DENDRITIC CELLS; BETA-CHAIN; MICE AB previously described unique features of the IL-15 receptor (IL-15R)alpha. IL-15R alpha by itself forms stable complexes with IL-15 on cell surfaces and presents IL-15 in trans to neighboring natural killer/T cells. Moreover, the membrane IL-15/IL-15R alpha complexes (membIL-15) undergo endosomal internalization but survive lysosomal degradation, allowing the complexes to recycle back to the cell surface. Here, we show that membIL-15(+) cells act as a persistent source of IL-15 for the surrounding microenvironment (intercellular reservoir effect). Additionally, membIL-15+ cells give rise to augmented retention of IL-15 in the circulation as well as in tissues. Curiously, IL-15 retention was particularly associated with lungs, rather than with lymph nodes, in normal unstimulated mice, which correlated with the preferential homing of antigen-specific CD8 T cells to lungs during their contraction phase in an IL-15R alpha-dependent manner. Furthermore, membIL-15, unlike soluble IL-15, caused sustained IL-15 signal transduction in the target cells. Collectively, these characteristics define IL-15 as a unique cytokine with prolonged in vivo survival and sustained biological action on the target cells, which may account for the proposed persistent action of IL-15 that helps the long-term survival of functional CD8 memory T cells in vivo. C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Canc Res Ctr, NIH, Bldg 10,Room 4N117,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tawald@mail.nih.gov FU Intramural NIH HHS NR 37 TC 86 Z9 88 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 9 PY 2007 VL 104 IS 2 BP 588 EP 593 DI 10.1073/pnas.0610115104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125MG UT WOS:000243445400035 PM 17202253 ER PT J AU Pareek, TK Keller, J Kesavapany, S Agarwal, N Kuner, R Pant, HC Iadarola, MJ Brady, RO Kulkarni, AB AF Pareek, Tej K. Keller, Jason Kesavapany, Sashi Agarwal, Nitin Kuner, Rohini Pant, Harish C. Iadarola, Michael J. Brady, Roscoe O. Kulkarni, Ashok B. TI Cyclin-dependent signaling through transient receptor kinase 5 modulates nociceptive direct phosphorylation of potential vanilloid 1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE p35; pain ID DORSAL-ROOT GANGLIA; CAPSAICIN RECEPTOR; AXONAL-TRANSPORT; MICE LACKING; CDK5; PAIN; NEURONS; ROSCOVITINE; CHANNEL; BRAIN AB Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Funct Genom Sect, Craniofacial Dev Biol & Regenerat Branch, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Neurobiol & Pain Therapeut Sect, Bethesda, MD 20892 USA. Univ Heidelberg, Inst Pharmacol, D-69120 Heidelberg, Germany. NINDS, Cytoskeletal Prot Regulat Sect, NIH, Bethesda, MD 20892 USA. RP Brady, RO (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. EM bradyr@mail.nih.gov; ak40m@nih.gov OI Pareek, Tej/0000-0001-5134-1647 FU Intramural NIH HHS NR 36 TC 50 Z9 53 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 9 PY 2007 VL 104 IS 2 BP 660 EP 665 DI 10.1073/pnas.0609916104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125MG UT WOS:000243445400047 PM 17194758 ER PT J AU Snyder, ER Ricker, JL Chen, Z Van Waes, C AF Snyder, Eric R. Ricker, Justin L. Chen, Zhong Van Waes, Carter TI Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines SO CANCER LETTERS LA English DT Article DE Fanconi Anemia; FANCF; FANCD2; mono-ubiquitination; cisplatinum; squamous cell carcinoma ID UBIQUITIN LIGASE; CANCER; GLUTATHIONE; PROTEIN; FANCD2; TUMORS; BRCA1 AB Fancom Anemia has recently been associated with a high risk of head and neck squamous cell carcinoma (HNSCC). Inactivation of the Fancom Anemia (FANC-BRCA) pathway via promoter methylation of the FANCF gene has been proposed to be responsible for variation in cisplatinum (CDDP) sensitivity seen in ovarian and HNSCCs. Promoter methylation of the FANCF gene has been observed in 15% of HNSCC specimens, but the relationship to FANC pathway activation and CDDP sensitivity has not been reported. In the present study, 10 HNSCC cell lines were examined for expression of nine genes involved in the FANCBRCA pathway by RT-PCR: FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, BRCA1 and BRCA2. FANC pathway function was evaluated by western blotting for FANCD2 mono-ubiquitination. All of the cell lines were also analyzed for variation in CDDP cytotoxicity. While significant differences were found in CDDP cytotoxicity, Fanconi pathway defects are an infrequent cause, as no evidence of transcriptional down-regulation of FANCF or other FANC mRNAs, or functional FANCBRCA pathway defects were observed. These findings suggest that the variation in CDDP sensitivity of many HNSCCs is most frequently due to factors other than FANC-BRCA pathway inactivation. Published by Elsevier Ireland Ltd. C1 NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, CRC Bldg 10,Room 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU Intramural NIH HHS NR 17 TC 8 Z9 9 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 8 PY 2007 VL 245 IS 1-2 BP 75 EP 80 DI 10.1016/j.canlet.2005.12.028 PG 6 WC Oncology SC Oncology GA 135IA UT WOS:000244146100009 PM 16466850 ER PT J AU Kam, YW Kien, F Roberts, A Cheung, YC Lamirande, EW Vogel, L Chu, SL Tse, J Guarner, J Zaki, SR Subbarao, K Peiris, M Nal, B Altmeyer, R AF Kam, Yin Wing Kien, Francois Roberts, Anjeanette Cheung, Yan Chung Lamirande, Elaine W. Vogel, Leatrice Chu, Shui Ling Tse, Jane Guarner, Jeannette Zaki, Sherif R. Subbarao, Kanta Peiris, Malik Nal, Beatrice Altmeyer, Ralf TI Antibodies against trimeric S glycoprotein protect hamsters against SARS-CoV challenge despite their capacity to mediate Fc gamma RII- dependent entry into B cells in vitro SO VACCINE LA English DT Article DE SARS-CoV; protection; ADE ID ACUTE RESPIRATORY SYNDROME; SYNDROME-ASSOCIATED CORONAVIRUS; HUMAN MONOCLONAL-ANTIBODY; TRANSMISSIBLE GASTROENTERITIS CORONAVIRUS; POTENT NEUTRALIZING ANTIBODIES; RECEPTOR-BINDING DOMAIN; SPIKE PROTEIN; DC-SIGN; ENHANCING ANTIBODIES; FUNCTIONAL RECEPTOR AB Vaccine-induced antibodies can prevent or, in the case of feline infectious peritonitis virus, aggravate infections by coronaviruses. We investigated whether a recombinant native full-length S-protein trimer (triSpike) of severe acute respiratory syndrome coronavirus (SARS-CoV) was able to elicit a neutralizing and protective immune response in animals and analyzed the capacity of anti-S antibodies to mediate antibody-dependent enhancement (ADE) of virus entry in vitro and enhancement of replication in vivo. SARS-CoV-specific serum and mucosal immunoglobulins were readily detected in immunized animals. Serum IgG blocked binding of the S-protein to the ACE2 receptor and neutralized SARS-CoV infection in vitro. Entry into human B cell lines occurred in a Fc gamma RII-dependent and ACE2-independent fashion indicating that ADE of virus entry is a novel cell entry mechanism of SARS-CoV. Vaccinated animals showed no signs of enhanced lung pathology or hepatitis and viral load was undetectable or greatly reduced in lungs following challenge with SARS-CoV. Altogether our results indicate that a recombinant trimeric S protein was able to elicit an efficacious protective immune response in vivo and warrant concern in the safety evaluation of a human vaccine against SARS-CoV. (c) 2006 Elsevier Ltd. All rights reserved. C1 HKU Pasteur Res Ctr, Hong Kong, Hong Kong, Peoples R China. Univ Hong Kong, Dept Microbiol, Hong Kong, Hong Kong, Peoples R China. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. CombinatorX, Singapore 128667, Singapore. RP Kam, YW (reprint author), HKU Pasteur Res Ctr, Dexter HC Man Bldg,8 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. EM Jasonkamyiuwing@yahoo.com.hk RI Guarner, Jeannette/B-8273-2013; OI Nal, Beatrice/0000-0003-3452-7524; , Yiu Wing/0000-0002-8360-9537 FU NIAID NIH HHS [AI95357] NR 65 TC 31 Z9 31 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 8 PY 2007 VL 25 IS 4 BP 729 EP 740 DI 10.1016/j.vaccine.2006.08.011 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 129PR UT WOS:000243741900019 PM 17049691 ER PT J AU Maceyka, M Milstien, S Spiegel, S AF Maceyka, Michael Milstien, Sheldon Spiegel, Sarah TI Shooting the messenger oxidative stress regulates sphingosine-1-phosphate SO CIRCULATION RESEARCH LA English DT Editorial Material DE sphingosine-1-phosphate; reactive oxygen species; monoamine oxidase; ceramide; apoptosis ID ISCHEMIA-REPERFUSION INJURY; SPHINGOSINE KINASE; NEUTRAL SPHINGOMYELINASE; CARDIOMYOCYTE APOPTOSIS; CELL-DEATH; CERAMIDE; HEART; ACTIVATION; RECEPTOR; HYPOXIA C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, 1101 E Marshall St, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU Intramural NIH HHS; NCI NIH HHS [5T32 CA085159-04]; NIGMS NIH HHS [R37 GM43880] NR 25 TC 21 Z9 21 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 5 PY 2007 VL 100 IS 1 BP 7 EP 9 DI 10.1161/01.RES.0000255895.19868.a3 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 124XY UT WOS:000243407300003 PM 17204658 ER PT J AU Tocchetti, CG Wang, W Froehlich, JP Huke, S Aon, MA Wilson, GM Di Benedetto, G O'Rourke, B Gao, WD Wink, DA Toscano, JP Zaccolo, M Bers, DM Valdivia, HH Cheng, HP Kass, DA Paolocci, N AF Tocchetti, Carlo G. Wang, Wang Froehlich, Jeffrey P. Huke, Sabine Aon, Miguel A. Wilson, Gerald M. Di Benedetto, Giulietta O'Rourke, Brian Gao, Wei Dong Wink, David A. Toscano, John P. Zaccolo, Manuela Bers, Donald M. Valdivia, Hector H. Cheng, Heping Kass, David A. Paolocci, Nazareno TI Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling SO CIRCULATION RESEARCH LA English DT Article DE nitroxyl; contractility; ryanodine receptor; sarcoplasmic reticulum Ca2+ -ATPase; excitation/contraction coupling ID CALCIUM-RELEASE CHANNEL; RYANODINE RECEPTORS; NITRIC-OXIDE; IN-VIVO; FAILING HEARTS; FAILURE; PHOSPHOLAMBAN; INOTROPY; ANION; INACTIVATION AB Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca2+. A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca2+ pump and the ryanodine receptor 2, leading to increased Ca2+ uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca2+-release channels and accelerates Ca2+ reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca2+ transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca2+ cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure. C1 Johns Hopkins Med Inst, Div Cardiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Maryland, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. Loyola Univ, Dept Physiol, Maywood, IL 60153 USA. Venetian Inst Mol Med, Dulbecco Telethon Inst, Padua, Italy. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. Univ Wisconsin, Sch Med, Dept Physiol, Madison, WI 53706 USA. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. RP Paolocci, N (reprint author), Johns Hopkins Med Inst, Div Cardiol, 720 Rutland Ave,Ross Bldg 835, Baltimore, MD 21205 USA. EM npaoloc1@jhmi.edu RI Zaccolo, Manuela/B-3802-2011; Aon, Miguel/A-6564-2008; Bers, Donald/C-4507-2012; OI Aon, Miguel/0000-0002-4355-5431; Di Benedetto, Giulietta/0000-0002-1489-3896; tocchetti, carlo gabriele/0000-0001-5983-688X; Wang, Wang/0000-0001-9093-412X; Bers, Donald/0000-0002-2237-9483; Paolocci, Nazareno/0000-0001-7011-997X FU NHLBI NIH HHS [R01 HL047511, HL075265, HL30077, HL47511, P01 HL059408, P01 HL077180, P01HL077180, P01HL59408, R01 HL030077, R01 HL055438, R01 HL075265, R01 HL075265-04, R37 HL030077, R37 HL030077-27]; Telethon [GGP05113] NR 39 TC 115 Z9 121 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JAN 5 PY 2007 VL 100 IS 1 BP 96 EP 104 DI 10.1161/01.RES.0000253904.53601.c9 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 124XY UT WOS:000243407300014 PM 17138943 ER PT J AU Kleinau, G Claus, M Jaeschke, H Mueller, S Neumann, S Paschke, R Krause, G AF Kleinau, Gunnar Claus, Maren Jaeschke, Holger Mueller, Sandra Neumann, Susanne Paschke, Ralf Krause, Gerd TI Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN THYROTROPIN RECEPTOR; PROTEIN-COUPLED RECEPTORS; VIRUS TYPE-1 ENTRY; TSH RECEPTOR; CONSTITUTIVE ACTIVATION; INTRACELLULAR LOOP; SOMATIC MUTATIONS; DOMAIN; BINDING; IDENTIFICATION AB A number of alanine mutations in extracellular loop two (ECL2) of the thyroid-stimulating hormone receptor (TSHR) were found to increase or decrease basal activity when compared with the wild type receptor. K565A was identified as a mutant with decreased basal activity, and strongly impaired hormone induced signaling activity. To gain insights into how ECL2 mutants affect basal activity, we focused on constitutively activating pathogenic mutant 1568V in ECL2, which exhibits elevated basal activity. Because our molecular model suggests that Ile-568 is embedded in an environment of hydrophobic residues provided by transmembrane helix bundle, we tested mutants in this region to identify potential interaction partner(s) for Ile-568. Indeed, the double mutant 1568V/1640L (ECL2/TMH6) suppresses the increased basal activity exhibited by 1568V alone. We suggest a spatial and functional relationship between ECL2 and TMH6 in which side chain interaction between Ile-568 and Ile-640 constrains the receptor in a conformation with low basal activity. Although the single mutant 1640L exhibits basal activity lower than wild type, its differently branched and bulkier side chain complements the reduced side chain bulk in 1568V, restoring wild type basal activity to the double mutant. This scenario is confirmed by the reciprocal double mutant 1640V/I568L. The combination of basally increased activity of 1640V and basally decreased activity of mutant 1568L also restores basal activity of wild type TSHR. These and other mutant phenotypes reported here support a dynamic interface between TMH6 and ECL2. Disruption of this critical interface for signaling by introduction of mutations in TSHR can either increase or decrease basal activity. C1 Leibniz Inst Mol Pharmakol, D-13125 Berlin, Germany. Univ Leipzig, Dept Med 3, D-04103 Leipzig, Germany. NIDDK, NIH, Bethesda, MD 20814 USA. RP Krause, G (reprint author), Leibniz Inst Mol Pharmakol, Robert Rossle Str 10, D-13125 Berlin, Germany. EM gkrause@fmp-berlin.de RI Horstmann, Britta/C-2154-2008; OI Claus, Maren/0000-0001-8732-0645 NR 49 TC 46 Z9 47 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 5 PY 2007 VL 282 IS 1 BP 518 EP 525 DI 10.1074/jbc.M606176200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 121OI UT WOS:000243166500057 PM 17079233 ER PT J AU Tian, E Ten Hagen, KG AF Tian, E. Ten Hagen, Kelly G. TI A UDP-GaINAc : polypeptide N-acetylgalactosaminyltransferase is required for epithelial tube formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DROSOPHILA TRACHEAL SYSTEM; ZONULA ADHERENS FORMATION; SEPTATE JUNCTIONS; APICAL MEMBRANE; CELL POLARITY; CAENORHABDITIS-ELEGANS; SIZE CONTROL; EXPRESSION; CRUMBS; MORPHOGENESIS AB Epithelial tubes are essential for the proper function of a diverse array of eukaryotic organs. Here we present a novel class of genes required for maintaining epithelial cell shape, polarity, and paracellular barrier function in the Drosophila embryonic tracheal system. Mutations in one member of the UDP-GaINAc:polypeptide N-acetylgalactosaminyltransferase family (pgant3SA) are recessive lethal and result in tracheal tubes that are irregular in diameter and morphology. Further analysis of the pgant35A mutants reveals diminished levels of the apical determinant Crbs and the luminal marker 2A12, concomitant with increased staining in cytoplasmic vesicles within tracheal cells. GalNAc-containing glycoproteins are severely diminished along the apical region of the tracheal system as well. Tracheal cells become irregular in size and shape, and septate junction proteins are mislocalized to a more apical position. Most notably, paracellular barrier function is lost in the tracheal system of the mutants. Overexpression of wild type pgant35A under control of the trachea-specific breathless (btl) promoter results in partial rescue of the lethality. We propose a model where pgant35A is required to establish proper apical composition of tracheal cells by influencing apical delivery of proteins/glycoproteins. Disruption of the normal apical content results in altered cell morphology and loss of paracellular barrier function. These studies demonstrate a previously unrecognized requirement for mucin-type O-glycosylation in epithelial tube integrity and have obvious implications for epithelial morphogenesis in higher eukaryotes, since a unique ortholog to pgant35A exists in mammals. C1 NIDCR, Dev Glycobiol Unit, NIH, Bethesda, MD 20892 USA. RP Ten Hagen, KG (reprint author), NIDCR, Dev Glycobiol Unit, NIH, Bldg 30,Rm 4A400,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM Kelly.Tenhagen@nih.gov FU Intramural NIH HHS NR 49 TC 42 Z9 42 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 5 PY 2007 VL 282 IS 1 BP 606 EP 614 DI 10.1074/jbc.M606268200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 121OI UT WOS:000243166500066 PM 17098739 ER PT J AU Pan, YP Nussinov, R AF Pan, Yongping Nussinov, Ruth TI Structural basis for p53 binding-induced DNA bending SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; CORE DOMAIN; COOPERATIVE BINDING; CRYSTAL-STRUCTURE; RESPONSE ELEMENT; CONSENSUS DNA; RECOGNITION; SITE; COMPLEX; TETRAMERIZATION AB Specific p53 binding-induced DNA bending has important biological implications such as transcription activation. However, the detailed structures of the bent DNA and the p53-DNA complex are still unavailable, hampering our understanding of the mechanism for p53-induced DNA bending and its consequent biological significance. To gain insight into the p53 binding-induced DNA bending, we performed molecular dynamics simulations on DNA segments with the consensus sequence for p53-specific binding, half site DNA-p53 complexes, and full site DNA-p53 complexes. We show that each DNA-bound p53 core domain caused a local DNA conformational change within the quarter site; upon the binding of the p53 dimer, there was an apparent DNA bending at the center of the half site; when bound with two p53 dimers, the full site DNAs with two different sequences bent 20 and 35 degrees, respectively. These results are in agreement with experimental observations. Our simulations demonstrate that the two p53 dimers favored a staggered conformation in which they make favorable interactions at the interface. This dimer-dimer interface organization necessitated conformational changes in the DNA, leading to the bending at the center of the full site, which in turn is dependent on the DNA sequence. Overall, our results provide the detailed atomic model for the DNA-p53 tetramer complex and delineate the roles of DNA-p53, p53 dimer-dimer interactions, and DNA sequence in specific p53 binding-induced DNA conformational changes. C1 NCI, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Bldg 469,Rm 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 39 TC 23 Z9 23 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 5 PY 2007 VL 282 IS 1 BP 691 EP 699 DI 10.1074/jbc.M605908200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 121OI UT WOS:000243166500074 PM 17085447 ER PT J AU Das, K Sarafianos, SG Clark, AD Boyer, PL Hughes, SH Arnold, E AF Das, Kalyan Sarafianos, Stefan G. Clark, Arthur D., Jr. Boyer, Paul L. Hughes, Stephen H. Arnold, Eddy TI Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE conformational flexibility; drug design; drug resistance; polymerase ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; DRUG-RESISTANCE MUTATIONS; ANTIBODY FAB FRAGMENT; DNA-POLYMERASE-I; WILD-TYPE; HBY 097; POSITIONAL ADAPTABILITY; CONFORMATIONAL-CHANGES; COMBINATION THERAPY AB Lys103Asn and Tyr181Cys are the two mutations frequently observed in patients exposed to various non-nucleoside reverse transcriptase inhibitor drugs (NNRTIs). Human immunodeficiency virus (HIV) strains containing both reverse transcriptase (RT) mutations are resistant to all of the approved NNRTI drugs. We have determined crystal structures of Lys103Asn/Tyr181Cys mutant HIV-1 RT with and without a bound non-nucleoside inhibitor (HBY 097, (S)-4-isopropoxycarbonyl-6-methoxy-3(methylthio-methyl)-3,4-dihydroquinoxalin-2(1H)-thione) at 3.0 angstrom and 2.5 angstrom resolution, respectively. The structure of the double mutant RT/HBY 097 complex shows a rearrangement of the isopropoxycarbonyl group of HBY 097 compared to its binding with wild-type RT. HBY 097 makes a hydrogen bond with the thiol group of Cys181 that helps the drug retain potency against the Tyr181Cys mutation. The structure of the unliganded double mutant HIV-1 RT showed that Lys103Asn mutation facilitates coordination of a sodium ion with Lys101, Asn103 N and 061, Tyr188 01, and two water molecules. The formation of the binding pocket requires the removal of the sodium ion. Although the RT alone and the RT/HBY 097 complex were crystallized in the presence of ATP, only the RT has an ATP coordinated with two Mn2+ at the polymerase active site. The metal coordination mimics a reaction intermediate state in which complete octahedral coordination was observed for both metal ions. Asp186 coordinates at an axial position whereas the carboxylates of Asp110 and Asp185 are in the planes of coordination of both metal ions. The structures provide evidence that NNRTIs restrict the flexibility of the YMDD loop and prevent the catalytic aspartate residues from adopting their metal-binding conformations. C1 CABM, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. NIH, Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), CABM, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu OI Sarafianos, Stefan G/0000-0002-5840-154X FU Intramural NIH HHS; NIAID NIH HHS [AI 27690]; NIGMS NIH HHS [P01 GM066671] NR 62 TC 58 Z9 58 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 5 PY 2007 VL 365 IS 1 BP 77 EP 89 DI 10.1016/j.jmb.2006.08.097 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 122AY UT WOS:000243199300008 PM 17056061 ER PT J AU Gunasekaran, K Nussinov, R AF Gunasekaran, Kannan Nussinov, Ruth TI How different are structurally flexible and rigid binding sites? Sequence and structural features discriminating proteins that do and do not undergo conformational change upon ligand binding SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE binding site; conformational flexibility; backbone conformational change; ligand binding; Ramachandran disallowed conformations ID SIDE-CHAIN FLEXIBILITY; CRYSTAL-STRUCTURES; STEREOCHEMICAL CRITERIA; COMPUTATIONAL DESIGN; GLOBULAR-PROTEINS; DRUG DISCOVERY; PEPTIDE UNITS; BETA-TURNS; RESIDUES; ENZYME AB Proteins are dynamic molecules and often undergo conformational change upon ligand binding. It is widely accepted that flexible loop regions have a critical functional role in enzymes. Lack of consideration of binding site flexibility has led to failures in predicting protein functions and in successfully docking ligands with protein receptors. Here we address the question: which sequence and structural features distinguish the structurally flexible and rigid binding sites? We analyze high-resolution crystal structures of ligand bound (holo) and free (apo) forms of 41 proteins where no conformational change takes place upon ligand binding, 35 examples with moderate conformational change, and 22 cases where a large conformational change has been observed. We find that the number of residue-residue contacts observed per-residue (contact density) does not distinguish flexible and rigid binding sites, suggesting a role for specific interactions and amino acids in modulating the conformational changes. Examination of hydrogen bonding and hydrophobic interactions reveals that cases that do not undergo conformational change have high polar interactions constituting the binding pockets. Intriguingly, the large, aromatic amino acid tryptophan has a high propensity to occur at the binding sites of examples where a large conformational change has been noted. Further, in large conformational change examples, hydrophobic-hydrophobic, aromatic-aromatic, and hydrophobic-polar residue pair interactions are dominant. Further analysis of the Ramachandran dihedral angles (phi,psi) reveals that the residues adopting disallowed conformations are found in both rigid and flexible cases. More importantly, the binding site residues adopting disallowed conformations clustered narrowly into two specific regions of the L-Ala Ramachandran map. Examination of the dihedral angles changes upon ligand binding shows that the magnitude of phi, psi changes are in general minimal, although some large changes particularly between right-handed alpha-helical and extended conformations are seen. Our work further provides an account of conformational changes in the dihedral angles space. The findings reported here are expected to assist in providing a framework for predicting protein-ligand complexes and for template-based prediction of protein function. C1 NCI, Basic Res Program, SAIC Frederick Inc, Canc Res Ctr,Nanobiol Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Gunasekaran, K (reprint author), Amgen Inc, 1201 Amgen Court W,AW2-D3262, Seattle, WA 98119 USA. EM guna.kannan@yahoo.com; ruthn@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 68 TC 77 Z9 85 U1 0 U2 14 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 5 PY 2007 VL 365 IS 1 BP 257 EP 273 DI 10.1016/j.jmb.2006.09.062 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 122AY UT WOS:000243199300022 PM 17059826 ER PT J AU Harburg, GC Hall, FS Harrist, AV Sora, I Uhl, GR Eisch, AJ AF Harburg, G. C. Hall, F. S. Harrist, A. V. Sora, I. Uhl, G. R. Eisch, A. J. TI Knockout of the mu opioid receptor enhances the survival of adult-generated hippocampal granule cell neurons SO NEUROSCIENCE LA English DT Review DE mu; hippocampus; dentate gyrus; adult neurogenesis; BrdU; stereology ID UNBIASED STEREOLOGICAL ESTIMATION; MORPHINE-INDUCED ANALGESIA; CENTRAL-NERVOUS-SYSTEM; RAT DENTATE GYRUS; PROGENITOR PROLIFERATION; SYNAPTIC TRANSMISSION; AXONAL PROJECTIONS; OPIATE RECEPTOR; CEREBRAL-CORTEX; MICE LACKING AB Recent evidence suggests that mu opiold receptors (MOR) are key regulators of hippocampal structure and function. For example, exogenous MOR agonists morphine and heroin negatively impact hippocampal function and decrease adult hippocampal neurogenesis. Here we explored the role of MOR in the birth and survival of hippocampal progenitor cells by examining adult neurogenesis in mice that lack MOR. Adult male mice lacking exon 1 of MOR were injected with the S phase marker bromodeoxyuridine (BrdU) and killed either 2 hours or 4 weeks later to evaluate proliferating and surviving BrdU-immunoreactive (IR) cells, respectively, in the adult hippocampal granule cell layer. Wildtype (WT), heterozygote, and homozygote mice did not differ in the number of BrdU-IR cells at a proliferation time point. However, 4 weeks after BrdU injection, heterozygote and homozygote mice had 57% and 54% more surviving BrdU-IR cells in the hippocampal granule cell layer as compared with WT mice. A decrease in apoptosis in the heterozygote and homozygote mice did not account for the difference in number of surviving BrdU-IR cells since there were no alterations in number of pyknotic, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive, or activated caspase 3-IR cells compared with WT. In concordance with the increased numbers of granule cells maturing into neurons, heterozygote and homozygote mice had larger hippocampal granule cell layers and increased numbers of granule cells. These findings indicate that MOR may play a role in regulating progenitor cell survival and more generally encourage further exploration of how MOR activation can influence hippocampal structure and function. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. NIDA, Mol Neurobiol Branch, IRP, NIH,DHHS, Baltimore, MD USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Tohoku Univ, Grad Sch Med, Dept Neurosci, Sendai, Miyagi, Japan. RP Eisch, AJ (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM amelia.eisch@utsouthwestern.edu RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Intramural NIH HHS; NIDA NIH HHS [T32 DA007290, K02 DA023555, R01 DA016765] NR 102 TC 54 Z9 56 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD JAN 5 PY 2007 VL 144 IS 1 BP 77 EP 87 DI 10.1016/j.neuroscience.2006.09.018 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 117GD UT WOS:000242860100009 PM 17055658 ER PT J AU Armakolas, A Klar, AJS AF Armakolas, Athanasios Klar, Amar J. S. TI Left-right dynein motor implicated in selective chromatid segregation in mouse cells SO SCIENCE LA English DT Article ID LEFT-RIGHT ASYMMETRY; DNA AB During cell division, copies of mouse chromosome 7 are segregated selectively or randomly to daughter cells depending on the cell type. The mechanism for differential segregation is unknown. Because mouse left-right dynein (LRD) gene mutations result in randomization of visceral organs' laterality, we hypothesized that LRD may also function in selective chromatid segregation. Indeed, upon knock-down by RNA interference methods, LRD depletion disrupts biased segregation. LRD messenger RNA presence or absence correlates with the observed segregation patterns. This work supports the claim that LRD functions in a mechanism for selective chromatid segregation. C1 NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Ctr Canc Res, POB B, Frederick, MD 21702 USA. EM klar@ncifcrf.gov FU Intramural NIH HHS NR 11 TC 53 Z9 53 U1 0 U2 8 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 5 PY 2007 VL 315 IS 5808 BP 100 EP 101 DI 10.1126/science.1129429 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 122WU UT WOS:000243259100045 PM 17204651 ER PT J AU McHale, CM Zhang, L Hubbard, AE Zhao, X Baccarelli, A Pesatori, AC Smith, MT Landi, MT AF McHale, Cliona M. Zhang, Luoping Hubbard, Alan E. Zhao, Xin Baccarelli, Andrea Pesatori, Angela C. Smith, Martyn T. Landi, Maria Teresa TI Microarray analysis of gene expression in peripheral blood mononuclear cells from dioxin-exposed human subjects SO TOXICOLOGY LA English DT Article DE tetrachlorodibenzo-p-dioxin (TCDD); microarray; gene expression; biomarkers; leukemia; blood ID OXIDATIVE STRESS-RESPONSE; HYDROCARBON RECEPTOR; SEVESO; TCDD; ACCIDENT; IMMUNOTOXICITY; IDENTIFICATION; LYMPHOCYTES; POPULATION; CHLORACNE AB Tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen and exerts toxic effects on the skin (chloracne). Effects on reproductive, immunological, and endocrine systems have also been observed in animal models. TCDD acts through the aryl hydrocarbon receptor (AhR) pathway influencing largely unknown gene networks. An industrial accident in Seveso, Italy in 1976 exposed thousands of people to substantial quantities of TCDD. Twenty years after the exposure, this study examines global gene expression in the mononuclear cells of 26 Seveso female never smokers, with similar age, alcohol consumption, use of medications, and background plasma levels of 22 dioxin congeners unrelated to the Seveso accident. Plasma dioxin levels were still elevated in the exposed subjects. We performed analyses in two different comparison groups. The first included high-exposed study subjects compared with individuals with background TCDD levels (average plasma levels 99.4 and 6.7 ppt, respectively); the second compared subjects who developed chloracne after the accident, and those who did not develop this disease. Overall, we observed a modest alteration of gene expression based on dioxin levels or on chloracne status. In the comparison between high levels and background levels of TCDD, four histone genes were up-regulated and modified expression of HIST1H3H was confirmed by real-time PCR. In the comparison between chloracne case-control subjects, five hemoglobin genes were upregulated. Pathway analysis revealed two major networks for each comparison, involving cell proliferation, apoptosis, immunological and hematological disease, and other pathways. Further examination of the role of these genes in dioxin induced-toxicity is warranted. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. Univ Milan, Ctr Ricerca Epidemiol Occupaz Clin & Ambientale, I-20122 Milan, Italy. Osped Maggiore Policlin, Milan, Italy. Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP McHale, CM (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, 140 Warren Hall, Berkeley, CA 94720 USA. EM cmchale@berkeley.edu OI Baccarelli, Andrea/0000-0002-3436-0640; pesatori, angela/0000-0002-0261-3252 NR 39 TC 28 Z9 29 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JAN 5 PY 2007 VL 229 IS 1-2 BP 101 EP 113 DI 10.1016/j.tox.2006.10.004 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 125TZ UT WOS:000243467000011 PM 17101203 ER PT J AU Ribeiro, JMC Arca, B Lombardo, F Calvo, E Phan, VM Chandra, PK Wikel, SK AF Ribeiro, Jose M. C. Arca, Bruno Lombardo, Fabrizio Calvo, Eric Phan, Van My Chandra, Prafulla K. Wikel, Stephen K. TI An annotated catalogue of salivary gland transcripts in the adult female mosquito, Aedes aegypti SO BMC GENOMICS LA English DT Article ID YELLOW-FEVER MOSQUITO; VECTOR ANOPHELES-GAMBIAE; MALARIA VECTOR; SNAKE-VENOM; PLASMODIUM DEVELOPMENT; SEQUENCE ALIGNMENT; PROTEIN DATABASE; XANTHURENIC ACID; BINDING PROTEIN; INNATE IMMUNITY AB Background: Saliva of blood-sucking arthropods contains a cocktail of antihemostatic agents and immunomodulators that help blood feeding. Mosquitoes additionally feed on sugar meals and have specialized regions of their glands containing glycosidases and antimicrobials that might help control bacterial growth in the ingested meals. To expand our knowledge on the salivary cocktail of des aeypti, a vector of dengue and yellow fevers, we analyzed a set of 4,232 expressed sequence tags from cDNA libraries of adult female mosquitoes. Results: A nonredundant catalogue of 614 transcripts ( 573 of which are novel) is described, including 136 coding for proteins of a putative secretory nature. Additionally, a two-dimensional gel electrophoresis of salivary gland (SG) homogenates followed by tryptic digestion of selected protein bands and MS/MS analysis revealed the expression of 24 proteins. Analysis of tissue-specific transcription of a subset of these genes revealed at least 31 genes whose expression is specific or enriched in female SG, whereas 24 additional genes were expressed in female SG and in males but not in other female tissues. Most of the 55 proteins coded by these SG transcripts have no known function and represent high-priority candidates for expression and functional analysis as antihemostatic or antimicrobial agents. An unexpected finding is the occurrence of four protein families specific to SG that were probably a product of horizontal transfer from prokaryotic organisms to mosquitoes. Conclusion: Overall, this paper contributes to the novel identification of 573 new transcripts, or near 3% of the AE aeypti proteome assuming a 20,000-protein set, and to the best-described sialome of any blood-feeding insect. C1 NIAID, Lab Malaria & Vector Res, Sect Vector Biol, NIH, Rockville, MD 20852 USA. Univ Naples Federico 2, Dept Struct & Funct Biol, Naples, Italy. Univ Roma La Sapienza, Dept Publ Hlth, Parasitol Sect, Rome, Italy. Univ Connecticut, Ctr Hlth, Sch Med, Dept Immunol, Farmington, CT 06030 USA. RP Ribeiro, JMC (reprint author), NIAID, Lab Malaria & Vector Res, Sect Vector Biol, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov; arca@unina.it; fabrizio.lombardo@uniroma1.it; ecalvo@niaid.nih.gov; vpham@niaid.nih.gov; chandra@biology.rutgers.edu; swikel@up.uchc.edu RI Lombardo, Fabrizio/J-8511-2014; OI Lombardo, Fabrizio/0000-0002-8563-0612; Arca, Bruno/0000-0002-4029-0984; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 89 TC 124 Z9 150 U1 5 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JAN 4 PY 2007 VL 8 AR 6 DI 10.1186/1471-2164-8-6 PG 27 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 134AD UT WOS:000244054100001 PM 17204158 ER PT J AU Yang, W AF Yang, Wei TI Human MutL alpha: The jack of all trades in MMR is also an endonuclease SO DNA REPAIR LA English DT Article DE mismatch repair (MMR); endonuclease activity; regulation; strand specificity; ATPase; DNA binding; divalent cation ID DNA MISMATCH REPAIR; C-TERMINAL DOMAIN; NONPOLYPOSIS COLON-CANCER; REPLICATION INITIATION; CRYSTAL-STRUCTURE; DAM METHYLASE; CROSS-LINKING; PROTEIN MUTS; HELICASE II; COMPLEX AB Recently, Paul Modrich's group reported the discovery of an intrinsic endonuclease activity for human MutL alpha. This breakthrough provides a satisfactory answer to the longstanding puzzle of a missing nuclease activity in human mismatch repair and will undoubtedly lead to new investigations of DNA repair and replication. Here, the implications of this exciting new finding are discussed in the context of mismatch repair in Escherichia coli and humans. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. EM Wei.Yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK036119-10] NR 34 TC 17 Z9 18 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 4 PY 2007 VL 6 IS 1 BP 135 EP 139 DI 10.1016/j.dnarep.2006.10.021 PG 5 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 129FK UT WOS:000243713800016 PM 17142111 ER PT J AU Reinlib, L Friedberg, EC AF Reinlib, Leslie Friedberg, Errol C. TI Report of the Working Group on Integrated Translational Research in DNA Repair SO DNA REPAIR LA English DT Editorial Material DE DNA repair; genome instability; NIEHS; Working Group ID NUCLEOTIDE EXCISION-REPAIR; SUSCEPTIBILITY; EXPRESSION; MARKER AB On September 28-29, 2006, the National Institute of Environmental Health Sciences led a team from the National Institutes of Health in hosting a Working Group on Integrated Translational Research in DNA Repair, in Berkeley, CA. In recognition of the far-reaching goals for this area of investigation, the Working Group was charged with conceiving a vision to facilitate projects that would apply the lessons of DNA Repair research to clinical application and public health. The participants included basic and physician scientists working in the various areas of DNA Repair and genome stability, as well as agency representatives of the National Cancer Institute and the National Institute of General Medical Sciences. In constructing this vision of practical research recommendations, the Working Group was asked to identify roadblocks to progress, suggest enabling technologies, and to consider areas that are ripe for translation. This report summarizes the rationale for this initiative and the recommendations that emerged. C1 US Dept Hlth & Human Serv, Div Extramural Res & Training, NIH, NIEHS, Res Triangle Pk, NC USA. Univ Texas, SW Med Ctr, Dept Pathol, Lab Mol Pathol, Dallas, TX USA. RP Reinlib, L (reprint author), US Dept Hlth & Human Serv, Div Extramural Res & Training, NIH, NIEHS, POB 12233,MD EC-21, Res Triangle Pk, NC USA. EM Reinlib@niehs.nih.gov NR 7 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD JAN 4 PY 2007 VL 6 IS 1 BP 145 EP 147 DI 10.1016/j.dnarep.2006.11.006 PG 3 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 129FK UT WOS:000243713800018 PM 17283494 ER PT J AU Roth, BL AF Roth, Bryan L. TI Focus on research - Drug and valvular heart disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID FENFLURAMINE C1 Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Pharm, Dept Med Chem, Chapel Hill, NC USA. Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. RI Roth, Bryan/F-3928-2010 NR 5 TC 247 Z9 251 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JAN 4 PY 2007 VL 356 IS 1 BP 6 EP 9 DI 10.1056/NEJMp068265 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 122EX UT WOS:000243209600003 PM 17202450 ER PT J AU Jiang, S Li, P Lee, SL Lin, CY Long, YQ Johnson, MD Dickson, RB Roller, PP AF Jiang, Sheng Li, Peng Lee, Sheau-Ling Lin, Cheng Yong Long, Ya-Qiu Johnson, Michael D. Dickson, Robert B. Roller, Peter P. TI Design and synthesis of redox stable analogues of sunflower trypsin inhibitors (SFTI-1) on solid support, potent inhibitors of matriptase SO ORGANIC LETTERS LA English DT Article ID RING-CLOSING METATHESIS; SERINE-PROTEASE; CHEMICAL-SYNTHESIS; AMINO-ACIDS; SEEDS; HIMASTATIN; PEPTIDES AB Matriptase is a member of the emerging class of type II transmembrane serine proteases. It was found that the sunflower trypsin inhibitor (SFTI-1), isolated from sunflower seeds, inhibits matriptase with a subnanomolar K-i of 0.92 nM. On the basis of this result, we designed and synthesized its proteolytically stable analogues, SFTI-2 and SFTI-3. SFTI-3 exhibited very good binding affinity to matriptase, and it was metabolically stable. C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20057 USA. RP Jiang, S (reprint author), NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM johnsom@georgetown.edu; proll@helix.nih.gov FU NCI NIH HHS [R01 CA 104944-01, R01 CA096851] NR 26 TC 32 Z9 32 U1 2 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD JAN 4 PY 2007 VL 9 IS 1 BP 9 EP 12 DI 10.1021/ol0621497 PG 4 WC Chemistry, Organic SC Chemistry GA 120ZF UT WOS:000243124900003 PM 17192072 ER PT J AU Emanuel, EJ AF Emanuel, Ezekiel J. TI Changing premedical requirements - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM eemanuel@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 3 PY 2007 VL 297 IS 1 BP 38 EP 39 DI 10.1001/jama.297.1.38-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 123BS UT WOS:000243271900010 ER PT J AU Good, CH AF Good, Cameron H. TI Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID SYNAPSES; RELEASE C1 NIDA, Electrophysiol Res Unit, Cellular Neurobiol Branch,Electrophysiol Res Unit, Intramural Res Program,Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. RP Good, CH (reprint author), NIDA, Electrophysiol Res Unit, Cellular Neurobiol Branch,Electrophysiol Res Unit, Intramural Res Program,Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM goodc@mail.nih.gov FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 1 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 3 PY 2007 VL 27 IS 1 BP 1 EP 3 DI 10.1523/JNEUROSCI.4842-06.2007 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 122VF UT WOS:000243254500002 PM 17205618 ER PT J AU Rusnak, M Toth, ZE House, SB Gainer, H AF Rusnak, Milan Toth, Zsuzsanna E. House, Shirley B. Gainer, Harold TI Depolarization and neurotransmitter regulation of vasopressin gene expression in the rat suprachiasmatic nucleus in vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article DE SCN; organotypic cultures; vasopressin; circadian rhythm; gene regulation; VIP; VPAC2 receptor ID VASOACTIVE INTESTINAL POLYPEPTIDE; MAMMALIAN CIRCADIAN CLOCK; MAGNOCELLULAR NEURONS; VPAC(2) RECEPTOR; CYCLIC-AMP; SUPRAOPTIC NUCLEUS; KINASE; TRANSCRIPTION; RHYTHMS; CREB AB Vasopressin (VP) transcription in the rat suprachiasmatic nucleus (SCN) in organotypic culture was studied by in situ hybridization histochemistry using an intron-specific VP heteronuclear RNA probe. The circadian peak of VP gene transcription in the SCN in vitro is completely blocked by a 2 h exposure to tetrodotoxin (TTX) in the culture medium, and this TTX inhibition of VP gene transcription is reversed by exposure of the SCN to either forskolin or potassium depolarization. This suggests that an intrinsic, spontaneously active neuronal mechanism in the SCN is responsible for the cAMP- and depolarization-dependent pathways involved in maintaining peak VP gene transcription. In this paper, we evaluate a variety of neurotransmitter candidates, membrane receptors, and signal-transduction cascades that might constitute the mechanisms responsible for the peak of VP gene transcription. We find that vasoactive intestinal peptide (VIP) and a VPAC2 (VIP receptor subtype 2) receptor-specific agonist, Ro-25-1553, are the most effective ligands tested in evoking a cAMP- mitogen-activated protein kinase signal transduction cascade leading to an increase in VP gene transcription in the SCN. In addition, a second independent pathway involving depolarization activating L-type voltage-gated calcium channels and a Ca-dependent kinase pathway [inhibited by KN62 (1-[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine)] rescues VP gene transcription in the presence of TTX. In the absence of TTX, these independent pathways appear to act in a cooperative manner to generate the circadian peak of VP gene transcription in the SCN. C1 NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bldg 36,Room 4D-18, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU Intramural NIH HHS NR 61 TC 7 Z9 7 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 3 PY 2007 VL 27 IS 1 BP 141 EP 151 DI 10.1523/JNEUROSCI.3739-06.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 122VF UT WOS:000243254500017 PM 17202481 ER PT J AU Yabroff, KR Davis, WW Lamont, EB Fahey, A Topor, M Brown, ML Warren, JL AF Yabroff, K. Robin Davis, William W. Lamont, Elizabeth B. Fahey, Angela Topor, Marie Brown, Martin L. Warren, Joan L. TI Patient time costs associated with cancer care SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article; Proceedings Paper CT 5th World Congress of the International-Health-Economics-Association CY JUL, 2005 CL Barcelona, SPAIN SP Int Hlth Econ Assoc ID SEER-MEDICARE DATA; BREAST-CANCER; COLORECTAL-CANCER; RADIATION-THERAPY; LUNG-CANCER; STAGE; SURGERY; CLAIMS; TRAVEL; AGE AB Background Although costs of medical care for cancer have been investigated extensively, patient time costs associated with cancer care have rarely been estimated systematically. In this study, we estimated patient time costs associated with cancer care in patients aged 65 years and older in the United States. Methods We identified 763527 patients with breast, colorectal, corpus uteri, gastric, head and neck, lung, melanoma of the skin, ovary, prostate, renal, and urinary bladder cancers from linked Surveillance, Epidemiology, and End Results-Medicare files and 1 145159 noncancer control subjects among Medicare enrollees who were matched by sex, age-group, and geographic location. Frequency of service use was calculated by category for patients and control subjects using Medicare claims data from 1995 to 2001. For each service category, time estimates were combined with service frequency and an hourly value of patient time. Net patient time costs were summed in the initial, continuing, and last-year-of-life phases of care for each tumor site. Net time cost estimates for the initial phase of care were applied to national estimates of numbers of new cancers in 2005 to obtain national time costs for the initial phase of care. Results Net patient time costs during the initial phase of care ranged from $271 (95% confidence interval [CI] = $213 to $329) and $842 (95% CI = $806 to $878) for melanoma of the skin and prostate cancer, respectively, to $5348 (95% CI = $4978 to $5718) and $5605 (95% CI = $5273 to $5937) for gastric and ovarian cancers, respectively. Net patient time costs for care during the last year of life ranged from $1509 (95% CI = $1343 to $1675) for melanoma of the skin to $7799 (95% CI = $7433 to $8165), $7435 (95% CI = $7207 to $7663), and $7388 (95% CI = $7018 to $7758) for gastric, lung, and ovarian cancers, respectively. In 2005, patient time costs for the initial phase of care were $2.3 billion. Conclusions Patient time costs for cancer care in the United States are substantial and vary by tumor site and phase of care, likely reflecting differences in stage at diagnosis and availability and intensity of treatment. C1 NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 35 TC 103 Z9 105 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 3 PY 2007 VL 99 IS 1 BP 14 EP 23 DI 10.1093/jnci/djk001 PG 10 WC Oncology SC Oncology GA 126GF UT WOS:000243499900006 PM 17202109 ER PT J AU Kleinerman, RA Tucker, MA Abramson, DH Seddon, JM Tarone, RE Fraumeni, JF AF Kleinerman, Ruth A. Tucker, Margaret A. Abramson, David H. Seddon, Johanna M. Tarone, Robert E. Fraumeni, Joseph F., Jr. TI Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID 2ND MALIGNANT NEOPLASMS; LONG-TERM SURVIVORS; SOLID TUMORS; BILATERAL RETINOBLASTOMA; CHILDHOOD-CANCER; URINARY-BLADDER; FOLLOW-UP; LEIOMYOSARCOMA; RADIOTHERAPY; GENE AB Background Survivors of hereditary retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated. Methods We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined. Results We observed 69 soft tissue sarcomas in 68 patients with hereditary retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [CI] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% CI = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 435, 95% CI = 258 to 687). Among patients treated with radiotherapy for retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for retinoblastoma was 13.1% (95% CI = 9.7% to 17.0%). Conclusion Long-term follow-up of a cohort of survivors of hereditary retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years. C1 NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Mem Sloan Kettering Canc Ctr, Ophthalm Oncol Serv, New York, NY 10021 USA. Massachusetts Eye & Ear Infirm, Epidemiol Serv, Boston, MA 02114 USA. Int Epidemiol Inst, Rockville, MD USA. RP Kleinerman, RA (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, EPS 7044,6120 Execut Blvd, Rockville, MD 20852 USA. EM kleinerr@mail.nih.gov RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS NR 44 TC 81 Z9 85 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 3 PY 2007 VL 99 IS 1 BP 24 EP 31 DI 10.1093/jnci/djk002 PG 8 WC Oncology SC Oncology GA 126GF UT WOS:000243499900007 PM 17202110 ER PT J AU Ren, JQ Jin, P Wang, E Liu, E Harlan, DM Li, X Stroncek, DF AF Ren, Jiaqiang Jin, Ping Wang, Ena Liu, Eric Harlan, David M. Li, Xin Stroncek, David F. TI Pancreatic islet cell therapy for type I diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID INSULIN GENE-TRANSCRIPTION; EMBRYONIC STEM-CELLS; SHORT-TERM REGULATION; ISOLATED RAT ISLETS; BETA-CELLS; MESSENGER-RNA; PROINSULIN BIOSYNTHESIS; TRANSLATIONAL CONTROL; PROTEIN-SYNTHESIS; DUODENAL HOMEOBOX-1 AB While insulin replacement remains the cornerstone treatment for type I diabetes mellitus (T1DM), the transplantation of pancreatic islets of Langerhans has the potential to become an important alternative. And yet, islet transplant therapy is limited by several factors, including far too few donor pancreases. Attempts to expand mature islets or to produce islets from stem cells are far from clinical application. The production and expansion of the insulin-producing cells within the islet ( so called beta cells), or even creating cells that secrete insulin under appropriate physiological control, has proven difficult. The difficulty is explained, in part, because insulin synthesis and release is complex, unique, and not entirely characterized. Understanding beta-cell function at the molecular level will likely facilitate the development of techniques to manufacture beta-cells from stem cells. We will review islet transplantation, as well as the mechanisms underlying insulin transcription, translation and glucose stimulated insulin release. C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM renj@mail.nih.gov; PJin@mail.cc.nih.gov; EWang@cc.nih.gov; ericliu@niddk.nih.gov; DavidmH@intra.niddk.nih.gov; lixin2@cc.nih.gov; DStroncek@cc.nih.gov NR 119 TC 11 Z9 16 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JAN 3 PY 2007 VL 5 AR 1 DI 10.1186/1479-5876-5-1 PG 15 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 129HI UT WOS:000243719000001 PM 17201925 ER PT J AU Park, ES Lee, JS Woo, HG Zhan, FH Shih, JH Shaughnessy, JD Mushinski, JF AF Park, Eun Sung Lee, Ju-Seog Woo, Hyun Goo Zhan, Fenghuang Shih, Joanna H. Shaughnessy, John D., Jr. Mushinski, J. Frederic TI Heterologous Tissue Culture Expression Signature Predicts Human Breast Cancer Prognosis SO PLOS ONE LA English DT Article AB Background. Cancer patients have highly variable clinical outcomes owing to many factors, among which are genes that determine the likelihood of invasion and metastasis. This predisposition can be reflected in the gene expression pattern of the primary tumor, which may predict outcomes and guide the choice of treatment better than other clinical predictors. Methodology/Principal Findings. We developed an mRNA expression-based model that can predict prognosis/outcomes of human breast cancer patients regardless of microarray platform and patient group. Our model was developed using genes differentially expressed in mouse plasma cell tumors growing in vivo versus those growing in vitro. The prediction system was validated using published data from three cohorts of patients for whom microarray and clinical data had been compiled. The model stratified patients into four independent survival groups (BEST, GOOD, BAD, and WORST: log-rank test p = 1.7x10(-8)). Conclusions. Our model significantly improved the survival prediction over other expression-based models and permitted recognition of patients with different prognoses within the estrogen receptor-positive group and within a single pathological tumor class. Basing our predictor on a dataset that originated in a different species and a different cell type may have rendered it less sensitive to proliferation differences and endowed it with wide applicability. Significance. Prognosis prediction for patients with breast cancer is currently based on histopathological typing and estrogen receptor positivity. Yet both assays define groups that are heterogeneous in survival. Gene expression profiling allows subdivision of these groups and recognition of patients whose tumors are very unlikely to be lethal and those with much grimmer outlooks, which can augment the predictive power of conventional tumor analysis and aid the clinician in choosing relaxed vs. aggressive therapy. C1 [Park, Eun Sung; Mushinski, J. Frederic] NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lee, Ju-Seog; Woo, Hyun Goo] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Zhan, Fenghuang; Shaughnessy, John D., Jr.] Univ Arkansas Med Sci, Donna & Donald Lambert Lab Myeloma Genet, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. RP Park, ES (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM parkeu@mail.nih.gov; jm8p@nih.gov FU NIH; National Cancer Institute; National Institutes of Health [CA55819, CA97513] FX This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. JDS and FZ were supported by National Institutes of Health grants CA55819 and CA97513, the Fund to Cure Myeloma and the Peninsula Community Foundation. NR 28 TC 6 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JAN 3 PY 2007 VL 2 IS 1 AR e145 DI 10.1371/journal.pone.0000145 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DD UT WOS:000207443800007 PM 17206280 ER PT J AU Mulligan, K Yang, Y Wininger, DA Koletar, SL Parker, RA Alston-Smith, BL Schouten, JT Fielding, RA Basar, MT Grinspoon, S AF Mulligan, Kathleen Yang, Yang Wininger, David A. Koletar, Susan L. Parker, Robert A. Alston-Smith, Beverly L. Schouten, Jeffrey T. Fielding, Roger A. Basar, Michael T. Grinspoon, Steven TI Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio SO AIDS LA English DT Article DE fat distribution; HIV; insulin resistance; lipodystrophy; metformin; rosiglitazone ID BODY-FAT DISTRIBUTION; RANDOMIZED CONTROLLED-TRIAL; II DIABETES-MELLITUS; INSULIN SENSITIVITY; DOUBLE-BLIND; ANTIRETROVIRAL THERAPY; COMBINATION THERAPY; MITOCHONDRIAL-DNA; LIPODYSTROPHY; TROGLITAZONE AB Objective: To evaluate the effects of metformin and rosiglitazone, alone or in combination, on fat distribution, insulin sensitivity, and lipids in HIV-infected patients with insulin resistance and changes in fat distribution. Methods: A total of 105 subjects were randomly assigned to receive metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks) with rosiglitazone placebo (Met/P, N=26); rosiglitazone (4 mg/day) with metformin placebo (Rosi/P, N=27); rosiglitazone (4 mg/day) plus metformin (500 mg twice a day increasing to 1000 mg twice a day after 2 weeks; Met/Rosi, N=25); or dual placebo (P/P, N=27) for 16 weeks. Efficacy assessments included oral glucose tolerance testing, abdominal computed tomography, whole-body dual-energy X-ray absorptiometry, and the measurement of fasting lipids and other biochemical indices. Safety was monitored throughout. Intent-to-treat analyses were performed using non-parametric methods. Results: The median insulin area under the curve (AUC) decreased significantly compared with baseline in both groups randomly assigned to rosiglitazone (Rosi/P -25.7 mu IU/ml, P=0.012; Met/Rosi -17.7 mu IU/ml, P=0.002); and tended to decrease in the Met/P group (-11.1 mu IU/ml, P=0.058). The change in AUC with combination therapy was significant compared with placebo (P=0.032). No treatment was associated with significant changes in visceral or subcutaneous abdominal fat. Leg fat increased in subjects on Rosi/P compared with placebo (+4.8 versus -8.3%, P=0.034). Rosiglitazone, but not metformin, increased adiponectin but also increased LDL-cholesterol and decreased HDL-cholesterol. Gastrointestinal effects occurred frequently in subjects on metformin. Conclusion: Both treatments improved insulin sensitivity, but neither reduced visceral fat. Rosiglitazone may increase subcutaneous fat in some individuals. (c) 2007 Lippincott Williams & Wilkins. C1 Univ Calif San Francisco, Div Endocrinol, San Francisco Gen Hosp, San Francisco, CA 94110 USA. Harvard Univ, Stat & Data Anal Ctr, Boston, MA 02115 USA. Ohio State Univ, Columbus, OH 43210 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Tufts Univ, Boston, MA 02111 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Mulligan, K (reprint author), Univ Calif San Francisco, Div Endocrinol, San Francisco Gen Hosp, Bldg 30,Room 3501K,1001 Potrero Ave, San Francisco, CA 94110 USA. EM kmulligan@sfghgcrc.ucsf.edu FU NCRR NIH HHS [RR00096, RR000750, RR00052, RR00083]; NIAID NIH HHS [AI34853, AI46370, AI27673, AI25897, AI27660, AI38855, AI25924, AI27665, AI25903, AI027666, AI032783, AI27663, AI25859, AI27661, AI27664, AI46339, AI25915, AI27670, AI27659, AI38858, AI27668] NR 37 TC 60 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 2 PY 2007 VL 21 IS 1 BP 47 EP 57 DI 10.1097/QAD.0b013e328011220e PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 125CK UT WOS:000243418900006 PM 17148967 ER PT J AU Morrison, CS Richardson, BA Mmiro, F Chipato, T Celentano, DD Luoto, J Mugerwa, R Padian, N Rugpao, S Brown, JM Cornelisse, P Salata, RA AF Morrison, Charles S. Richardson, Barbra A. Mmiro, Francis Chipato, Tsungai Celentano, David D. Luoto, Joanne Mugerwa, Roy Padian, Nancy Rugpao, Sungwal Brown, Joelle M. Cornelisse, Peter Salata, Robert A. CA HC-HIV Study Grp TI Hormonal contraception and the risk of HIV acquisition SO AIDS LA English DT Article DE hormonal contraception; HIV acquisition; oral contraceptives; Depo-provera; heterosexual transmission; women; herpes virus ID IMMUNODEFICIENCY-VIRUS TYPE-1; SEXUALLY-TRANSMITTED-DISEASES; NORTHERN THAILAND; CERVICAL ECTOPY; SEX WORKERS; INFECTION; TRANSMISSION; WOMEN; SEROCONVERSION; EPITHELIUM AB Background: Combined oral contraceptives (COC) and depot-medroxyprogesterone acetate (DMPA) are among the most widely used family planning methods; their effect on HIV acquisition is not known. Objective: To evaluate the effect of COC and DMPA on HIV acquisition and any modifying effects of other sexually transmitted infections. Methods: This multicenter prospective cohort study enroled 6109 HIV-uninfected women, aged 18-35 years, from family planning clinics in Uganda, Zimbabwe and Thailand. Participants received HIV testing quarterly for 15-24 months. The risk of HIV acquisition with different contraceptive methods was assessed (excluding Thailand, where there were few HIV cases). Results: HIV infection occurred in 213 African participants (2.8/100 woman-years). Use of neither COC [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.69-1.42] nor DMPA (HR, 1.25; 95% CI, 0.89-1.78) was associated with risk of HIV acquisition overall, including among participants with cervical or vaginal infections. While absolute risk of HIV acquisition was higher among participants who were seropositive for herpes simplex virus 2 (HSV-2) than in those seronegative at enrolment, among the HSV-2-seronegative participants, both COC (HR, 2.85; 95% CI, 1.39-5.82) and DMPA (HR, 3.97; 95% CI, 1.98-8.00) users had an increased risk of HIV acquisition compared with the non-hormonal group. Conclusions: No association was found between hormonal contraceptive use and HIV acquisition overall. This is reassuring for women needing effective contraception in settings of high HIV prevalence. However, hormonal contraceptive users who were HSV-2 seronegative had an increased risk of HIV acquisition. Additional research is needed to confirm and explain this finding. (c) 2007 Lippincott Williams & Wilkins. C1 Family Hlth Int, Dept Clin Res, Res Triangle Pk, NC 27709 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent SCHARP, Seattle, WA 98104 USA. Childrens Hosp & Reg Med Ctr, Stat Anal Unit, Cyst Fibrosis Therapeut Dev Network, Seattle, WA USA. Makerere Univ, Fac Med, Kampala, Uganda. Univ Zimbabwe, Dept Obstet & Gynecol, Harare, Zimbabwe. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NICHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. Chiang Mai Univ, RIHES, Res Inst Hlth Sci, Chiang Mai 50000, Thailand. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. RP Morrison, CS (reprint author), Family Hlth Int, Dept Clin Res, POB 13950, Res Triangle Pk, NC 27709 USA. EM cmorrison@fhi.org FU NICHD NIH HHS [N01-HD-0-3310] NR 39 TC 133 Z9 136 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 2 PY 2007 VL 21 IS 1 BP 85 EP 95 DI 10.1097/QAD.0b013e3280117c8b PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 125CK UT WOS:000243418900011 PM 17148972 ER PT J AU Thiebaut, ACM Freedman, LS Carroll, RJ Kipnis, V AF Thiebaut, Anne C. M. Freedman, Laurence S. Carroll, Raymond J. Kipnis, Victor TI Is it necessary to correct for measurement error in nutritional epidemiology? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID DIETARY MEASUREMENT ERROR; RELATIVE RISK; CONFIDENCE-INTERVALS; CALIBRATION; EXPOSURE; CANCER; DESIGN; COHORT C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Gertner Inst Epidemiol & Hlth Policy Res, IL-52161 Tel Hashomer, Israel. Texas A&M Univ, College Stn, TX 77843 USA. RP Kipnis, V (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. EM kipnisv@mail.nih.gov FU NCI NIH HHS [CA-57030]; NIEHS NIH HHS [P30-ES09106] NR 17 TC 18 Z9 19 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 2 PY 2007 VL 146 IS 1 BP 65 EP W10 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 188BK UT WOS:000247893300010 PM 17200225 ER PT J AU Kieburtz, K Ravina, B Galpern, WR Tilley, B Shannon, K Tanner, C Wooten, GF AF Kieburtz, Karl Ravina, Bernard Galpern, Wendy R. Tilley, Barbara Shannon, Kathleen Tanner, Caroline Wooten, G. Frederick CA NINDS TI A randomized clinical trial of coenzyme Q(10) and GPI-1485 in early Parkinson disease SO NEUROLOGY LA English DT Article ID GERIATRIC DEPRESSION SCALE; IMMUNOPHILIN LIGANDS; LIPID-PEROXIDATION; NERVE REGENERATION; FUTILITY; MITOCHONDRIA; PROGRESSION; MORTALITY; MODELS AB Objective: To determine if future studies of coenzyme Q(10) and GPI-1485 in Parkinson disease (PD) may be warranted. Methods: We conducted a randomized, double-blind, calibrated futility clinical trial of coenzyme Q(10) and GPI-1485 in early untreated PD using placebo data from the DATATOP study to establish the futility threshold. Results: The primary outcome measure ( change in total Unified Parkinson's Disease Rating Scale scores over 1 year) did not meet the prespecified criteria for futility for either agent. Secondary analyses using calibration controls and other more recent placebo data question the appropriateness of the predetermined definition of futility, and suggest that a more restrictive threshold may be needed. Conclusions: Coenzyme Q(10) and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. Additional factors (cost, availability of other agents, more recent data on placebo outcomes, other ongoing trials) should also be considered in the selection of agents for Phase III studies. C1 Univ Rochester, Med Ctr, Coordinat Ctr, Rochester, NY 14620 USA. NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Ctr Stat, Charlotte, NC USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Parkinsons Inst, Sunnyvale, CA USA. Univ Virginia, Charlottesville, VA USA. RP Kieburtz, K (reprint author), Univ Rochester, Med Ctr, Coordinat Ctr, 1351 Mt Hope Ave,Ste 223, Rochester, NY 14620 USA. EM Karl.Kieburtz@ctcc.rochester.edu OI Miyasaki, Janis/0000-0002-6372-6007 NR 44 TC 131 Z9 133 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 2 PY 2007 VL 68 IS 1 BP 20 EP 28 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 122KA UT WOS:000243224000007 ER PT J AU Cohen, JI AF Cohen, Jeffrey I. TI Varicella-zoster vaccine virus: Evolution in action SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID COMPLETE DNA-SEQUENCE; PHYLOGENETIC ANALYSIS; OKA; GENOTYPES; STRAIN; SPREAD; RECOMBINATION; TRANSMISSION; ATTENUATION; LEUKEMIA C1 Natl Inst Hlth, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20982 USA. RP Cohen, JI (reprint author), Natl Inst Hlth, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20982 USA. EM jcohen@niaid.nih.gov NR 20 TC 2 Z9 3 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2007 VL 104 IS 1 BP 7 EP 8 DI 10.1073/pnas.0610016103 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125QF UT WOS:000243456300003 PM 17185410 ER PT J AU Tanaka, M Chock, PB Stadtman, ER AF Tanaka, Mikiei Chock, P. Boon Stadtman, Earl R. TI Oxidized messenger RNA induces translation errors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 8-oxoguanosine; firefly luciferase; premature termination; RNA oxidation; reactive oxygen species ID ALZHEIMERS-DISEASE; PROMINENT FEATURE; OXIDATIVE DNA; DAMAGE; NEURONS AB To investigate the effect of RNA oxidation on normal cellular functions, we studied the translation of nonoxidized and oxidized luciferase mRNA in both rabbit reticulocyte lysate and human HEK293 cells. When HEK293 cells transfected with nonoxidized mRNA encoding the firefly lucif erase protein were cultured in the presence of paraquat, there was a paraquat concentration-dependent increase in the formation of luciferase short polypeptides (SPs) concomitant with an increase in 8-oxoguanosine. Short polypeptides were also formed when the mRNA was oxidized in vitro by the Fe-ascorbate-H2O2 metal-catalyzed oxidation system before its transfection into cells. Translation of the in vitro oxidized mRNA in rabbit reticulocyte lysate also led to formation of SPs. The SPs formed by either procedure contained the N-terminal and the C-terminal portions of the tagged luciferase. In addition, the oxidized mRNA was able to associate with ribosomes to form polysomes similar to those formed with nonoxidized mRNA preparations, indicating that the oxidized mRNAs are mostly intact; however, their translation fidelity was significantly reduced. Nevertheless, our results indicate that the SPs were derived from both premature termination of the translation process of the oxidized mRNA and the proteolytic degradation of the modified full-length luciferase resulting from translation errors induced by oxidized mRNA. In light of these findings, the physiological consequences of mRNA oxidation are discussed. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Chock, PB (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2134,50 S Dr,MSC-8012, Bethesda, MD 20892 USA. EM bchock@nih.gov; erstadtman@nih.gov FU Intramural NIH HHS NR 15 TC 107 Z9 108 U1 2 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2007 VL 104 IS 1 BP 66 EP 71 DI 10.1073/pnas.0609737104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125QF UT WOS:000243456300014 PM 17190801 ER PT J AU Kubler-Kielb, J Majadly, F Wu, YM Narum, DL Guo, CY Miller, LH Shiloach, J Robbins, JB Schneerson, R AF Kubler-Kielb, Joanna Majadly, Fathy Wu, Yimin Narum, David L. Guo, Chunyan Miller, Louis H. Shiloach, Joseph Robbins, John B. Schneerson, Rachel TI Long-lasting and transmission-blocking activity of antibodies to Plasmodium falciparum elicited in mice by protein conjugates of Pfs25 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE malaria; vaccine ID VACCINE CANDIDATE; SEXUAL STAGE; MALARIA; IMMUNOGENICITY; TARGET; ANTIGENS AB Malaria is a leading cause of morbidity and mortality, estimated to cause > 1 million childhood deaths annually. Plasmodium falciparum causes the most severe form of the disease. There is as yet no licensed vaccine for this disease, despite over a half century of research. In this study, we investigated a transmission-blocking vaccine candidate, the ookinete surface protein Pfs25. Antibodies against Pfs25, drawn in during a bite, can block parasite development in the mosquito midgut, preventing transmission to other individuals. Pfs25 is a low-molecular-weight protein, by itself not immunogenic. To increase its immunogenicity, we investigated several methods of conjugating Pfs25 to itself and to other proteins: recombinant Pseudomonas aeruginosa exotoxin A, and ovalbumin, using amide, hydrazone, or thioether linkages. All conjugates were immunogenic and induced booster responses in mice. The scheme to form amide bonds between proteins by using adipic acid dihydrizide as a linker produced the most immunogenic conjugates. Adsorption of the conjugates onto aluminum hydroxide further increased the antibody response. Remarkably, the antibody levels 3 or 7 months after the last injection were significantly higher than those 1 wk after that injection. The observed transmission-blocking activity of immune sera correlated with antibody levels measured by ELISA. C1 NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. NICHHD, Dev & Mol Immun Lab, NIH, Rockville, MD 20852 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, 5640 Fishers Lane,MSC 8152, Rockville, MD 20852 USA. EM louis_miller@nih.gov; schneerr@mail.nih.gov FU Intramural NIH HHS NR 29 TC 53 Z9 60 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2007 VL 104 IS 1 BP 293 EP 298 DI 10.1073/pnas.0609885104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125QF UT WOS:000243456300054 PM 17190797 ER PT J AU Nikolenko, GN Delviks-Frankenberry, KA Palmer, S Maldarelli, F Fivash, MJ Coffin, JM Pathak, VK AF Nikolenko, Galina N. Delviks-Frankenberry, Krista A. Palmer, Sarah Maldarelli, Frank Fivash, Matthew J., Jr. Coffin, John M. Pathak, Vinay K. TI Mutations in the connection domain of HIV-1 reverse transcriptase increase 3 '-azido-3 '-deoxythymidine resistance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug resistance; excision; recombination; RNase H; thymidine analog mutations ID IMMUNODEFICIENCY-VIRUS TYPE-1; RNASE-H ACTIVITY; TERMINATED DNA-SYNTHESIS; M184V MUTATION; L74V MUTATION; PRIMER GRIP; ZIDOVUDINE; FREQUENCY; REPLICATION; NUCLEOSIDE AB We previously proposed that a balance between nucleotide excision and template RNA degradation plays an important role in nucleoside reverse transcriptase inhibitor (NRTI) resistance. To explore the predictions of this concept, we analyzed the role of patient-derived C-terminal domains of HIV-1 reverse transcriptase (RT) in NRTI resistance. We found that when the polymerase domain contained previously described thymidine analog resistance mutations, mutations in the connection domain increased resistance to 3'-azido-3'-deoxythymidine (AZT) from 11-fold to as much as 536-fold over wild-type RT. Mutational analysis showed that amino acid substitutions E312Q, G335C/D, N3481, A3601/V, V36511 and A376S were associated strongly with the observed increase in AZT resistance; several of these mutations also decreased RT template switching, suggesting that they alter the predicted balance between nucleotide excision and template RNA degradation. These results indicate that mutations in the C-terminal domain of RT significantly enhance clinical NRTI resistance and should be considered in genotypic and phenotypic drug resistance studies. C1 NCI, Viral Mutat Sect, Frederick, MD 21702 USA. NCI, Host Virus Interact Unit, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Data Management Serv Inc, Frederick, MD 21702 USA. RP Coffin, JM (reprint author), NCI, Viral Mutat Sect, Frederick, MD 21702 USA. EM john.coffin@tufts.edu; vpathak@ncifcrf.gov RI Delviks-Frankenberry, Krista/M-4822-2013 FU Intramural NIH HHS NR 24 TC 100 Z9 105 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2007 VL 104 IS 1 BP 317 EP 322 DI 10.1073/pnas.0609642104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125QF UT WOS:000243456300058 PM 17179211 ER PT J AU Rummel, A Eichner, T Weil, T Karnath, T Gutcaits, A Mahrhold, S Sandhoff, K Proia, RL Acharya, KR Bigalke, H Binz, T AF Rummel, Andreas Eichner, Timo Weil, Tanja Karnath, Tino Gutcaits, Aleksandrs Mahrhold, Stefan Sandhoff, Konrad Proia, Richard L. Acharya, K. Ravi Bigalke, Hans Binz, Thomas TI Identification of the protein receptor binding site of botulinum neurotoxins B and G oroves the double-receptor concept SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE synaptotagmin; tetanus ID TETANUS TOXIN REQUIRES; C-TERMINAL HALF; CLOSTRIDIAL NEUROTOXINS; GANGLIOSIDE BINDING; SENSITIVE RECEPTOR; MEMBRANE-RECEPTORS; CRYSTAL-STRUCTURE; SYNAPTOTAGMIN-I; FRAGMENT C; H-C AB Botulinum neurotoxins (BoNTs) cause muscle paralysis by selectively cleaving core components of the vesicular fusion machinery within motoneurons. Complex gangliosides initially bind into a pocket that is conserved among the seven BoNTs and tetanus neurotoxin. Productive neurotoxin uptake also requires protein receptors. The interaction site of the protein receptor within the neurotoxin is currently unknown. We report the identification and characterization of the protein receptor binding site of BoNT/B and BoNT/G. Their protein receptors, synaptotagimins I and II, bind to a pocket at the tip of their H-cc (C-terminal domain of the C-terminal fragment of the heavy chain) that corresponds to the unique second carbohydrate binding site of tetanus neurotoxin, the sialic acid binding site. Substitution of amino acids in this region impaired binding to synaptotagmins and drastically decreased toxicity at mouse phrenic nerve preparations; CD-spectroscopic analyses evidenced that the secondary structure of the mutated neurotoxins was unaltered. Deactivation of the synaptotagmin binding site by single mutations led to virtually inactive BoNT/B and BoNT/G when assayed at phrenic nerve preparations of complex-ganglioside-deficient mice. Analogously, a BoNT B mutant with deactivated ganglioside and synaptotagmin binding sites lacked appreciable activity at wild-type mouse phrenic nerve preparations. Thus, these data exclude relevant contributions of any cell surface molecule other than one ganglioside and one protein receptor to the entry process of BoNTs, which substantiates the double-receptor concept. The molecular characterization of the synaptotagmin binding site provides the basis for designing a novel class of potent binding inhibitors. C1 Hannover Med Sch, Inst Biochem, D-30625 Hannover, Germany. Hannover Med Sch, Inst Toxikol, D-30625 Hannover, Germany. Merz Pharmaceut GmbH, D-60318 Frankfurt, Germany. Univ Bonn, Kekule Inst Organ Chem & Biochem, D-53121 Bonn, Germany. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. RP Rummel, A (reprint author), Hannover Med Sch, Inst Biochem, OE 4310,Carl Neuberg Str 1, D-30625 Hannover, Germany. EM rummel.andreas@mh-hannover.de; binz.thomas@mh-hannover.de RI Proia, Richard/A-7908-2012; Rummel, Andreas/I-7449-2013 NR 40 TC 104 Z9 108 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 2 PY 2007 VL 104 IS 1 BP 359 EP 364 DI 10.1073/pnas.0609713104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 125QF UT WOS:000243456300065 PM 17185412 ER PT B AU Srivastava, NR Troyk, PR Towle, VL Curry, D Schmidt, E Kufta, C Dagnelie, G AF Srivastava, N. R. Troyk, P. R. Towle, V. L. Curry, D. Schmidt, E. Kufta, C. Dagnelie, G. GP IEEE TI Estimating phosphene maps for psychophysical experiments used in testing a cortical visual prosthesis device SO 2007 3RD INTERNATIONAL IEEE/EMBS CONFERENCE ON NEURAL ENGINEERING, VOLS 1 AND 2 LA English DT Proceedings Paper CT 3rd International IEEE/EMBS Conference on Neural Engineering CY MAY 02-05, 2007 CL Kohala Coast, HI SP IEEE, EMBS ID PIXELIZED VISION SYSTEM; HUMAN OCCIPITAL CORTEX; ELECTRICAL-STIMULATION; INTRACORTICAL MICROSTIMULATION; BLIND; HUMANS; AREAS AB Visual prosthesis devices are being developed to restore vision for those with blindness. Researchers working in the field of visual prosthesis are taking different approaches to develop a practical device. Some are targeting the retina for stimulation, whereas at least one group is targeting the optical nerve, and our laboratory is developing a system for the visual cortex. To estimate the kind of response they might expect from a typical user, researchers are conducting psychophysical. experiments on normally-sighted persons. The device being developed in our laboratory is a first generation visual prosthesis system, designed to test the limits of artificial visual pattern recognition. Targeting the visual cortex area with our first generation device has limitations including limitations in lateral cortical surface area for electrode implantation, surgical difficulties and the lack of understanding as to how to use an artificial interface for communication with the visual cortex. Here, we discuss the uncertainties related to visotopic mapping of the lateral surface of the occipital lobe in humans. C1 [Srivastava, N. R.; Troyk, P. R.] IIT, Dept Biomed Engn, Chicago, IL 60616 USA. [Towle, V. L.] Univ Chicago, Dept Neurol, Chicago, IL 60637 USA. [Curry, D.] Univ Chicago, Chicago, IL 60637 USA. [Schmidt, E.] NIH, Easton, MD USA. [Kufta, C.] NIH, Frederick, MD USA. [Dagnelie, G.] Johns Hopkins Univ, Baltimore, MD USA. RP Srivastava, NR (reprint author), IIT, Dept Biomed Engn, Chicago, IL 60616 USA. EM srivnis@iit.edu FU Brain Research Foundation; private donations; NIH [R01 EB002184] FX Funding by the Brain Research Foundation, private donations, and NIH grant R01 EB002184. NR 24 TC 1 Z9 1 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0791-0 PY 2007 BP 130 EP + DI 10.1109/CNE.2007.369629 PG 2 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Neurosciences SC Engineering; Science & Technology - Other Topics; Neurosciences & Neurology GA BGM68 UT WOS:000248513500034 ER PT B AU Li, RJ Principe, JC Bradley, M Ferrari, V AF Li, Ruijiang Principe, Jose C. Bradley, Margaret Ferrari, Vera GP IEEE TI Single-trial ERP estimation based on spatio-temporal filtering SO 2007 3RD INTERNATIONAL IEEE/EMBS CONFERENCE ON NEURAL ENGINEERING, VOLS 1 AND 2 LA English DT Proceedings Paper CT 3rd International IEEE/EMBS Conference on Neural Engineering CY MAY 02-05, 2007 CL Kohala Coast, HI SP IEEE, EMBS ID INDEPENDENT COMPONENT ANALYSIS; EEG; LOCALIZATION AB This paper introduces a new approach to the problem of single-trial event-related potentials (ERP) estimation in EEG data with very low signal-to-noise (SNR) ratio. The method relies on modeling of the ERP component descriptors to be estimated and utilizes a spatial filter to constrain the output in the temporal domain. Results on cognitive EEG data with very low SNR show that our method successfully extracts the P300 component while other traditional methods fail. Some possible improvements on the present method are also discussed. C1 [Li, Ruijiang; Principe, Jose C.] Univ Florida, Dept Elect & Comp Engn, Computat Neuroengn Lab, Gainesville, FL 32611 USA. [Bradley, Margaret; Ferrari, Vera] Univ Florida, Ctr Study Emot & Attent, NIMH, Gainesville, FL 32611 USA. RP Li, RJ (reprint author), Univ Florida, Dept Elect & Comp Engn, Computat Neuroengn Lab, Gainesville, FL 32611 USA. EM ruijiang@cnel.ufl.edu; principe@cnel.ufl.edu; bradley@ufl.edu; ferrari@biocfarm.unibo.it FU Graduate Alumni Fellowship from University of Florida and the National Institute of Mental Health (NIMH) [P50 MH072850-01] FX This work was jointly supported by Graduate Alumni Fellowship from University of Florida and the National Institute of Mental Health (NIMH) grant P50 MH072850-01. NR 15 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0791-0 PY 2007 BP 538 EP + DI 10.1109/CNE.2007.369728 PG 2 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Neurosciences SC Engineering; Science & Technology - Other Topics; Neurosciences & Neurology GA BGM68 UT WOS:000248513500133 ER PT S AU Aksit, P Derbyshire, JA Prince, JL AF Aksit, Pelin Derbyshire, John A. Prince, Jerry L. GP IEEE TI Three-point method for fast and robust field mapping for EPI geometric distortion correction SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE magnetic resonance imaging; error correction; phase distortion; phase measurement AB Because of its superb temporal resolution, echo planar imaging (EPI) is widely used for functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and monitoring dynamic processes. EPI suffers from geometric distortions caused by magnetic field inhomogeneities, and although these distortions can be corrected by field mapping, current methods require lengthy auxiliary image acquisitions and/or phase unwrapping. We present a 3-point method for field mapping that circumvents these problems and is robust to additive noise. Results demonstrate that the performance of this approach is markedly better than the standard two-oint method and is comparable to methods requiring much longer auxiliary image acquisitions. C1 [Aksit, Pelin] GE Healthcare, Global Appl Sci Lab, Uppsala, Sweden. NIH, NHLBI, Cardiac Energet Lab, Bethesda, MD USA. Johns Hopkins Univ, Elect & Comp Engn, Image Anal & Commun Lab, Baltimore, MD 21218 USA. RP Aksit, P (reprint author), GE Healthcare, Global Appl Sci Lab, Uppsala, Sweden. RI Prince, Jerry/A-3281-2010; Ciris, Pelin/A-2796-2016 OI Prince, Jerry/0000-0002-6553-0876; Ciris, Pelin/0000-0002-6405-2462 NR 8 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 141 EP + DI 10.1109/ISBI.2007.356808 PG 3 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300036 ER PT S AU Aganj, L Bartesaghi, A Borgnia, M Liao, HY Sapiro, G Subramaniam, S AF Aganj, L. Bartesaghi, A. Borgnia, M. Liao, H. Y. Sapiro, G. Subramaniam, S. GP IEEE TI Regularization for inverting the radon transform with wedge consideration SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE limited angle tomography; missing wedge; non linear regularization; directional smoothing ID ANGLE TOMOGRAPHY; RECONSTRUCTION AB In limited angle tomography, with applications such as electron microscopy, medical imaging, and industrial testing, the object of interest is scanned over a limited angular range, which is less than the full 180 mathematically required for density reconstruction. The use of standard full-range reconstruction algorithms produces results with notorious "butterfly" or "wedge" artifacts. In this work we propose a reconstruction technique with a regularization term that takes into account the orientation of the missing angular range, also denoted as missing wedge. We show that a regularization that penalizes non-uniformly in the orientation space produces reconstructions with less artifacts, thereby improving the recovery of the "invisible" edges due to the missing wedge. We present the underlying framework and results for a challenging phantom and real cryo-electron microscopy data. C1 [Aganj, L.; Sapiro, G.] Univ Minnesota, Dept Elect Engn, 200 Union St SE, Minneapolis, MN 55455 USA. [Liao, H. Y.] Univ Minnesota, Inst Math & Its Appl, Minneapolis, MN 55455 USA. [Bartesaghi, A.; Borgnia, M.; Subramaniam, S.] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Aganj, L (reprint author), Univ Minnesota, Dept Elect Engn, 200 Union St SE, Minneapolis, MN 55455 USA. FU NSF; NIH; ONR; NGA; DARPA; IMA; MCKNIGHT FOUNDATION FX WORK SUPPORTED BY NSF, NIH, ONR, NGA, DARPA, IMA, AND THE MCKNIGHT FOUNDATION NR 10 TC 2 Z9 2 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 217 EP + DI 10.1109/ISBI.2007.356827 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300055 ER PT S AU Subramaniam, S AF Subramaniam, Sriram GP IEEE TI Determination of protein structures in situ: Electron tomography of intact viruses and cells SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE AB Electron tomography is a powerful tool for investigation of the three-dimensional structures of large sub-cellular assemblies at resolutions one to two orders of magnitude higher than what is currently achieved using light microscopy. This field has seen a significant burst of activity in the last few years with the availability of tools for automated data acquisition using modern computerized microscopes. Efforts at imaging complex assemblies at room temperature using stained specimens, as well as cryogenic temperatures using unstained specimens have rapidly begun to provide many new insights into the 3D architecture of cells and viruses. In our laboratory, we are using three-dimensional electron microscopy as a tool to discover and analyze the spatial architectures of receptors and membrane assemblies in viruses, cells and tissues. The electron microscopic studies bridge the gap between cellular and molecular structure, and provide a foundation to integrate the structural information with biochemical and genetic analyses. Here, I focus on challenges in using electron tomography to extract structural information on proteins and protein complexes by molecular averaging (text is based largely on material presented in Subramaniam 2006 [1] and Zhang et al 2006 [2]). C1 NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 233 EP 235 DI 10.1109/ISBI.2007.356831 PG 3 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300059 ER PT S AU Bartesaghi, A Sprechmann, P Randall, G Sapiro, G Subramaniam, S AF Bartesaghi, A. Sprechmann, P. Randall, G. Sapiro, G. Subramaniam, S. GP IEEE TI Classification, averaging and reconstruction of macromolecules in electron tomography SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE tomography; image registration; image classification; clustering methods AB Electron tomography provides opportunities to determine three-dimensional cellular architecture at resolutions high enough to identify individual macromolecules such as proteins. Image analysis of such data poses a challenging problem due to the extremely low signal-to-noise ratios that makes individual volumes simply too noisy to allow reliable structural interpretation. This requires using averaging techniques to boost the signal-to-noise ratios, a common practice in electron microscopy single particle analysis where they have proven to be very powerful in elucidating high resolution structure. Although there are significant similarities in the way data is processed, several new problems arise in the tomography case that have to be properly dealt with. Such problems involve dealing with the missing wedge characteristic of limited angle tomography, the need for robust and efficient 3D alignment routines, and design of methods that account for diverse conformations through the use of classification. We present a framework for reconstruction via alignment, classification and averaging of volumes obtained from limited angle electron tomography, providing a powerful tool for high resolution structure determination and description of conformational variability in a biological context. C1 [Bartesaghi, A.; Subramaniam, S.] NIH, Canc Res Ctr, Bldg 10, Bethesda, MD 20892 USA. [Sprechmann, P.; Randall, G.] Univ Republic, Inst Ingn Elect, Montevideo 11800, Uruguay. [Sapiro, G.] Univ Minnesota, Elect & Comp Engn Dept, Minneapolis, MN 55455 USA. RP Bartesaghi, A (reprint author), NIH, Canc Res Ctr, Bldg 10, Bethesda, MD 20892 USA. FU ONR; NSF; DARPA; NGA FX This work has been partially supported by ONR, NSF, DARPA, and NGA. PS and GR performed part of this work while at the University of Minnesota visiting ECE and IMA NR 7 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 244 EP + DI 10.1109/ISBI.2007.356834 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300062 ER PT S AU McCullough, DP Gudla, PR Meaburn, K Kumar, A Kuehn, M Lockett, SJ AF McCullough, Dean P. Gudla, Prabhakar R. Meaburn, Karen Kumar, Amit Kuehn, Michael Lockett, Stephen J. GP IEEE TI 3D segmentation of whole cells and cell nuclei in tissue using dynamic programming SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE confocal microscopy; image segmentation; dynamic programming ID IMAGE SEGMENTATION; MODEL AB We present a highly robust, semi-automatic algorithm for segmenting individual, fluorescence-labeled, whole cells or cell nuclei (objects) from 3D confocal microscope images of tissue. The core of the algorithm is an extension of dynamic programming that finds the surface as a series of overlapping ribbons, where the mean intensity per unit area within each ribbon is a global maximum. Consequently, the segmented surface is not significantly affected by intermittent fluorescence labeling, diffuse borders or by spurious signals away from the borders. Minimal interaction by the user ensures correct segmentation of each object, yet segmenting 10s to 100s of objects per sample is feasible. The algorithm enables for the first time quantitative analysis and modeling of communication processes between cells in intact tissue. C1 [McCullough, Dean P.] High Performance Technologies Inc, Reston, VA 20190 USA. [Gudla, Prabhakar R.; Lockett, Stephen J.] NCI, Image Anal Lab, SAIC, Ft Detrick, MD 21702 USA. [Meaburn, Karen] NCI, Cell Biol Genomes Grp, Bethesda, MD USA. [Kumar, Amit; Kuehn, Michael] NCI, Lab Protein Dynam & Signalling, Frederick, MD USA. RP McCullough, DP (reprint author), High Performance Technologies Inc, Reston, VA 20190 USA. RI Kuehn, Michael/A-4573-2014; OI Kuehn, Michael/0000-0002-7703-9160; Meaburn, Karen/0000-0002-1327-5957 FU National Cancer Institute; National Institutes of Health [N01-CO-1240] FX This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health under contract N01-CO-1240. NR 13 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 276 EP + DI 10.1109/ISBI.2007.356842 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300070 ER PT S AU Narasimha, R Aganj, I Borgnia, M Sapiro, G McLaughlin, S Milne, J Subramaniamo, S AF Narasimha, Rajesh Aganj, Iman Borgnia, Mario Sapiro, Guillermo McLaughlin, Steven Milne, Jacqueline Subramaniamo, Sriram GP IEEE TI From gigabytes to bytes: Automated denoising and feature identification in electron tomograms of intact bacterial cells SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE electron tomography; denoising; feature extraction; diffusion; automated techniques; template matching ID IMAGE; DIFFUSION AB Advances in automated data acquisition in electron tomography have led to an explosion in the amount of data that can be obtained about the spatial architecture of a variety of biologically and medically relevant objects with resolutions in the "nano" range of 10-1000 nm. The development of methods to automatically analyze the vast amounts of information contained in these tomograms is a major challenge since the electron tomograms are intrinsically very noisy. A fundamental step in the automatic analysis of large amounts of data for statistical inference is to segment relevant 3D features in cellular tomograms. Procedures for segmentation must work robustly and rapidly in spite of the low signal to noise ratios inherent to biological electron microscopy. This work first evaluates various non-linear denoising techniques on tomograms recorded at cryogenic temperatures. Using datasets of bacterial tomograms as an example, we demonstrate that non-linear diffusion techniques significantly improve the fidelity of automated feature extraction. Our approach represents an important step in automating the efficient extraction of useful information from large datasets in biological tomography, and facilitates the overall goal of speeding up the process of reducing gigabyte-sized tomograms to relevant byte-sized data. C1 [Narasimha, Rajesh; Borgnia, Mario; Milne, Jacqueline; Subramaniamo, Sriram] NCI, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. [Aganj, Iman; Milne, Jacqueline] Georgia Inst Technol, Atlanta, GA USA. [Borgnia, Mario; McLaughlin, Steven] Univ Minnesota, Minneapolis, MN USA. RP Narasimha, R (reprint author), NCI, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. EM rajesh@ece.gatech.edu; iman@umn.edu; borgnia@mail.nih.gov; guille@umn.edu; swm@ece.gatech.edu; jmilne@nih.gov; ssl@nih.gov FU NSF; NIH FX Work partially supported by NSF and NIH NR 12 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 304 EP + DI 10.1109/ISBI.2007.356849 PG 3 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300077 ER PT S AU Samuelson, FW Petrick, N Paquerault, S AF Samuelson, Frank W. Petrick, Nicholas Paquerault, Sophie GP IEEE TI Advantages and examples of resampling for CAD evaluation SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE evaluation; FROG; resampling; bootstrap; permutation; computer-aided diagnosis ID FROC CURVES; MODEL; LOCALIZATION; MAMMOGRAPHY; OBSERVER AB Comparison of performance accuracy between different computer-aided diagnosis (CAD) devices is a challenging task. Anatomical structure of the patient and imaging geometry introduce many possible correlations among scores produced by a CAD. Numerous analysis methods have been designed to account for the correlations among CAD scores or the variable number of CAD marks, but usually not both. However, methods that resample by case incorporate both of these sources of variability while accounting for in-case correlations. In this paper we present some examples of the use of resampling on CAD score data. C1 [Samuelson, Frank W.; Petrick, Nicholas; Paquerault, Sophie] US FDA, Ctr Devices & Radiol Hlth, CDRH NIBIB Lab Assessment Med Imaging Syst, Rockville, MD USA. RP Samuelson, FW (reprint author), US FDA, Ctr Devices & Radiol Hlth, CDRH NIBIB Lab Assessment Med Imaging Syst, HFZ 140,12720 Twinbrook Pkwy, Rockville, MD USA. NR 14 TC 16 Z9 16 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 492 EP 495 DI 10.1109/ISBI.2007.356896 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300124 ER PT S AU Summers, RM AF Summers, Ronald M. GP IEEE TI Current concepts in computer-aided detection for CT colonography SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE colorectal cancer; polyps; shape; curvature ID ASSISTED READER SOFTWARE; POLYP DETECTION; COLONIC POLYPS; FALSE POSITIVES; VIRTUAL COLONOSCOPY; ILEOCECAL VALVE; CLASSIFICATION; REDUCTION; FEASIBILITY; DIAGNOSIS AB Computer-aided detection (CAD) for CT colonogaphy has been under development for about eight years. It is now sufficiently accurate that clinically significant polyps 1 cm and larger can be reliably detected with 90% sensitivity. The research focus is now shifting to improving sensitivity for detection of smaller polyps, reducing the number of false positive detections, integrating CAD into clinical practice and applying CAD to the setting of fecal tagging and laxative-free bowel preparations. This is a dynamic research field which requires the use of state-of-the-art image processing and machine learning techniques. C1 Natl Inst Hlth Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), Natl Inst Hlth Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. EM rms@nih.gov NR 38 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 496 EP 499 DI 10.1109/ISBI.2007.356897 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300125 ER PT S AU Yao, JH O'Connor, SD Summers, RM AF Yao, Jianhua O'Connor, Stacy D. Summers, Ronald M. GP IEEE TI Computer aided detection of lytic bone metastases in the spine using routine CT images SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE bone metastases; chest/abdominal CT; CAD AB Bone metastases occur when cancer cells from the primary tumor relocate to the bones. This paper presents a computer aided detection system to identify lytic bone metastases in the thoracolumbar spine using routine chest/abdominal CT scans. The spine is segmented using a hybrid technique of thresholding, mathematical morphology, directed graph search, and a four-part vertebral model. A watershed algorithm is applied to search for lytic detections that match size, shape, location and intensity criteria. To reduce the number of false positives, we computed 26 quantitative features (density, shape and location) and fed them to a support vector machine (SVM). We have tested our method on 50 data sets and 90 bone metastases. The perpatient sensitivities are 85.7%, 91.7% and 100% for bone lesions>0cm(2), >0.2cm(2) and >0.8cm(2) in the test sets, with 5.7 false positive per patient. C1 [Yao, Jianhua; O'Connor, Stacy D.; Summers, Ronald M.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 5 Z9 5 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 512 EP 515 DI 10.1109/ISBI.2007.356901 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300129 ER PT S AU Jian, B Vemuri, BC Ozarslan, E Carney, P Mareci, T AF Jian, Bing Vemuri, Baba C. Ozarslan, Evren Carney, Paul Mareci, Thomas GP IEEE TI A continuous mixture of tensors model for diffusion-weighted MR signal reconstruction SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE biomedical imaging; magnetic resonance imaging; biomedical image processing; diffusion processes ID RESOLUTION AB Diffusion MRI is a non-invasive imaging technique that allows the measurement of water molecular diffusion through tissue in vivo. In this paper, we present a novel statistical model which describes the diffusion-attenuated MR signal by the Laplace transform of a probability distribution over symmetric positive definite matrices. Using this new model, we analytically derive a Rigaut-type asymptotic fractal law for the MR signal decay which has been phenomenologically used before. We also develop an efficient scheme for reconstructing the multiple fiber bundles from the DW-MRI measurements. Experimental results on both synthetic and real data sets are presented to show the robustness and accuracy of the proposed algorithms. C1 [Jian, Bing; Vemuri, Baba C.] Univ Florida, Dept Comp & Informat Sci & Engn, Gainesville, FL 32611 USA. [Carney, Paul] Univ Florida, Dept Pediatr, Gainesville, FL 32611 USA. [Mareci, Thomas] Univ Florida, Dept Biochem & Mol Bio, Gainesville, FL 32611 USA. [Ozarslan, Evren] Natl Inst Hlth, NICHD, LIMB, STBB, Bethesda, MD 20892 USA. RP Jian, B (reprint author), Univ Florida, Dept Comp & Informat Sci & Engn, Gainesville, FL 32611 USA. RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU NIH [EB007082, NS42075, EB004752] FX This research was in part supported by NIH EB007082, NIH NS42075 to BCV and NIH EB004752 to PC & TM. NR 14 TC 1 Z9 1 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 772 EP + DI 10.1109/ISBI.2007.356966 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300194 ER PT S AU Freidlin, RZ Assaf, Y Basser, PJ AF Freidlin, Raisa Z. Assaf, Yaniv Basser, Peter J. GP IEEE TI Multivariate hypothesis testing of DTI data for tissue clustering SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE DTI; diffusion tensor; parsimonious; clustering; hypothesis testing ID DIFFUSION TENSOR AB In this work we investigate the feasibility and effectiveness of unsupervised tissue clustering and classification algorithms for DTI data. Tissue clustering and classification are among the most challenging tasks in DT image analysis. While clustering separates acquired data into objects, tissue classification provides in-depth information about each region of interest. The unsupervised clustering algorithm utilizes a framework proposed by Hext and Snedecor, where the null hypothesis of diffusion tensors arising from the same distribution is determined by an F-test. Tissue type is classified according to one of three possible diffusion models (general anisotropic, prolate, or oblate), which is determined with a parsimonious model selection framework. This approach, also adapted from Snedecor, chooses among different models of diffusion within a voxel using a series of F-tests. Both numerical phantoms and DWI data obtained from excised rat spinal cord are used to test and validate these tissue clustering and classification approaches. C1 [Freidlin, Raisa Z.] NIH, TAIS, DCB, CIT, Bldg 10, Bethesda, MD 20892 USA. [Freidlin, Raisa Z.] George Washington Univ, Dept Elect & Comp Engn, Washington, DC 20052 USA. [Assaf, Yaniv] Tel Aviv Univ, Dept Neurobiochem, Ramat Aviv, Israel. [Basser, Peter J.] NIH, NICHD, LIMB, STBB, Bethesda, MD USA. RP Freidlin, RZ (reprint author), NIH, TAIS, DCB, CIT, Bldg 10, Bethesda, MD 20892 USA. NR 9 TC 2 Z9 2 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 776 EP + DI 10.1109/ISBI.2007.356967 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300195 ER PT S AU Tan, S Yao, JH Ward, MM Yao, L Summers, RM AF Tan, Sovira Yao, Jianhua Ward, Michael M. Yao, Lawrence Summers, Ronald M. GP IEEE TI 3D multi-scale level set segmentation of vertebrae SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE segmentation; multi-scale; level set; vertebra AB We present a 3D multi-scale segmentation algorithm for vertebrae based on a cascade of level sets. We validated the performance of the algorithm in terms of accuracy, robustness and speed and compared it with its original single-scale version using a synthetic vertebra and a semi-synthetic one containing natural structured noise. The multi-scale algorithm was found to be 4 to 5 times faster and could be half a voxel more accurate than the single-scale algorithm. Synthetic vertebrae also allowed us to try a large number of level set parameters. Analysis of the results revealed trends about parameter combinations leading to leakage or under-segmentation. After selecting a good set of parameters we tested the algorithm on 50 real vertebrae. The success rates were 90% and 80% respectively for the multi-scale and single-scale algorithms. C1 [Tan, Sovira; Yao, Jianhua; Ward, Michael M.; Yao, Lawrence; Summers, Ronald M.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Tan, S (reprint author), NIH, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 5 Z9 5 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 896 EP 899 DI 10.1109/ISBI.2007.356997 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300225 ER PT S AU Yao, JH Summers, RM AF Yao, Jianhua Summers, Ronald M. GP IEEE TI Detection and segmentation of colonic polyps on haustral folds SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE colonic polyps; deformable model; CT colonography; CAD AB Detections on baustral folds constitute a large portion of false positive findings in CT colonography, and polyps on the folds are more likely to be missed by a CAD system. This paper presents an approach to improve the segmentation of colonic polyps on haustral folds. The method is based on a combination of 3D knowledge-guided intensity adjustment, fuzzy clustering, and adaptive deformable model. We propose a dual-distance algorithm to detect the fold region. We then introduce a counter force in the model evolution to alleviate the over-segmentation problem that often occurs to polyps on haustral folds. The experiment was conducted on 395 patients with 83 polyps. The results were validated against manual measurement. The volumetric measurements were strongly correlated and there was no significant difference (P=0.37 in paired t-test). The median Dice coefficient for volume overlap between automatic and manual segmentation was 0.75 (standard deviation 0.15). The counter force improves the segmentation accuracy of polyps on-fold by 21%. C1 [Yao, Jianhua; Summers, Ronald M.] NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NR 7 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 900 EP 903 DI 10.1109/ISBI.2007.356998 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300226 ER PT S AU Patterson, GH Betzig, E Lippincott-Schwartz, J Hess, HF AF Patterson, George H. Betzig, Eric Lippincott-Schwartz, Jennifer Hess, Harald F. GP IEEE TI Developing Photoactivated Localization Microscopy (PALM) SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE fluorescence; image resolution; diffraction ID PROTEINS; RESOLUTION; CELLS AB In conventional biological imaging, diffraction places a limit on the minimal xy distance at which two marked objects can be discerned. Consequently, resolution of target molecules within cells is typically coarser by two orders of magnitude than the molecular scale at which the proteins are spatially distributed. Photoactivated Localization Microscopy (PALM) optically resolves selected subsets of photoactivatable fluorescent probes within cells at mean separations of <25 nanometers. It involves serial photoactivation and subsequent photobleaching of numerous sparse subsets of photoactivated fluorescent protein molecules. Individual molecules are localized at near molecular resolution by determining their centers of fluorescent emission via a statistical fit of their point-spread-function. The position information from all subsets is then assembled into a super-resolution image, in which individual fluorescent molecules are isolated at high molecular densities. In this paper, some of the limitations for PALM imaging under current experimental conditions are discussed. C1 [Patterson, George H.; Lippincott-Schwartz, Jennifer] NCI, Cell Biol & Metab Branch, NICHHD, Bethesda, MD 20892 USA. [Betzig, Eric; Hess, Harald F.] Janelia Farm Res Campus, Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Betzig, Eric] New Millennium Res, LLC, Okemos, MA 48864 USA. [Hess, Harald F.] NuQuest Res, LLC, La Jolla, CA 92037 USA. RP Patterson, GH (reprint author), NCI, Cell Biol & Metab Branch, NICHHD, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 8 U2 28 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 940 EP + DI 10.1109/ISBI.2007.357008 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300236 ER PT S AU Li, G Xie, HC Citrin, D Capal, J Maass-Moreno, R Arora, BA Coleman, CN Camphausen, K Miller, RW AF Li, Guang Xie, Huchen Citrin, Deborah Capala, Jacek Maass-Moreno, Roberto Arora, Barbara A. Coleman, C. Norman Camphausen, Kevin Miller, Robert W. GP IEEE TI Registering molecular imaging information into anatomic images with improved spatial accuracy SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE ID REGISTRATION AB To make molecular imaging useful in the clinic, accurate image registration must be done to correlate nano-scale events to macro-scale anatomy. The 3D volumetric image registration technique uses visual and quantitative measures to identify the most homogeneous color distribution on a volumetric anatomical landmark. Four phantom PET/CT images were acquired with 5.0 +/- 0.1 mm shift interval. The image registration shift was compared with the positioning shift. An accuracy of 0.1 and 0.1 mm was achieved. Cranial PET/CT images from 39 patients were examined. It was found that the average head motion was 0.5-1 degrees and 1-3 mm, even with a stringent head holder. This small but significant misalignment is beyond the capability of conventional visual-based fusion methods used clinically. The 100 mu m accuracy is a step forward to register molecular activities to anatomy for high precision interventions. C1 [Li, Guang; Xie, Huchen; Citrin, Deborah; Capala, Jacek; Arora, Barbara A.; Coleman, C. Norman; Camphausen, Kevin; Miller, Robert W.] NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. [Maass-Moreno, Roberto] NIH, Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. RP Li, G (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 1144 EP + DI 10.1109/ISBI.2007.357059 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300287 ER PT S AU Van Uitert, RL Li, J Summers, RM AF Van Uitert, Robert L. Li, Jiang Summers, Ronald M. GP IEEE TI Computer-aided detection of colonic diverticular disease SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE DE image segmentation; object detection; medical diagnosis ID CT COLONOGRAPHY; SEGMENTATION AB While CT colonography (CTC) is becoming a more prevalent and accepted method to diagnose colon cancer, the leading cause of nondiagnostic segmental evaluation of CT colonography is colonic diverticular disease (CDD). An essential element of detecting CDD in conjunction with CT colonography (CTC) is the accurate segmentation of the colonic wall. We have developed a level set based method to determine from a CTC scan the location of the outer wall of the colon, the serosal-tissue boundary. The algorithm then segments the entire outer colon wall at subvoxel precision and determines the thickness of the wall throughout the colon. Potential CDD detections are clustered based on the thickness of the colon wall and CT intensity values at the outer wall's position. Finally, a support-vector machine classifier is used to determine the location of diverticular disease. The algorithm has been validated on 10 CTC datasets, half of which have CDD present. At 100% sensitivity for the diverticular disease detections, the system has 0.2 false positives per patient. C1 [Van Uitert, Robert L.; Li, Jiang; Summers, Ronald M.] NIH, Bethesda, MD 20892 USA. RP Van Uitert, RL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 1244 EP 1247 DI 10.1109/ISBI.2007.357084 PG 4 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300312 ER PT S AU Hsu, ER Gallas, BD Jeronimo, J AF Hsu, Elizabeth R. Gallas, Brandon D. Jeronimo, Jose GP IEEE TI Methods for MRMC ROC analysis and components-of-variance modeling using colposcopy images SO 2007 4TH IEEE INTERNATIONAL SYMPOSIUM ON BIOMEDICAL IMAGING : MACRO TO NANO, VOLS 1-3 SE IEEE International Symposium on Biomedical Imaging LA English DT Proceedings Paper CT 4th IEEE International Symposium on Biomedical Imaging CY APR 12-15, 2007 CL Arlington, VA SP IEEE AB In cervical cancer screening, colposcopically-directed biopsies determine disease severity and management. Multi-reader multi-case receiver operating characteristic (MRMC ROC) analysis can be used to evaluate the diagnostic performance and reader variability of colposcopy. We describe the constrained one-shot variance estimate of the empirical area under the ROC curve and analyze a dataset of colposcopists reading images of the cervix. We demonstrate how to extrapolate the variance estimate to larger studies and how to estimate essential components of variance: reader, case, and an interaction component. These methods allow us to investigate the variance reduction of strategies for adding more cases. For our data (21 readers, 16 normal and 4 diseased cases), variance decreases the fastest by adding more diseased cases (short-term) or a ratio of diseased and normal cases (long-term). C1 [Hsu, Elizabeth R.; Gallas, Brandon D.] US FDA, Ctr Devices & Radiol Hlth,NIBI CDRH, Off Sci Engn Lab,Div Imaging & Appl Math, Lab Assessment Med Imaging Syst, Rockville, MD 20857 USA. [Hsu, Elizabeth R.] Natl Inst Hlth, Natl Canc Inst, Canc Prevent Fellowship & Inter Agcy oncol Task F, Bethesda, MD USA. [Jeronimo, Jose] Natl Inst Hlth, Natl Canc Inst, Div Canc Edidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD USA. RP Hsu, ER (reprint author), US FDA, Ctr Devices & Radiol Hlth,NIBI CDRH, Off Sci Engn Lab,Div Imaging & Appl Math, Lab Assessment Med Imaging Syst, Rockville, MD 20857 USA. OI Gallas, Brandon/0000-0001-7332-1620 NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1945-7928 BN 978-1-4244-0671-5 J9 I S BIOMED IMAGING PY 2007 BP 1264 EP + DI 10.1109/ISBI.2007.357089 PG 2 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Imaging Science & Photographic Technology SC Computer Science; Engineering; Imaging Science & Photographic Technology GA BHG38 UT WOS:000252957300317 ER PT B AU Wong, TS Brough, B Christman, KL Kolodziej, CM Huang, A Lam, R Forbes, JG Wang, K Maynard, HD Ho, CM AF Wong, Tak Sing Brough, Branden Christman, Karen L. Kolodziej, Christopher M. Huang, Adam Lam, Robert Forbes, Jeffrey G. Wang, Kuan Maynard, Heather D. Ho, Chih-Ming GP IEEE TI Manufacture of Nanoscale Structures through Integrated Top-down and Bottom-up Approaches SO 2007 7TH IEEE CONFERENCE ON NANOTECHNOLOGY, VOL 1-3 LA English DT Proceedings Paper CT 7th IEEE Conference on Nanotechnology CY AUG 02-05, 2007 CL Hong Kong, PEOPLES R CHINA SP IEEE, IEEE Nanotechnol Council, IEEE Electron Devices Soc, Chinese Univ Hong Kong, Ctr Micro & Nano Syst, ETH, Inst Robot & Intelligent Syst, GETI, KC Wong Educ Fdn, US Army Int Technol Ctr, ACS NANO, CRC Press, Taylor & Francis Grp, intel DE actin polymerization; bottom-up fabrication; complex pattern formation; crystallization; and top-down fabrication ID SELF-ASSEMBLED MONOLAYERS; ACTIN-FILAMENTS; PROTEINS; POLYMERIZATION; SIMULATION; MOTILITY; GELSOLIN; ARRAYS AB Manufacturing technology designed to interface natural molecular components with a solid surface is fundamental in building higher-order complex functional structures from the nanoscale domain. Here, we present top-down fabrication approaches that define and guide the growth of natural molecular components, such as inorganic ions and proteins, and investigate how external control parameters can influence the growth of the resultant structures. Specifically, electron beam lithography was used to create nanoscale hydrophilic patterns on a hydrophobic substrate to entrap attoliter volumes of liquid containing inorganic ions. As these nanoscale droplets evaporated, they initiated the crystallization of the ions, resulting in the synthesis of nanoscale inorganic structures (similar to 50 nm - 300 nm). Through the use of scanning electron and atomic force microscopy, the effects of external control parameters, such as humidity and size of the hydrophilic patterns, to the formation of the resulting structures were quantified. In a separate but related effort, self-assembling actin filaments were grown from nanoscale binding sites created by electron beam lithography. High-aspect-ratio (similar to 1000:1) structures were demonstrated while maintaining the nanoscale surface geometries. These two technologies have laid down a foundation for the systematic study of these synthesized structures in artificial engineered environments. C1 [Wong, Tak Sing; Brough, Branden; Christman, Karen L.; Kolodziej, Christopher M.; Maynard, Heather D.; Ho, Chih-Ming] Univ Calif Los Angeles, Ctr Scalable & Integrated Nanomfg, Los Angeles, CA 90095 USA. [Wong, Tak Sing; Brough, Branden; Lam, Robert; Ho, Chih-Ming] Univ Calif Los Angeles, Mech & Aerosp Engn Dept, Los Angeles, CA 90095 USA. [Christman, Karen L.; Kolodziej, Christopher M.; Maynard, Heather D.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Huang, Adam] Univ Arkansas, Dept Mech Engn, Fayetteville, AR 72701 USA. [Brough, Branden; Forbes, Jeffrey G.; Wang, Kuan] Natl Inst Hlth, Lab Muscle Biol, Muscle Proteom & Nanotechnol Sect, Bethesda, MD 20892 USA. RP Wong, TS (reprint author), Univ Calif Los Angeles, Ctr Scalable & Integrated Nanomfg, Los Angeles, CA 90095 USA. EM tswong@ucla.edu; broughb@mail.nih.gov; christman@chem.ucla.edu RI Ho, Chih-ming/I-6537-2012 FU NSF; Center for Scalable and Integrated Nanomanufacturing [DMI-0327077]; NIAMS; NIH; NIH NHLBI through NRSA; NSF IGERT; Materials Creation Training Program (MCTP) [DGE-0114443] FX This work was supported by NSF funded Center for Scalable and Integrated Nanomanufacturing (DMI-0327077) and by the Intramural Research Program of NIAMS, NIH (to KW). Support from the NIH NHLBI through a NRSA postdoctoral fellowship (KLC) is also appreciated. CMK would like to thank the NSF IGERT: Materials Creation Training Program (MCTP) DGE-0114443 for the funding. The authors thank Prof. Thomas Ward of the University of Neuchatel for kindly donating recombinant, unlabelled streptavidin, Gustavo Guitierrez-Cruz and Patrick Nahirney of the Lab of Muscle Biology, NIAMS for the preparation of the biotinylated FX45 and image analysis respectively, Kristien Zaal of the Light Imaging Section of NIAMS for expert assistance with confocal microscopy, and Daniel Garcia of UCLA for technical assistance with the e-beam writer. NR 25 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0607-4 PY 2007 BP 126 EP + PG 2 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA BIO98 UT WOS:000261434900027 ER PT S AU Silva, S Basser, PJ Miranda, PC AF Silva, Sofia Basser, Peter J. Miranda, Pedro C. GP IEEE TI The activation function of TMS on a finite element model of a cortical sulcus SO 2007 ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY, VOLS 1-16 SE PROCEEDINGS OF ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY LA English DT Proceedings Paper CT 29th Annual International Conference of the IEEE-Engineering-in-Medicine-and-Biology-Society CY AUG 22-26, 2007 CL Lyon, FRANCE SP IEEE Engn Med & Biol Soc ID STIMULATION; MECHANISMS AB TMS is a promising tool for the non-invasive stimulation of the cerebral cortex, with applications in Neurology and the Neurosciences. From cable theory, it is known that the activation function for neuronal stimulation in TMS may contain contributions from the electric field and the component of the electric field gradient along the direction of the nerve. Here we present a calculation of the spatial distribution of the induced electric field by TMS using a finite element model of the cerebral cortex and surrounding tissues. This distribution allows us to calculate the activation function for different experimental conditions, and is expected to provide new insight into the mechanisms of TMS in the cortex. C1 [Silva, Sofia; Miranda, Pedro C.] Univ Lisbon, Fac Sci, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. [Basser, Peter J.] NIH, NICHD, Tissue Biophys & Biomimet, Bethesda, MD 20892 USA. RP Silva, S (reprint author), Univ Lisbon, Fac Sci, Inst Biophys & Biomed Engn, P-1749016 Lisbon, Portugal. EM ssitva@fc.ul.pt; pjbasser@helix.nih.gov; pcmiranda@fc.ul.pt RI Miranda, Pedro/A-5643-2013 OI Miranda, Pedro/0000-0002-6793-8111 FU Intramural Research Program of the National Institutes of Child Health and Human Development; NIH; Ciencia e a Tecnologia [SFRH/BD/13815/2003] FX This work was supported in part by the Intramural Research Program of the National Institutes of Child Health and Human Development, NIH. Sofia Silva was supported by the Fundacao para a Ciencia e a Tecnologia, under Grant number SFRH/BD/13815/2003. NR 7 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1094-687X BN 978-1-4244-0787-3 J9 P ANN INT IEEE EMBS PY 2007 BP 6657 EP + PG 2 WC Engineering, Biomedical; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA BHI92 UT WOS:000253467005193 ER PT S AU Boronikolas, V Michaelides, M Wang, GJ Blackband, S Grant, SC Metaxas, D Volkow, ND Thanos, PK AF Boronikolas, Vasilios Michaelides, Michael Wang, Gene-Jack Blackband, Steve Grant, Samuel C. Metaxas, Dimitris Volkow, Nora D. Thanos, Panayotis K. GP IEEE TI Brain region morphological and volumetric quantitative assessment using the 17.6T MRI in rats chronically exposed to methylphenidate SO 2007 IEEE 33RD ANNUAL NORTHEAST BIOENGINEERING CONFERENCE SE Annual IEEE Northeast Bioengineering Conference LA English DT Proceedings Paper CT IEEE 33rd Annual Northeast Bioengineering Conference CY MAR 10-11, 2007 CL Long Isl, NY SP IEEE, EMB, AIChE ID DEFICIT HYPERACTIVITY DISORDER AB Methylphenidate (MPH) is presently the primary pharmacotherapy for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). It has not been determined though what impact long-term treatment with this psychostimulant would have on behavior, neurochemistry or neuroanatomy. Previous studies have shown that the striatum is a major target of MPH treatment, consistent with human MRI studies. Also previous results have shown that long term-exposure to MP in adolescent rats has produced changes in dopamine D2 receptor levels and significantly enhanced cocaine self-administration in adulthood (Thanos et al. 2004). Different animal studies imply that the effects of MPH may depend on the neural responder system whereas structural and functional parameters are improved by MPH in animals with psychomotor impairments, they remain unaltered or get worse in healthy controls. Here we measured the effects of chronic treatment (8 months) with oral MP (I or 2 mg/kg) or water, which was initiated in adolescent rats (4 weeks old). Following this treatment, rats in adulthood (9 month old) were perfused intracardially and their brains removed and imaged with a 17.6 T MRI for neuroanatomical volume assessment. C1 [Boronikolas, Vasilios; Michaelides, Michael; Wang, Gene-Jack; Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Blackband, Steve; Grant, Samuel C.] Univ Florida, McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA. [Metaxas, Dimitris] Rutgers State Univ, Div Comp & Informat Sci, Piscataway, NJ 08855 USA. [Volkow, Nora D.; Thanos, Panayotis K.] NIAAA, NIH, Lab Neuroimaging, Dept Hlth & Human Services, Bethesda, MD USA. RP Boronikolas, V (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. FU NIDA; NIAAA (Intramural Research Program, LNI); U.S. Department of Energy [DEAC02-98CH10886] FX Support Contributed By: NIDA, NIAAA (Intramural Research Program, LNI), by the U.S. Department of Energy under contract DEAC02-98CH10886. NR 8 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0277-1063 BN 978-1-4244-1032-3 J9 NORTHEAST BIOENGIN C PY 2007 BP 43 EP + DI 10.1109/NEBC.2007.4413271 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Materials Science, Biomaterials; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Materials Science; Radiology, Nuclear Medicine & Medical Imaging GA BHP13 UT WOS:000255100600022 ER PT S AU Parvaz, MA Maloney, T Woicik, PA Alia-Klein, N Telang, F Wang, GJ Volkow, ND Goldstein, RZ AF Parvaz, M. A. Maloney, T. Woicik, P. A. Alia-Klein, N. Telang, F. Wang, G-J Volkow, N. D. Goldstein, R. Z. GP IEEE TI Compromised sensitivity to relative monetary reward in current cocaine addiction: evidence from the P300 SO 2007 IEEE 33RD ANNUAL NORTHEAST BIOENGINEERING CONFERENCE SE Annual IEEE Northeast Bioengineering Conference LA English DT Proceedings Paper CT IEEE 33rd Annual Northeast Bioengineering Conference CY MAR 10-11, 2007 CL Long Isl, NY SP IEEE, EMB, AIChE AB Using functional magnetic resonance imaging (fMRI), we previously reported compromised neural sensitivity to monetary reward in cocaine-addicted individuals as compared to control subjects. In the current study, we sought to replicate this result using the event-related potential (ERP) recordings. Given the demonstration that the P3 waveform, previously implicated in valence processing, coded for monetary value in young healthy individuals, we currently examined this effect in 18 individuals with current cocaine use disorders (CUD) and 18 age-matched control subjects. Monetary reward (00, 10 and 450) varied across blocks of trials. Results revealed that the P3 amplitude was significantly larger for 450 than the 00 condition in the control subjects, while this gradation was absent in the CUD individuals; the behavioral results paralleled these ERP results: only the control subjects adjusted speed of response to the high as compared to the no reward condition. In addition, the CUD subjects manifested significantly faster P3 waveforms than their control counterparts; this was associated with higher self-reported excitement for the task. These current ERP results confirm. our previous fMRI results and suggest a compromised neuronal sensitivity to the relative value of a secondary reward in cur-rent CUD individuals; this impairment may be translated into impulsivity or an inability to use subjective motivation to guide behavior. C1 [Parvaz, M. A.; Maloney, T.; Woicik, P. A.; Alia-Klein, N.; Telang, F.; Wang, G-J; Goldstein, R. Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Parvaz, M. A.] SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. [Telang, F.; Volkow, N. D.] NIAAA, Rockville, MD 20857 USA. [Wang, G-J] Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA. [Volkow, N. D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Parvaz, MA (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. OI Parvaz, Muhammad/0000-0002-2671-2327 FU NIDA [1K23 DA15517-01]; NARSAD; LDRD; GCRC [5-MO1-RR-10710] FX Supported by grants from the NIDA (1K23 DA15517-01); NARSAD Young Investigator Award; LDRD from U.S. Department of Energy (OBER); and GCRC (5-MO1-RR-10710). We are grateful to the subjects who volunteered in this study. NR 5 TC 0 Z9 0 U1 1 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0277-1063 BN 978-1-4244-1032-3 J9 NORTHEAST BIOENGIN C PY 2007 BP 60 EP + DI 10.1109/NEBC.2007.4413279 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Materials Science, Biomaterials; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Materials Science; Radiology, Nuclear Medicine & Medical Imaging GA BHP13 UT WOS:000255100600030 ER PT S AU Hu, TCC Chuang, KH Yanasak, N Koretsky, AP AF Hu, Tom C. -C. Chuang, Kai-Hsiang Yanasak, Nathan Koretsky, Alan P. GP IEEE TI Improved cardiac manganese-enhanced MRI (MEMRI) with T-1 mapping in rodent SO 2007 IEEE 33RD ANNUAL NORTHEAST BIOENGINEERING CONFERENCE SE Annual IEEE Northeast Bioengineering Conference LA English DT Proceedings Paper CT IEEE 33rd Annual Northeast Bioengineering Conference CY MAR 10-11, 2007 CL Long Isl, NY SP IEEE, EMB, AIChE AB Manganese ion (Mn2+) is an intracellular contrast agent that enters viable myocardial cells via voltage gated calcium channels. Along with its T-1 shortening effect and relatively long half-life in cells, it becomes a very useful molecular contrast agent to study calcium influx. One major concern for using Mn2+ is getting quantitative information over a range of concentrations. Therefore, in this study, a T-1 mapping method has been implemented for cardiac manganese-enhanced MRI (MEMRI) to increase the sensitivity and enable the quantitative estimate of a range of concentrations. C1 [Hu, Tom C. -C.; Chuang, Kai-Hsiang; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging 1, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. [Hu, Tom C. -C.; Yanasak, Nathan] Med Coll Georgia, Dept Radiol, Small Anim Imaging, Augusta, GA 30912 USA. RP Hu, TCC (reprint author), NINDS, Lab Funct & Mol Imaging 1, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. OI Chuang, Kai-Hsiang/0000-0002-8356-0657 NR 4 TC 1 Z9 1 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 0277-1063 BN 978-1-4244-1032-3 J9 NORTHEAST BIOENGIN C PY 2007 BP 73 EP + DI 10.1109/NEBC.2007.4413285 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic; Materials Science, Biomaterials; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Materials Science; Radiology, Nuclear Medicine & Medical Imaging GA BHP13 UT WOS:000255100600036 ER PT B AU Bornstein, MH Arterberry, ME Mash, C AF Bornstein, Marc H. Arterberry, Martha E. Mash, Clay GP IEEE TI Infant perception and categorization of object-context relations SO 2007 IEEE 6TH INTERNATIONAL CONFERENCE ON DEVELOPMENT AND LEARNING SE IEEE International Conference on Development and Learning LA English DT Proceedings Paper CT 6th IEEE International Conference on Development Learning CY JUL 11-13, 2007 CL London, ENGLAND SP IEEE DE categorization; eye tracking; habituation ID MEMORY RETRIEVAL; STIMULUS CONTEXT; RECOGNITION AB In two experiments infants' attention to and use of object (figure) and context (ground) relations were investigated. Experiment I used a habituation-categorization procedure. Infants categorized animals and vehicles when placed in congruent object-context relations (e.g., animals in fields, vehicles on streets) but not in incongruent object-context relations (e.g., animals on streets, vehicles in fields). Experiment 2 used an eye tracking paradigm. When viewing animals, infants looked more to animals than their contexts when the object-context relations were congruent, but they looked equally to the animals and contexts when the object-context relations were incongruent. Infants, however, looked more to vehicles than their contexts whether vehicles were placed in congruent or incongruent object-context relations. Object-context relations play a role in infants' categorization, and infants process natural kinds and designed artifacts differently. C1 [Bornstein, Marc H.; Mash, Clay] NICHHD, NIH, USDHHS, Bethesda, MD 20892 USA. [Arterberry, Martha E.] Colby Coll, Dept Psychol, Waterville, ME 04901 USA. EM Marc.H.Bornstein@nih.gov; Martha.Arterberry@colby.edu; MashC@tnail.nih.gov FU Intramural Research Division of the National Institute of Child Health and Human Development, National Institutes of Health FX This work was supported by the Intramural Research Division of the National Institute of Child Health and Human Development, National Institutes of Health. NR 17 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1115-3 J9 INT C DEVEL LEARN PY 2007 BP 312 EP + PG 3 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics; Computer Science, Theory & Methods; Education & Educational Research; Psychology, Educational; Engineering, Electrical & Electronic; Psychology, Developmental; Psychology SC Computer Science; Education & Educational Research; Psychology; Engineering GA BHH90 UT WOS:000253369100054 ER PT S AU Wang, S Chuang, KH Talagala, L AF Wang, Shumin Chuang, Kai-Hsiang Talagala, Lalith GP IEEE TI RIF power duty cycle restrictions of Continuous Arterial Spin Labeling coil for 7.0 Tesla perfusion magnetic resonance imaging SO 2007 IEEE ANTENNAS AND PROPAGATION SOCIETY INTERNATIONAL SYMPOSIUM, VOLS 1-12 SE IEEE Antennas and Propagation Society International Symposium LA English DT Proceedings Paper CT IEEE Antennas-and-Propagation-Society International Symposium CY JUN 09-15, 2007 CL Honolulu, HI SP IEEE, Antennas & Propagat Soc C1 [Wang, Shumin; Chuang, Kai-Hsiang; Talagala, Lalith] NINDS, LFMI, Bethesda, MD 20892 USA. RP Wang, S (reprint author), NINDS, LFMI, 10 Ctr Dr,10-B1D728, Bethesda, MD 20892 USA. EM wangshu@ninds.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-3965 BN 978-1-4244-0877-1 J9 IEEE ANTENNAS PROP PY 2007 BP 3911 EP 3914 PG 4 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA BHS60 UT WOS:000255973402160 ER PT S AU Mao, S Mansukhani, P Thoma, GR AF Mao, Song Mansukhani, Praveer Thoma, George R. GP IEEE TI Combining static classifiers and class syntax models for logical entity recognition in scanned historical documents SO 2007 IEEE CONFERENCE ON COMPUTER VISION AND PATTERN RECOGNITION, VOLS 1-8 SE IEEE Conference on Computer Vision and Pattern Recognition LA English DT Proceedings Paper CT IEEE Conference on Computer Vision and Pattern Recognition CY JUN 17-22, 2007 CL Minneapolis, MN SP IEEE, hp invent, INI-GraphicsNet, VIOSO ID FEATURE-SELECTION AB Class syntax can be used to 1) model temporal or locational evolvement of class labels of feature observation sequences, 2) correct classification errors of static classifiers if feature observations from different classes overlap in feature space, and 3) eliminate redundant features whose discriminative information is already represented in the class syntax. In this paper, we describe a novel method that combines static classifiers with class syntax models for supervised feature subset selection and classification in unified algorithms. Posterior class probabilities given feature observations are first estimated from the output of static classifiers, and then integrated into a parsing algorithm to find an optimal class label sequence for the given feature observation sequence. Finally, both static classifiers and class syntax models are used to search for an optimal subset of features. An optimal feature subset, associated static classifiers, and class syntax models are all learned from training data. We apply this method to logical entity recognition in scanned historical U.S. Food and Drug Administration (FDA) documents containing court case Notices of Judgments (NJs) of different layout styles, and show that the use of class syntax models not only corrects most classification errors of static classifiers, but also significantly reduces the dimensionality of feature observations with negligible impact on classification performance. C1 [Mao, Song; Thoma, George R.] Natl Lib Med, Bethesda, MD 20894 USA. [Mansukhani, Praveer] Univ Buffalo, Comp Sci & Engn Dept, Buffalo, NY 14260 USA. RP Mao, S (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM smao@mail.nih.gov; pdm5@btiffalo.edu; gthoma@mail.nih.gov NR 15 TC 0 Z9 0 U1 1 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1063-6919 BN 978-1-4244-1179-5 J9 PROC CVPR IEEE PY 2007 BP 2173 EP + PG 3 WC Computer Science, Software Engineering; Mathematical & Computational Biology; Remote Sensing; Imaging Science & Photographic Technology SC Computer Science; Mathematical & Computational Biology; Remote Sensing; Imaging Science & Photographic Technology GA BGT02 UT WOS:000250382804038 ER PT B AU Wu, JL Hallett, M AF Wu, Jinglong Hallett, Mark GP ieee TI A new research field and a new society, complex medical engineering SO 2007 IEEE/ICME INTERNATIONAL CONFERENCE ON COMPLEX MEDICAL ENGINEERING, VOLS 1-4 LA English DT Proceedings Paper CT IEEE/ICME International Conference on Complex Medical Engineering CY MAY 23-27, 2007 CL Beijing, PEOPLES R CHINA SP IEEE, ICME ID EEG; MOVEMENTS C1 [Wu, Jinglong] Kagawa Univ, Fac Engn, Dept Intelligent Mech Syst, Hayashi Cho 2217-20, Takamatsu, Kagawa 7610369, Japan. [Hallett, Mark] NIH, NINDS, Med Neurol Branch, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Wu, JL (reprint author), Kagawa Univ, Fac Engn, Dept Intelligent Mech Syst, Hayashi Cho 2217-20, Takamatsu, Kagawa 7610369, Japan. EM wu@eng.kagawa-u.ac.jp; hallettm@ninds.nih.gov FU Advanced Research Practice Support Program ofthe Ministry ofEducation, Culture, Sports, Science and Technology, Japan; Japanese Society for the Promotion of Science [17360117]; Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, Japan FX This project was supported by Advanced Research Practice Support Program ofthe Ministry ofEducation, Culture, Sports, Science and Technology, Japan. A part of the research work was supported by Grant-in-Aid for Scientific Research 17360117 from the Japanese Society for the Promotion of Science and Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We are very grateful to people who joined or supported the CME-related research activities, and in particular, the ICME council members NR 10 TC 4 Z9 4 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1077-4 PY 2007 BP 1 EP 4 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BHL89 UT WOS:000254165300001 ER PT B AU Hallett, M Bai, O Bonin, C AF Hallett, M. Bai, O. Bonin, C. GP ieee TI Predicting movement: When, which and where SO 2007 IEEE/ICME INTERNATIONAL CONFERENCE ON COMPLEX MEDICAL ENGINEERING, VOLS 1-4 LA English DT Proceedings Paper CT IEEE/ICME International Conference on Complex Medical Engineering CY MAY 23-27, 2007 CL Beijing, PEOPLES R CHINA SP IEEE, ICME DE voluntary movement; EEG; Bereitschaftspotential; event-related desynchronization; intention ID CORTICAL POTENTIALS; VOLUNTARY; EEG; INITIATION; PATTERNS; ACTS; HZ AB People have the perception that prior to making a voluntary movement, there is an intention to move. The timing of this subjective impression has been measured using Libet's clock and is on average about 300 ms prior to EMG onset. EEG and MEG show activity prior to movement, and by the voltage measurement, there is a rising negativity called the Bereitschaftspotential beginning about 1.5 s prior to EMG onset. This indicates that the brain mechanisms for generating a voluntary movement begin prior to the subjective intention, that is, unconsciously. If it were possible to detect relevant EEG signals with single events in real time, then it would be possible to identify that movement is being prepared prior to, or at least simultaneously with, the subjective experience. Work in our laboratory has been making progress in identifying EEG and MEG activity indicating the intention to move and which movement will be made. Such signals could be used to drive a brain-computer interface. C1 [Hallett, M.; Bai, O.; Bonin, C.] NINDS, NIH, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, NIH, Human Motor Control Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. FU NINDS Division of Intramural Research FX Research is supported by the NINDS Division of Intramural Research. This work is modified and up-dated from a previous version [13]. A product of the US Government, it has no copyright. NR 13 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1077-4 PY 2007 BP 5 EP 7 DI 10.1109/ICCME.2007.4381681 PG 3 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BHL89 UT WOS:000254165300002 ER PT B AU Kayagil, T Bai, O Lin, P Furlani, S Vorbach, S Hallett, M AF Kayagil, T. Bai, O. Lin, P. Furlani, S. Vorbach, S. Hallett, M. GP ieee TI Binary EEG control for two-dimensional cursor movement: An online approach SO 2007 IEEE/ICME INTERNATIONAL CONFERENCE ON COMPLEX MEDICAL ENGINEERING, VOLS 1-4 LA English DT Proceedings Paper CT IEEE/ICME International Conference on Complex Medical Engineering CY MAY 23-27, 2007 CL Beijing, PEOPLES R CHINA SP IEEE, ICME AB Electroencephalography (EEG) is an appealing basis for brain-computer interface technology because EEG is non-invasive. However, because EEG signals are spatially blurred and typically have very low signal-to-noise ratios, extracting relevant information in the single-event case is challenging. The most easily accessible information is one-dimensional (for example, mu rhythm amplitude, average hemispherical power, or presence of a P300 evoked potential). Many studies have attempted to use such one-dimensional parameters as a basis for control. Robust results may be obtained when control is restricted to answering "yes" or "no" questions, such as comparison of a value to a threshold. However, possible applications of such control have been limited, and more dimensions of control are desirable. This research presents a new technique for obtaining more dimensions of control from existing technology. Yes/no answers are taken sequentially in groups of n, and in combination designate a specific choice from 2 A n possible values. This is homologous to the function of bits, and consequently has been termed "binary control." To demonstrate this approach, a two-dimensional cursor control paradigm was developed in MATLAB. Users move a cursor among squares of a grid towards a target while avoiding a trap. At each move, there are up to four positions into which the cursor may be directed (up, down, left, and right). In this embodiment, control is achieved by twice comparing average alpha- and beta-frequency power of each hemisphere during continuous imagined lateralized hand movement. The first comparison narrows the four choices to two, and the second uniquely determines the cursor movement. This paradigm was shown to be compatible with the Brain-Computer Interface-to-Virtual Reality (BCI2VR) software, and preliminary tests were run on normal volunteers. These tests demonstrated the feasibility of pursuing future research with binary control. Binary control is promising because of its robust underlying principles, and because it is easily expandable and adaptable. The source of control may be any EEG feature that can signal a yes/no answer, and the quantity of possible choices doubles with the addition of each answer "bit." This might provide means for more complex control, such as of a robotic arm or virtual keyboard. The binary approach might also prove more efficient than current EEG-based control methods, possibly with less computational demand. C1 [Kayagil, T.; Bai, O.; Lin, P.; Furlani, S.; Vorbach, S.; Hallett, M.] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Kayagil, T (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1077-4 PY 2007 BP 1542 EP 1545 DI 10.1109/ICCME.2007.4382005 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BHL89 UT WOS:000254165301115 ER PT B AU Morash, V Bai, O Furlani, S Lin, P Hallett, M AF Morash, V. Bai, O. Furlani, S. Lin, P. Hallett, M. GP ieee TI Prediction of multiple movement intentions from CNV signal for multi-dimensional BCI SO 2007 IEEE/ICME INTERNATIONAL CONFERENCE ON COMPLEX MEDICAL ENGINEERING, VOLS 1-4 LA English DT Proceedings Paper CT IEEE/ICME International Conference on Complex Medical Engineering CY MAY 23-27, 2007 CL Beijing, PEOPLES R CHINA SP IEEE, ICME AB Patients that suffer from loss of motor control would benefit from a brain-computer interface (110) that would, optimally, be noninvasive, allow multiple dimensions of control, and be controlled with quick and simple means. Ideally, the control mechanism would be natural to the patient so that little training would be required; and the device would respond to these control signals in a predictable way and on a predictable time scale. It would also be important for such a device to be usable by patients capable and incapable of making physical movements. A BCI was created that used electroencephalography (EEG). Multiple dimensions of control were achieved through the movement or motor imagery of the right hand, left hand, tongue, and right foot. The movements were non-sustained to be convenient for the user. The BCI used the 1.5 seconds of the Bereitschaftspotential prior to movement or motor imagery for classification. This could allow the BCI to execute an action on a time scale anticipated by the user. To test this BCI, eight healthy participants were fitted with 29 EEG electrodes over their sensorimotor cortex and one bipolar electrooculography electrode to detect eye movement. Each participant completed six blocks of 100 trials. A trial included visual presentation of three stimuli: a cross, an arrow, and a diamond. Participants rested during the presentation of the cross. The arrow indicated the action that the participant should perform: right hand squeeze, left hand squeeze, press of the tongue against the roof of the mouth, or right foot toe curl. The diamond indicated that the participant should execute the movement during the first three blocks; and that the participant should imagine executing the movement during the last three blocks. Trials affected by motion artifacts, in particular face muscle activity, were removed. Of the remaining data, about 80% were used to train a Bayesian classification and about 20% were used to test this classification. Prediction of the four movements reached accuracies above 150% that of random classification for both real and imagined movements. This suggests a promising future for this BCI. C1 [Morash, V.; Bai, O.; Furlani, S.; Lin, P.; Hallett, M.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Morash, V (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1077-4 PY 2007 BP 1946 EP 1949 DI 10.1109/ICCME.2007.4382087 PG 4 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BHL89 UT WOS:000254165301197 ER PT S AU Narasimha, R Bennett, A Zabransky, D Sougrat, R McLaughlin, S Subramaniam, S AF Narasimha, Rajesh Bennett, Adam Zabransky, Daniel Sougrat, Rachid McLaughlin, Steven Subramaniam, Sriram GP IEEE TI Gigabytes to bytes: Automated denoising and feature extraction as applied to the analysis of hiv architecture and variability using electron tomography SO 2007 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING, VOL I, PTS 1-3, PROCEEDINGS SE International Conference on Acoustics Speech and Signal Processing ICASSP LA English DT Proceedings Paper CT 32nd IEEE International Conference on Acoustics, Speech and Signal Processing CY APR 15-20, 2007 CL Honolulu, HI SP IEEE Signal Proc Soc DE electron tomography; denoising; feature extraction; HIV; dual-axis SIRT and automated techniques ID IMAGE; DIFFUSION AB Advances in automated data acquisition in electron tomography have led to an explosion in the amount of data that can be obtained about the spatial architecture of a variety of biologically and medically relevant objects with sizes in the "nano" range of 10-1000nm. The development of methods to analyze the vast amounts of information contained in these tomograms is a major challenge since the electron tomograms are intrinsically noisy. A fundamental step in the automatic analysis of large amounts of data for statistical inference is to segment 3D features in cellular tomograms that can work robustly and rapidly despite of low signal to noise ratios inherent to biological electron microscopy. This work evaluates various denoising techniques on tomograms obtained using dual-axis simultaneous iterative reconstruction (SIRT) technique. Using three-dimensional images of HIV in infected human macrophages as an example, we demonstrate that transform domain-denoising techniques significantly improve the fidelity of automated feature extraction. Importantly, our approaches represent an vital step in automating the efficient extraction of useful information from large datasets in biological tomography, and facilitate the overall goal of speeding up the process of reducing gigabyte-sized tomograms to byte-sized data. C1 [Narasimha, Rajesh; Bennett, Adam; Zabransky, Daniel; Sougrat, Rachid; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Narasimha, Rajesh; McLaughlin, Steven] Georgia Inst Technol, Atlanta, GA USA. RP Narasimha, R (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM rajesh@ece.gatech.edu; bennettad@mail.nih.gov; djzabr@wm.edu; sougrat@mail.nih.gov; ssl@nih.gov; swm@ece.gatech.edu NR 12 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 BN 978-1-4244-0728-6 J9 INT CONF ACOUST SPEE PY 2007 BP 301 EP + PG 3 WC Acoustics; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Acoustics; Engineering; Imaging Science & Photographic Technology GA BGO60 UT WOS:000249040000076 ER PT S AU Li, X Tao, J Johnson, MT Soltis, J Savage, A Leong, KM Newman, JD AF Li, Xi Tao, Jidong Johnson, Michael T. Soltis, Joseph Savage, Anne Leong, Kirsten M. Newman, John D. GP IEEE TI Stress and emotion classification using jitter and shimmer features SO 2007 IEEE INTERNATIONAL CONFERENCE ON ACOUSTICS, SPEECH, AND SIGNAL PROCESSING, VOL IV, PTS 1-3 SE International Conference on Acoustics Speech and Signal Processing ICASSP LA English DT Proceedings Paper CT 32nd IEEE International Conference on Acoustics, Speech and Signal Processing CY APR 15-20, 2007 CL Honolulu, HI SP IEEE Signal Proc Soc DE jitter; shimmer; MFCC; GFCC; HMM ID RECOGNITION; SPEECH AB In this paper, we evaluate the use of appended jitter and shimmer speech features for the classification of human speaking styles and of animal vocalization arousal levels. Jitter and shimmer features are extracted from the fundamental frequency contour and added to baseline spectral features, specifically Me1-frequency Cepstral Coefficients (MFCCs) for human speech and Greenwood Function Cepstral Coefficients (GFCCs) for animal vocalizations. Hidden Markov Models (HMMs) with Gaussian Mixture Models (GMMs) state distributions are used for classification. The appended jitter and shimmer features result in an increase in classification accuracy for several illustrative datasets, including the SUSAS dataset for human speaking styles as well as vocalizations labeled by arousal level for African Elephant and Rhesus Monkey species. C1 [Li, Xi; Tao, Jidong; Johnson, Michael T.] Marquette Univ, Speech & Signal Proc, Milwaukee, WI 53201 USA. [Soltis, Joseph; Savage, Anne] Disneys Anim Kingdom, Orlando, FL 32830 USA. [Leong, Kirsten M.] Cornell Univ, Dept Nat Resources, Ithaca, NY 14850 USA. [Newman, John D.] NIH, Natl Inst Child Hlth & Human Dev, Dept Hlth & Human Serv, Lab Comparat Ethol, Poolesville, MD 20837 USA. RP Li, X (reprint author), Marquette Univ, Speech & Signal Proc, Milwaukee, WI 53201 USA. EM xi.li@marquette.edu; jidong.tao@marquette.edu; mike.johnson@marquette.edu; joseph.soltis@disney.com; anne.savage@disney.com; klm47@comell.edu; newmanj@lce.nichd.nih.gov FU National Science Foundation [IIS-0326395] FX The authors would like to acknowledge Marek B. Trawicki for provision of initial experiment code. This contribution is based on work supported by the National Science Foundation under Grant No. IIS-0326395. NR 14 TC 18 Z9 18 U1 1 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1520-6149 J9 INT CONF ACOUST SPEE PY 2007 BP 1081 EP + DI 10.1109/ICMLC.2007.4370304 PG 2 WC Acoustics; Engineering, Electrical & Electronic; Telecommunications SC Acoustics; Engineering; Telecommunications GA BGO04 UT WOS:000248909200271 ER PT S AU Zaslavsky, L Bao, Y Tatusova, TA AF Zaslavsky, Leonid Bao, Yiming Tatusova, Tatiana A. BE Chen, XW Damiani, E He, H Gao, J Li, JY Sidhu, AS Song, M Yoo, I Zhou, XH TI Multiresolution approaches to representation and visualization of large influenza virus sequence datasets SO 2007 IEEE INTERNATIONAL CONFERENCE ON BIOINFORMATICS AND BIOMEDICINE WORKSHOPS, PROCEEDINGS SE IEEE International Conference on Bioinformatics and Biomedicine Workshop-BIBMW LA English DT Proceedings Paper CT IEEE International Conference on Bioinformatics and Biomedicine CY NOV 02-04, 2007 CL Fremont, CA SP IEEE Comp Soc Local Chapter, Addison Wesley, AT&T Res, Bell Labs, Brio, Course Technol, Crystal Decis, Dell, Elsevier, Google, HP Res, Hyperion, IBM Silicon Valley, IBM, Intel Corp, Microsoft, NASA, Nokia, Oak Ridge Natl Labs, Oracle, Pfizer, Sony, Verizon, Yahoo AB Rapid growth of the amount of genome sequence data requires enhancing exploratory analysis tools, with analysis being performed in a fast and robust manner Users need data representations serving different purposes: from seeing overall structure and data coverage to evolutionary processes during a particular season. Our approach to the problem is in constructing hierarchies of data representations, and providing users with representations adaptable to specific goals. It can be done efficiently because the structure of a typical influenza dataset is characterized by low estimated values of the Kolmogorov (box) dimension. Multiscale methodologies allow interactive visual representation of the dataset and accelerate computations by importance sampling. Our tree visualization approach is based on a subtree aggregation with subscale resolution. It allows interactive refinements and coarsening of subtree views. For importance sampling large influenza datasets, we construct sets of well-scattered points (epsilon-nets). While a tree build for a global sample provides a coarse-level representation of the whole dataset, it can be complemented by trees showing more details in chosen areas. To reflect both global dataset structure and local details correctly, we perform local refinement gradually, using a multiscale hierarchy of epsilon-nets. Our hierarchical representations allow fast metadata searching. C1 [Zaslavsky, Leonid; Bao, Yiming; Tatusova, Tatiana A.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Zaslavsky, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM zaslavsk@ncbi.nlm.nih.gov; bao@ncbi.nlm.nih.gov; tatiana@ncbi.nlm.nih.gov NR 11 TC 0 Z9 0 U1 0 U2 0 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1264 USA SN 2163-6966 BN 978-1-4244-1604-2 J9 IEEE INT C BIO BIO W PY 2007 BP 109 EP 114 PG 6 WC Computer Science, Information Systems; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BHH89 UT WOS:000253368800016 ER PT S AU Yao, JH Li, J Summers, R AF Yao, Jianhua Li, Jiang Summers, Ronald GP IEEE TI CT colonography computer-aided polyp detection using topographical height map SO 2007 IEEE INTERNATIONAL CONFERENCE ON IMAGE PROCESSING, VOLS 1-7 SE IEEE International Conference on Image Processing ICIP LA English DT Proceedings Paper CT IEEE International Conference on Image Processing (ICIP 2007) CY SEP 16-19, 2007 CL San Antonio, TX SP IEEE DE CAD; CT Colonography; height map ID COLONIC POLYPS AB CT Colonography (CTC) is an emerging noninvasive technique for screening and diagnosing colon cancers. Computer Aided Detection (CAD) techniques can increase sensitivity and reduce false positives. We propose to employ topographical height maps in our CAD pipeline. For every detection, a height map is computed using a ray-casting algorithm. Since colonic polyps are protrusions outward from the colon wall and are round in contour, their height maps present concentric patterns. The projection direction is optimized through a multi-scale spherical search. We derive several topographic features from the map, and also compute texture features from the Haar wavelet coefficients. We send the selected features to a committee of support vector machines for classification. We have tested our method on 1186 patients with 226 polyps. Results showed that the height map features can reduce false positives by about 50%. C1 [Yao, Jianhua; Li, Jiang; Summers, Ronald] NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Yao, JH (reprint author), NIH, Dept Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 978-1-4244-1436-9 J9 IEEE IMAGE PROC PY 2007 BP 2273 EP 2276 PG 4 WC Engineering, Electrical & Electronic; Imaging Science & Photographic Technology SC Engineering; Imaging Science & Photographic Technology GA BHJ22 UT WOS:000253487201328 ER PT S AU Wang, ZS Maier, A Leopold, DA Liang, HL AF Wang, Zhisong Maier, Alexander Leopold, David A. Liang, Hualou GP IEEE TI Spatiotemporal integration of neuronal activity for single-trial classifications of bistable perception SO 2007 IEEE INTERNATIONAL JOINT CONFERENCE ON NEURAL NETWORKS, VOLS 1-6 SE IEEE International Joint Conference on Neural Networks (IJCNN) LA English DT Proceedings Paper CT International Joint Conference on Neural Networks CY AUG 12-17, 2007 CL Orlando, FL SP IEEE ID AREA MT; PERFORMANCE; RESPONSES; CHOICE AB This paper aims to understand how the discriminative information of neuronal population activity evolves and accumulates over time. We present two classes of approaches namely the probability-based and response-based approaches to predict the perceptual reports of a trained macaque monkey on a single-trial basis by integrating neural signals from multiple electrodes across time. We extend the probability-based integration originally using only the quadratic discriminant analysis (QDA) by considering also the linear discriminant analysis (LDA) and logistic regression methods. Furthermore, we introduce the response-based integration for the QDA, LDA and logistic regression methods. Experimental examples demonstrate the effectiveness of these approaches for determining the perceptual state of a brain under study by integrating its localized spatiotemporal neuronal activity. C1 [Wang, Zhisong; Liang, Hualou] Univ Texas Houston, Hlth Sci Ctr, Sch Hlth Informat Sci, 7000 Fannin,Suite 600, Houston, TX 77030 USA. [Maier, Alexander; Leopold, David A.] NIH, Unit Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. RP Liang, HL (reprint author), Univ Texas Houston, Hlth Sci Ctr, Sch Hlth Informat Sci, 7000 Fannin,Suite 600, Houston, TX 77030 USA. EM Hualou.Liang@uth.tmc.edu RI Maier, Alexander/B-7489-2009; OI Maier, Alexander/0000-0002-7250-502X; Leopold, David/0000-0002-1345-6360 FU NIH [RO1 NS0543 14, ROI MH072034]; Whitehall Foundation FX This work was supported in part by the NIH RO1 NS0543 14, ROI MH072034, and the Whitehall Foundation. NR 14 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 2161-4393 BN 978-1-4244-1379-9 J9 IEEE IJCNN PY 2007 BP 2189 EP + DI 10.1109/IJCNN.2007.4371297 PG 2 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering SC Computer Science GA BHM64 UT WOS:000254291102018 ER PT S AU Gandjbakhche, AH Hassan, M Chernomordik, V Lee, SB Capala, J AF Gandjbakhche, Amir H. Hassan, Moinuddin Chernomordik, Victor Lee, Sang Bong Capala, Jacek GP IEEE TI Time resolved fluorescence lifetime imaging system for in vivo characterization of tumors SO 2007 IEEE LEOS ANNUAL MEETING CONFERENCE PROCEEDINGS, VOLS 1 AND 2 SE IEEE Lasers and Electro-Optics Society (LEOS) Annual Meeting LA English DT Proceedings Paper CT 20th Annual Meeting of the IEEE-Lasers-and-Electro-Optics-Society CY OCT 21-25, 2007 CL Lake Buena Vista, FL AB We present a lifetime fluorescence imaging system for small animal imaging. The system uses a linear fiber array with given separations between a single source fiber and several detection fibers. The general goal is to detect and localize tumors, using specific fluorescent markers and investigate their progression. We investigated applications of the developed system to mouse imaging, using as contrast agent Alexa Fluor 750 conjugated to tumor specific antibodies (Herceptin). Realized 2D mapping of fluorescence lifetime indicate lower lifetime value in the tumor area. C1 [Gandjbakhche, Amir H.; Hassan, Moinuddin; Chernomordik, Victor] NICHHD, NIH, Bethesda, MD 20892 USA. [Lee, Sang Bong; Capala, Jacek] Natl Canc Inst, NIH, Bethesda, MD 20892 USA. RP Gandjbakhche, AH (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1092-8081 BN 978-1-4244-0924-2 J9 IEEE LEOS ANN MTG PY 2007 BP 7 EP + DI 10.1109/LEOS.2007.4382247 PG 2 WC Engineering, Electrical & Electronic; Nanoscience & Nanotechnology; Optics SC Engineering; Science & Technology - Other Topics; Optics GA BIG51 UT WOS:000259345200002 ER PT B AU Merk, I Bockrath, M Landi, M AF Merk, Isabella Bockrath, Marc Landi, Maria GP IEEE TI Novel nano-biosensors for life science systems and their applications in early, accurate, and non-invasive melanoma and other types of cancer detection SO 2007 IEEE/NIH LIFE SCIENCE SYSTEMS AND APPLICATIONS WORKSHOP LA English DT Proceedings Paper CT IEEE/NIH Life Science Systems and Applications Workshop CY SEP 05-07, 2007 CL Bethesda, MD SP IEEE, NIH ID FIELD-EFFECT TRANSISTORS; CARBON NANOTUBE; DYSPLASTIC NEVI; SINGLE; PROTEINS; SENSORS AB Melanoma (the 5(th) and 6(th) most common cancer in Caucasian males and females, respectively), is the most severe form of skin cancer, which is often fatal if recognized in its advanced stage. Melanoma is the tumor that originates from melanocytes (the cells that make the pigment melanin), and may develop from a nevus (commonly named "mole"). Clinically, it is very difficult to correctly differentiate nevi with atypical features or dysplastic nevi and nevi of special sites from melanoma. Clearly, new, more powerful, less invasive, time consuming and expensive tools are needed for an early and accurate detection of melanoma. In order to address this need, we propose a development of a new set of tools, namely, carbon-nanotube-based biosensors for the early and accurate detection of melanoma. Once successful, we will modify and apply this new technology to early and accurately detect other types of cancer. C1 [Merk, Isabella; Bockrath, Marc] CALTECH, Dept Engn & Appl Sci, 1200E California Blvd, Pasadena, CA 91125 USA. [Landi, Maria] NIH, Natl Canc Inst, Bethesda, MD USA. RP Merk, I (reprint author), CALTECH, Dept Engn & Appl Sci, 1200E California Blvd, Pasadena, CA 91125 USA. EM isabella@caltech.edu; landmi@exchange.nih.gov NR 18 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-1812-1 PY 2007 BP 128 EP + DI 10.1109/LSSA.2007.4400901 PG 2 WC Engineering, Biomedical; Engineering, Electrical & Electronic SC Engineering GA BHP91 UT WOS:000255229500032 ER PT S AU Barker, WC Thada, S AF Barker, W. Craig Thada, Shanthalaxmi GP IEEE TI GPU acceleration of MOLAR for HRRT list-mode OSEM reconstructions SO 2007 IEEE NUCLEAR SCIENCE SYMPOSIUM CONFERENCE RECORD, VOLS 1-11 SE IEEE NUCLEAR SCIENCE SYMPOSIUM - CONFERENCE RECORD LA English DT Proceedings Paper CT IEEE Nuclear Science Symposium/Medical Imaging Conference CY OCT 26-NOV 03, 2007 CL Honolulu, HI SP IEEE AB The Siemens ECAT HRRT PET scanner has the potential to produce images of the human brain with spatial resolution better than 3 mm. MOLAR (a Motion-compensation OSEM List-mode Algorithm for Resolution-recovery) was developed to provide reconstructions of HRRT data with the best possible accuracy and precision. However, a computer cluster is required to generate reconstructions in a reasonable amount of time. Strategies for computational efficiency have already been implemented in MOLAR but room for improvement remains. In this study we have begun the process of converting time-consuming components of MOLAR to parallelized code that runs on commodity graphics cards (GPUs) with much faster turnaround. We evaluated the performance of list-mode event forward projections and component-based normalization factor calculations, and we confirmed the numerical accuracy of images reconstructed with GPU-assisted code running on an HP xw8400 workstation with an NVEDIA Quadro FX 4600 graphics card. We evaluated simulated data projected through a 128x128x128 image volume that included the direct calculation of a gaussian resolution function for simulated fist-mode events. This was done using the Cg and CUDA programming APIs for implementation comparison. Both GPU versions ran up to 100 times faster than the CPU-only code. The CUDA version showed some improvement over Cg and was easier to program. We also examined measured Ge-68 phantom data projected through a 256x256x207 image volume with resolution functions obtained through array lookup rather than by direct calculation. The GPU-assisted code was observed to be up to 14 times faster than the CPU-only code, particularly when one million or more events were processed. Normalization processing was found to be up to 36 times faster. However, speedup decreased to a factor of 3 when disk I/O became dominant as more than one billion events were processed. We anticipate further acceleration of MOLAR as we convert other components to GPU-assisted code, in particular backprojection and scatter correction. (Backprojection is on hold until a next generation GPU which has atomic write capability becomes available.) C1 [Barker, W. Craig; Thada, Shanthalaxmi] NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Barker, WC (reprint author), NIH, PET Dept, Ctr Clin, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1082-3654 BN 978-1-4244-0922-8 J9 IEEE NUCL SCI CONF R PY 2007 BP 3004 EP 3008 DI 10.1109/NSSMIC.2007.4436766 PG 5 WC Physics, Applied; Imaging Science & Photographic Technology; Physics, Nuclear; Physics, Particles & Fields; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Physics; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA BHY13 UT WOS:000257380402096 ER PT B AU Yang, JY Yang, MQ Niemierko, A Luo, ZJ Li, ML AF Yang, Jack Y. Yang, Mary Qu Niemierko, Andrzej Luo, Zuojie Li, Manling GP IEEE TI Predicting Tumor Malignancies using Combined Computational Intelligence, Bioinformatics and Laboratory Molecular Biology Approaches SO 2007 IEEE SYMPOSIUM ON COMPUTATIONAL INTELLIGENCE IN BIOINFORMATICS AND COMPUTATIONAL BIOLOGY LA English DT Proceedings Paper CT IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology CY APR 01-05, 2007 CL Honolulu, HI DE computational intelligence; bioinformatics; parallel paradigm of caner; benign; maliganant transformation ID CELL-CYCLE REGULATORS; EXPRESSION; CANCER; P27(KIP1) AB Predicting tumor malignancies is an important but difficult task. For many tumors, especially neural and endocrine tumors, traditional pathological and histological analyses often can not effectively distinguish benign from malignant tumors. Developing synergistic bioinformatics and computational intelligence system is effective, because deterministic cancer markers do not always exist in individual patients. We proposed a parallel paradigm of cancer and use a number of ensemble methods including Boosting, Bagging and Consensus Networking, and have designed a novel classification scheme that advantageously combines several computational intelligence algorithms such as the variants of Self-Organizing Feature Map (SOFM) algorithms and the Maximum Contrast Tree (RMCT) algorithms. Boosting and Bagging have been advantageously combined. When all of the above are integrated into one synergistic intelligent medical decision system, the prediction power for the task has been significantly boosted. The system and features are validated by diagnosing new patients and by a number of laboratory molecular biology measurements. The outcomes of the research have improved cancer diagnosis and treatment planning, and may lead to diagnose microscopic diseases and better understanding of human genome mechanisms relating to malignant transformation. C1 [Yang, Jack Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Yang, Mary Qu] US Dept HHS, NHGRI, NIH, Rockville, MD 20852 USA. [Niemierko, Andrzej] Harvard Univ, Massachusetts Gen Hosp, Dept Radiat Oncol, Div Biomed & Biostat, Boston, MA 02114 USA. [Luo, Zuojie; Li, Manling] Guangxi Univ Tradit Chinese Med, Dept Endocrinol, Nanning 500021, Peoples R China. RP Yang, JY (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM jyang@hadron.mgh.harvard.edu; yangma@mail.nih.gov FU NIH/NCI [ROI CA50628-15]; NIH/NHGRI; Havard University/HMS/MGH Post Doctoral Research Specialist Fellowship Awards FX We thank Drs. Laura Elintiski (NIH/NHGRI), Okan K. Ersoy, Craig W. Codrington (Purdue University), Yinfen Qin, Minyi Wei, Yan Ma, Xinghuan Liang, Decheng Lu, Jing Xian (Guangxi Medical University) and Zhiheng He (Joslin Diabetes Center, Harvard University) for valuable discussions and or experimental supports. The research was partially supported by NIH/NCI ROI CA50628-15 and NIH/NHGRI and Havard University/HMS/MGH Post Doctoral Research Specialist Fellowship Awards. NR 21 TC 0 Z9 0 U1 2 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA BN 978-1-4244-0710-1 PY 2007 BP 46 EP + PG 2 WC Computer Science, Interdisciplinary Applications; Engineering, Electrical & Electronic; Mathematical & Computational Biology SC Computer Science; Engineering; Mathematical & Computational Biology GA BGM70 UT WOS:000248516200007 ER PT S AU O'Neill, BE Li, KCP Frenkel, V Vo, H Angstadt, M Wood, BJ Quinn, TP AF O'Neill, Brian E. Li, King C. P. Frenkel, Victor Vo, Howard Angstadt, Mary Wood, Bradford J. Quinn, Timothy P. GP IEEE TI Investigations into the potential contribution of a thermal mechanism for pulsed high intensity focused ultrasound mediated delivery SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE DE drug delivery; high intensity focused ultrasound; hyperthermia; thermal mechanism AB The mechanism behind pulsed high intensity focused ultrasound (pHIFU) effects leading to increased drug delivery is currently poorly understood. In this work the thermal dose and peak temperatures associated with a typical pHIFU treatment were measured in mouse muscle. A non-ultrasonic hyperthermia (HT) treatment was then applied, designed to mimic the thermal component of the pHIFU treatment. The delivery of 200 nm fluorescent nanoparticles was measured as a surrogate marker for drug delivery by pHIFU and HT treatments. Only the pHIFU treatment showed a significant increase In particle delivery. C1 [O'Neill, Brian E.; Li, King C. P.] Methodist Hosp, Dept Radiol, 6535 Fannin, Houston, TX 77030 USA. [Frenkel, Victor; Vo, Howard; Angstadt, Mary; Wood, Bradford J.] NIH, Dept Diagnost Radiol, Bethesda, MD USA. [Quinn, Timothy P.] Natl Inst Stand & Technol, Div Mat Reliabil, Boulder, CO USA. RP O'Neill, BE (reprint author), Methodist Hosp, Dept Radiol, 6535 Fannin, Houston, TX 77030 USA. EM beoneill@tmhs.org; vfrenkel@cc.nih.gov; quinn@boulder.nist.gov FU Research Associateship Program of the National Academies of Science FX Funded with support of the Research Associateship Program of the National Academies of Science. NR 11 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 1 EP + DI 10.1109/ULTSYM.2007.16 PG 2 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281800001 ER PT S AU Cannata, JM Williams, JA Zhou, Q Yu, H Sun, L Kim, ES Shung, KY AF Cannata, J. M. Williams, J. A. Zhou, Q. Yu, H. Sun, L. Kim, E. S. Shung, K. Y. GP IEEE TI Self-focused ZnO transducers for ultrasonic biomicroscopy SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE ID FABRICATION; MEMS AB A simple fabrication technique was developed to produce self-focused high frequency single element transducers with sputtered Zinc Oxide (ZnO) crystal films. The novelty of this technique lies in that the ZnO film can be sputtered directly onto a curved substrate. Two transducers were fabricated by sputtering an 18 mu m thick ZnO layer on 2 and 3mm diameter aluminum rods with ends shaped and polished to produce an f# equal to one. The aluminum rod served a dual purpose as the backing layer and positive electrode for the resultant transducers. A single 4 gm Parylene polymer matching layer was deposited on the transducers after housing and interconnect. The pulse-echo response for the 2 mm aperture transducer was centered at 109 MHz with a -6dB bandwidth of 43%. A 3 nun aperture transducer produced a 96 MHz echo response with a 52% bandwidth. The measured insertion loss for the 2 mm aperture was 45 dB and the 3 mm aperture was 42 dB. A wire phantom and adult zebrafish were imaged to show the capability of the transducers. C1 [Cannata, J. M.; Williams, J. A.; Zhou, Q.; Sun, L.; Shung, K. Y.] Univ Southern Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. [Yu, H.; Kim, E. S.] Univ Southern Calif, Dept Elect Engn Electrophys, Los Angeles, CA 90089 USA. RP Cannata, JM (reprint author), Univ Southern Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. FU National Institutes of Health [P41-EB2182] FX The authors would like to thank the National Institutes of Health for providing the funding for this project through grant # P41-EB2182. NR 7 TC 0 Z9 0 U1 0 U2 2 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 945 EP + DI 10.1109/ULTSYM.2007.241 PG 2 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281800226 ER PT S AU Liu, RB Kim, HH Cannata, JM Chen, GS Shung, KK AF Liu, Ruibin Kim, Hyung Ham Cannata, Jonathan M. Chen, Gin-Shin Shung, K. Kirk GP IEEE TI Self-focused 1-3 composite LiNbO3 single element transducers for high frequency HIFU applications SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE ULTRASONICS SYMPOSIUM LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE DE HIFU therapy; ultrasound transducers; lead free piezoelectric transducer; LiNbO3 crystal ID ULTRASONIC PHASED-ARRAY; SURGERY; TISSUE; GLAUCOMA AB In this paper It is shown that LiNbO3 single crystal may be used as a piezoelectric material for high frequency High Intensity Focused Ultrasound (HIFU) applications for its high Curie temperature and low dielectric constant and superior mechanical properties. Simulation results show that LiNbO3 with a 1-3 composite structure Is suitable to make large aperture (diameter 22-24 mm) and high frequency (> 10 MHz) single element transducer with desired impedance and required sustainable driving voltage for the expected acoustic Intensity in the focal zone. Prototype transducers with the diameter of 23 min and a surface curvature designed for f#/1 were designed and fabricated. The results are in good agreement with KLM model calculation. The measurement results show that center frequency is 10.5 MHz with the fractional bandwidth larger than 60%. The -6dB lateral and the axial beam widths were measured by a needle hydrophone and they are 160 gm and 98 mu m respectively, which are also In good agreement with theory (147 mu m and 83 mu m). C1 [Liu, Ruibin; Kim, Hyung Ham; Cannata, Jonathan M.; Chen, Gin-Shin; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Ultrasound Transducer Resources Ctr, Los Angeles, CA 90089 USA. RP Liu, RB (reprint author), Univ So Calif, Dept Biomed Engn, NIH, Ultrasound Transducer Resources Ctr, Los Angeles, CA 90089 USA. RI Chen, Gin-Shin /E-3988-2010 NR 22 TC 4 Z9 4 U1 1 U2 6 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 949 EP 952 DI 10.1109/ULTSYM.2007.242 PG 4 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281800227 ER PT S AU Zhou, QF Wu, D Djuth, FT Liu, CG Shung, KK AF Zhou, Q. F. Wu, D. Djuth, F. T. Liu, C. G. Shung, K. K. GP IEEE TI High-frequency piezoelectric PZT film micromachined ultrasonic transducers SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE AB This paper presents the latest development of MEMS high frequency ultrasound transducers with PZT piezoelectric thick films. Composite PZT solution was prepared and deposited on platinum-plated silicon wafers to fabricate active ferroelectrics thick-films. Particle size distribution (PSD) and powder of PZT-to-solution mass ratio effects of the composite solution were systematically studied to enhance electrical properties of PZT thick films. Improvements to the PZT film deposition process have yielded high quality, crack-free PZT films up to 18 mu m in thickness. High-frequency (> 80MHz) transducers based on these thick PZT films have been successfully fabricated. The measured results show that these transducers possess much better sensitivity than previous PZT film transducers. C1 [Zhou, Q. F.; Wu, D.; Shung, K. K.] Univ So Calif, NIH, Transducer Resources Ctr, Los Angeles, CA 90089 USA. [Djuth, F. T.; Liu, C. G.] Geospace Res Inc, El Segundo, CA 90245 USA. RP Zhou, QF (reprint author), Univ So Calif, NIH, Transducer Resources Ctr, Los Angeles, CA 90089 USA. FU NIH [P41-EB2182, NIH/NCI 2R44CA110214] FX We would like to thank Dr. D. S. Zhang for particle size test. This work was financially supported by NIH Grant #P41-EB2182 and NIH/NCI 2R44CA110214 NR 9 TC 0 Z9 0 U1 1 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 1057 EP + DI 10.1109/ULTSYM.2007.267 PG 2 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281801015 ER PT S AU Lee, J Shung, KK AF Lee, Jungwoo Shung, K. Kirk GP IEEE TI Design of steep intensity distribution for acoustic tweezer using multiple high frequency focused transducers SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE ULTRASONICS SYMPOSIUM LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE DE high frequency focused transducer; acoustic tweezer; beamwidth; tight focusing; intensity gradient; Field II ID RADIATION PRESSURE; FEASIBILITY; SPHERE; FORCES AB Sharp Intensity change around a focal point Is one of the most essential elements for acoustic tweezers. This paper presents a method to create such Intensity distribution by using multiple high frequency focused transducers. In addition to a 50 MHz tweezer transducer, 20 MHz holder transducers are needed for initial positioning of lipid particles into a water chamber. The results demonstrate that the arrangement can provide 3dB beamwidth of 30 mu m to ensure tweezer effect. Aperture sizes of holder and tweezer transducers are 4.4 mm and 2.8 mm, respectively. F-number of all transducers Is 0.5. Peak intensity and pressure at the focus are calculated to be 35.4 W/cm(2) and 0.7 MPa under 1 mW of acoustic power. Tight focusing is required to minimize acoustic streaming, which undermines the tweezing by acoustic radiation forces. Based on the field distribution obtained from Field II, it is concluded that its large Intensity gradient can generate the tweezer effect up to 340 pN In the vicinity of the focus. C1 [Lee, Jungwoo; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. RP Lee, J (reprint author), Univ So Calif, Dept Biomed Engn, NIH, Resource Ctr Med Ultrason Transducer Technol, Los Angeles, CA 90089 USA. NR 7 TC 0 Z9 0 U1 2 U2 6 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 1685 EP 1688 DI 10.1109/ULTSYM.2007.424 PG 4 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281801172 ER PT S AU Yu, HY Lee, CY Kim, ES Wu, DW Zhou, QF Shung, KK AF Yu, Hongyu Lee, Chuang-Yuan Kim, Eun Sok Wu, Dawei Zhou, Qifa Shung, K. Kirk GP IEEE TI High-overtone self-focusing acoustic transducer for high frequency ultrasonic imaging SO 2007 IEEE ULTRASONICS SYMPOSIUM PROCEEDINGS, VOLS 1-6 SE Ultrasonics Symposium LA English DT Proceedings Paper CT IEEE Ultrasonics Symposium CY OCT 28-31, 2007 CL New York, NY SP IEEE DE ultrasonic Imaging; self-focusing acoustic transducers; harmonic; lead zirconate titanate (PZT) AB This paper reports the use of high-overtone self-focusing acoustic transducers for high frequency ultrasonic imaging application. For an acoustic transducers working for ultrasonic Imaging, the resolution is primarily determined by the acoustic wavelength, which Is normally proportional to the piezoelectric substrate thickness. Using a harmonic frequency of a bulk PZT with a novel Fresnel lens based on air-reflectors for a focused acoustic beam, we reduce the wavelength and obtain strong signals at the center frequencies of the 3rd (60MHz) and 5th (100MHz) harmonics for ultrasonic Imaging. The bandwidth at -6dB was over 20 %, even without a front matching layer. C1 [Yu, Hongyu; Lee, Chuang-Yuan; Kim, Eun Sok] Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. [Wu, Dawei; Zhou, Qifa; Shung, K. Kirk] Univ So Calif, Dept Biomed Engn, NIH, Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Yu, HY (reprint author), Univ So Calif, Dept Elect Engn, Los Angeles, CA 90089 USA. FU NIH [P41-EB2182] FX This work has been partially supported by NIH grant # P41-EB2182. NR 4 TC 0 Z9 0 U1 0 U2 3 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1051-0117 BN 978-1-4244-1383-6 J9 ULTRASON PY 2007 BP 2401 EP + DI 10.1109/ULTSYM.2007.604 PG 2 WC Acoustics; Biophysics; Engineering, Electrical & Electronic; Physics, Applied; Imaging Science & Photographic Technology SC Acoustics; Biophysics; Engineering; Physics; Imaging Science & Photographic Technology GA BHM55 UT WOS:000254281802101 ER PT S AU Kam, AW Wang, HH Farahani, K Thomasson, D O'Neill, B Angstadt, M Jesson, J Li, KCP AF Kam, Anthony W. Wang, Honghui Farahani, Keyvan Thomasson, David O'Neill, Brian Angstadt, Mary Jesson, Johnny Li, King C. P. BE Coussios, CC TerHaar, G TI Safety of pulsed high intensity focused ultrasound for enhanced drug and gene delivery SO 6TH INTERNATIONAL SYMPOSIUM ON THERAPEUTIC ULTRASOUND SE AIP Conference Proceedings LA English DT Proceedings Paper CT 6th International Symposium on Therapeutic Ultrasound CY AUG 30-SEP 02, 2006 CL Oxford, ENGLAND SP Int Soc Therapeut Ultrasound, China Med Technologies, HAIFU, Phillips Med Syst, EDAP, Mianyang Son Elect Ltd, Imasonic, Ultra Shape Ltd, British Med Ultrasound Soc, ImRx Therapeut, Liposonix SA, Theraclion, SRA Dev Ltd, UKHIFU DE pulsed high intensity focused ultrasound; MR thermometry; safety; drug and gene delivery ID MODEL; THERMOMETRY; CELL AB For a limited range of exposure parameters, pulsed high intensity focused ultrasound (HIFU) has been shown to increase the delivery of certain systemically administered macromolecular diagnostic and therapeutic agents in mice. The mechanism for the enhanced delivery has not been demonstrated definitively and, in principle, can include thermal, cavitational, and non-cavitation mechanical effects. The sonicated tissue has no damage on histology. As a step towards clinical translation, the safety of this technique needs to be assessed in a clinically relevant manner. In this study, the safety of pulsed HIFU is evaluated with near real-time phase shift magnetic resonance (MR) thermometry and anatomic MR imaging using rabbits as subjects. MR guidance enables pulsed HIFU enhanced delivery to be implemented safely from a thermal standpoint. Although the effects of pulsed HIFU are not seen on anatomic MR images, they may be detected on MR sequences sensitive to permeability, diffusion, and elasticity. Such work that may optimize pulsed HIFU enhanced delivery is in progress. C1 [Kam, Anthony W.; Wang, Honghui; Thomasson, David; O'Neill, Brian; Angstadt, Mary; Jesson, Johnny; Li, King C. P.] NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Kam, Anthony W.] Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD USA. [Farahani, Keyvan] Natl Cancer Inst, Rockville, MD USA. [Jesson, Johnny] Walla Walla Coll, Coll Place, WA USA. RP Kam, AW (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. FU Intramural Research Program; Clinical Center of the National Institutes of Health FX We would like to thank Victor Frenkel for useful discussions. This work was supported by the Intramural Research Program and the Clinical Center of the National Institutes of Health. NR 10 TC 0 Z9 0 U1 0 U2 1 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 978-0-7354-0419-9 J9 AIP CONF PROC PY 2007 VL 911 BP 455 EP + PG 2 WC Acoustics; Physics, Multidisciplinary; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Physics; Radiology, Nuclear Medicine & Medical Imaging GA BGI56 UT WOS:000247342200071 ER PT J AU Chaurasia, CS Muller, M Bashaw, ED Benfeldt, E Bolinder, J Bullock, R Bungay, PM DeLange, ECM Derendorf, H Elmquist, WF Hammarlund-Udenaes, M Joukhadar, C Kellogg, DL Lunte, CE Nordstrom, CH Rollema, H Sawchuk, RJ Cheung, BWY Shah, VP Stahle, L Ungerstedt, U Welty, DF Yeo, H AF Chaurasia, Chandra S. Mueller, Markus Bashaw, Edward D. Benfeldt, Eva Bolinder, Jan Bullock, Ross Bungay, Peter M. DeLange, Elizabeth C. M. Derendorf, Hartmut Elmquist, William F. Hammarlund-Udenaes, Margareta Joukhadar, Christian Kellogg, Dean L., Jr. Lunte, Craig E. Nordstrom, Carl Henrik Rollema, Hans Sawchuk, Ronald J. Cheung, Belinda W. Y. Shah, Vinod P. Stahle, Lars Ungerstedt, Urban Welty, Devin F. Yeo, Helen TI AAPS-FDA workshop white paper: Microdialysis principles, application, and regulatory perspectives report from the joint AAPS-FDA workshop, November 4-5, 2005, Nashville, TN SO AAPS JOURNAL LA English DT Article ID IN-VIVO MICRODIALYSIS; BLOOD-BRAIN-BARRIER; ZERO-NET-FLUX; CONCENTRATION PROFILES; CEREBROSPINAL-FLUID; DIABETIC-PATIENTS; SKELETAL-MUSCLE; DRUG-DELIVERY; PHARMACOKINETICS; TISSUE C1 US FDA, Off Gener Drugs, Div Bioequivalence, Rockville, MD 20857 USA. Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria. US FDA, Off Clin Pharmacol, Div Clin Pharmacol 3, Silver Spring, MD USA. Univ Copenhagen, Dept Dermatol, Copenhagen NV, Denmark. Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Med, Stockholm, Sweden. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NIH, Off Res Serv, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. LACDR, Leiden, Netherlands. Univ Florida, Dept Pharmaceut, Gainesville, FL 32611 USA. Univ Minnesota, Dept Pharmaceut, Minneapolis, MN 55455 USA. Uppsala Univ, Dept Pharmaceut, Uppsala, Sweden. Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Kansas, Dept Chem, Lawrence, KS 66045 USA. Univ Lund Hosp, Dept Neurosurg, S-22185 Lund, Sweden. Pfizer Global Res, Dept Neurosci, Groton, CT USA. Astra Zeneca, Sodertalje, Sweden. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. Allergan Pharmaceut Inc, Pharmacokinet & Drug Metab, Irvine, CA 92715 USA. Roche, Dept Drug Metab & Pharmacokinet, Palo Alto, CA USA. RP Chaurasia, CS (reprint author), US FDA, Off Gener Drugs, Div Bioequivalence, Rockville, MD 20857 USA. EM chandra.chaurasia@fda.hhs.gov RI Derendorf, Hartmut/B-4628-2012 OI Derendorf, Hartmut/0000-0003-4016-1370 NR 61 TC 6 Z9 6 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PY 2007 VL 9 IS 1 BP E48 EP E59 AR 6 DI 10.1208/aapsj0901006 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160LT UT WOS:000245943200006 ER PT J AU Rothman, RB Blough, BE Baumann, MH AF Rothman, Richard B. Blough, Bruce E. Baumann, Michael H. TI Dual dopamine/serotonin releasers as potential medications for stimulante and alcohol addictions SO AAPS JOURNAL LA English DT Review DE alcohol; amphetamine; cocaine; dopamine; serotonin; treatment; transporter ID PROGRESSIVE-RATIO SCHEDULE; COCAINE-SEEKING BEHAVIOR; D-AMPHETAMINE TREATMENT; CENTRAL-NERVOUS-SYSTEM; NEUROTRANSMITTER TRANSPORTERS; INTRAVENOUS COCAINE; D-FENFLURAMINE; PULMONARY-HYPERTENSION; NUCLEUS-ACCUMBENS; 5-HT2B RECEPTORS AB We have advocated the idea of agonist therapy for treating cocaine addiction. This strategy involves administration of stimulant-like medications (eg, monoamine releasers) to alleviate withdrawal symptoms and prevent relapse. A major limitation of this approach is that many candidate medicines possess significant abuse potential because of activation of mesolimbic dopamine (DA) neurons in central nervous system reward circuits. Previous data suggest that serotonin (5-HT) neurons can provide an inhibitory influence over mesolimbic DA neurons. Thus, it might be predicted that the balance between DA and 5-HT transmission is important to consider when developing medications with reduced stimulant side effects. In this article, we discuss several issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, we discuss evidence supporting the existence of a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Then we summarize studies that have tested the hypothesis that 5-HT neurons can dampen the effects mediated by mesolimbic DA. For example, it has been shown that pharmacological manipulations that increase extracellular 5-HT attenuate stimulant effects produced by DA release, such as locomotor stimulation and self-administration behavior. Finally, we discuss our recently published data about PAL-287 (naphthylisopropylamine), a novel non-amphetamine DA-/5-HT-releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers might be useful therapeutic adjuncts for the treatment of cocaine and alcohol addiction, obesity, and even attention deficit disorder and depression. C1 NIDA, IRP, Clin Psychopharmacol Unit, US Dept HHS,NIH, Baltimore, MD 21224 USA. Res Triangle Inst Int, Chem & Life Sci Grp, Res Triangle Pk, NC USA. RP Rothman, RB (reprint author), NIDA, IRP, Clin Psychopharmacol Unit, US Dept HHS,NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [R01 DA12970] NR 84 TC 28 Z9 30 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J JI AAPS J. PY 2007 VL 9 IS 1 BP E1 EP E10 AR 1 DI 10.1208/aapsj0901001 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160LT UT WOS:000245943200001 PM 17408232 ER PT J AU Jain, N Machatha, SG Tabibi, SE Yalkowsky, SH AF Jain, Neera Machatha, Stephen G. Tabibi, S. Esmail Yalkowsky, Samuel H. TI Degradation kinetics and mechanism of RH1, a new anti-tumor agent: A technical note SO AAPS PHARMSCITECH LA English DT Article DE stability; RH1; solubility; degradation; mechanism ID AQUEOUS-SOLUTION; STABILITY; CARBOQUONE; 2,5-DIAZIRIDINYL-3,6-BIS(CARBOETHOXYAMINO)-1,4-BENZOQUINONE C1 Cydex Inc, Lenexa, KS 66214 USA. Wyeth Res, Pearl River, NY 10965 USA. NCI, Pharmaceut Resources Branch, NIH, Bethesda, MD 20892 USA. Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. RP Machatha, SG (reprint author), Cydex Inc, Lenexa, KS 66214 USA. EM smachatha@cydexinc.com FU NCI NIH HHS [CM-77109] NR 11 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHARMACEUTICAL SCIENTISTS PI ARLINGTON PA 2107 WILSON BLVD, STE 700, ARLINGTON, VA 22201-3042 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PY 2007 VL 8 IS 1 AR 16 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 160LS UT WOS:000245943100016 PM 17408216 ER PT J AU O'Connor, SD Summers, RM AF O'Connor, Stacy D. Summers, Ronald M. TI Revisiting oral barium sulfate contrast agents SO ACADEMIC RADIOLOGY LA English DT Review DE CT colonography; colonic polyps; villous adenoma ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; CT COLONOGRAPHY; VIRTUAL COLONOSCOPY; GASTROINTESTINAL-TRACT; COLORECTAL POLYPS; CATHARTIC PREPARATION; BOWEL PREPARATION; MAGNESIUM-IONS; SUSPENSIONS; MEDIA AB Oral contrast agents used during CT colonography (CTC) are valuable and may reduce false positive and false negative detections due to stool and residual fluid. Electronic cleansing algorithms are feasible, and oral contrast agents can eliminate the CTC requirement for a clean colon. Recent work shows oral contrast frequently adheres to polyps, with a preference for those with villous histology, a characteristic of advanced polyps. This finding encourages the development of contrast agents that highlight polyps at greatest risk for progression to malignancy. Our review summarizes numerous aspects of oral barium sulfate contrast agents as well as tests to assess adherence and coating ability of the agents, offering arenas to explore and tools for evaluation. C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Dept Diagnost Radiol, 10 Ctr Dr,Bldg 10,Rm 1C351,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU Intramural NIH HHS NR 55 TC 10 Z9 11 U1 0 U2 7 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JAN PY 2007 VL 14 IS 1 BP 72 EP 80 DI 10.1016/j.acra.2006.10.002 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 124JJ UT WOS:000243363800009 PM 17178368 ER PT J AU Krwawicz, J Arczewska, KD Speina, E Madejewska, A Grzesiuk, E AF Krwawicz, Joanna Arczewska, Katarzyna D. Speina, Elzbieta Madejewska, Agnieszka Grzesiuk, Elzbieta TI Bacterial DNA repair genes and their eukaryotic homologues: 1. Mutations in genes involved in base excision repair (BER) and DNA-end processors and their implication in mutagenesis and human disease SO ACTA BIOCHIMICA POLONICA LA English DT Review DE BER; DNA damage; DNA repair; glycosylase; AP endo nuclease; SSBs; mutagenesis ID STRAND BREAK REPAIR; NUCLEOSIDE-DIPHOSPHATE-KINASE; WERNER-SYNDROME PROTEIN; LUNG-CANCER RISK; ESCHERICHIA-COLI; POLYMERASE-BETA; POLY(ADP-RIBOSE) POLYMERASE-1; LONG-PATCH; OXIDATIVE STRESS; AP-ENDONUCLEASE AB Base excision repair (BER) pathway executed by a complex network of proteins is the major system responsible for the removal of damaged DNA bases and repair of DNA single strand breaks (SSBs) generated by environmental agents, such as certain cancer therapies, or arising spontaneously during cellular metabolism. Both modified DNA bases and SSBs with ends other than 3'-OH and 5'-P are repaired either by replacement of a single or of more nucleotides in the processes called short-patch BER (SP-BER) or long-patch BER (LP-BER), respectively. In contrast to Escherichia coli cells, in human ones, the two BER sub-pathways are operated by different sets of proteins. In this review the selection between SP-and LP-BER and mutations in BER and end-processors genes and their contribution to bacterial mutagenesis and human diseases are considered. C1 Polish Acad Sci, Inst Biochem & Biophys, Dept Mol Biol, Warsaw, Poland. NIH, NIA, Lab Mol Gerontol, Baltimore, MD USA. RP Krwawicz, J (reprint author), Polish Acad Sci, Inst Biochem & Biophys, Dept Mol Biol, Warsaw, Poland. EM asiak@ibb.waw.pl RI Maciejewska, Agnieszka/B-2287-2012 NR 180 TC 28 Z9 30 U1 0 U2 6 PU ACTA BIOCHIMICA POLONICA PI WARSAW PA PASTEURA 3, 02-093 WARSAW, POLAND SN 0001-527X J9 ACTA BIOCHIM POL JI Acta Biochim. Pol. PY 2007 VL 54 IS 3 BP 413 EP 434 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215OS UT WOS:000249819500001 PM 17893748 ER PT J AU Cooper, JA Li, WJ Bailey, LO Hudson, SD Lin-Gibson, S Anseth, KS Tuan, RS Washburn, NR AF Cooper, James A., Jr. Li, Wan-Ju Bailey, LeeAnn O. Hudson, Steve D. Lin-Gibson, Sheng Anseth, Kristi S. Tuan, Rocky S. Washburn, Newell R. TI Encapsulated chondrocyte response in a pulsatile flow bioreactor SO ACTA BIOMATERIALIA LA English DT Article DE cartilage; tissue engineering; poly(ethylene glycol) hydrogels; three-dimensional scaffold; biomaterials ID TISSUE-ENGINEERED CARTILAGE; ARTICULAR-CARTILAGE; MECHANICAL-PROPERTIES; DEFORMATION-BEHAVIOR; DYNAMIC COMPRESSION; MATRIX PRODUCTION; GENE-EXPRESSION; SCAFFOLDS; COLLAGEN; CULTURE AB We have developed a bioreactor-based millifluidic technique that allows for dynamic culture conditions and measurement of the fluid flow impinging upon a three-dimensional tissue engineering scaffold. Chondrocytes in scaffolds have been shown to require mechanical stimulation to produce an extracellular matrix that resembles native cartilage. This study investigates the effect of pulsatile flow on chondrocyte response in a model poly(ethylene glycol) dimethacrylate hydrogel. Bovine chondrocytes were encapsulated in the hydrogel and cultured for 7, 14 and 21 days at pulsatile flow frequencies of 0.5 Hz (15 ml/min) and 1.5 Hz (17 ml/min). The scaffolds cultured under dynamic conditions were compared to those cultured under static (non-flow) conditions. Quantitative real-time reverse transcription polymerase chain reaction was used to quantify collagen type I, collagen type II and aggrecan gene copy numbers as markers for chondrocyte phenotypic expression. Histological sections stained with hematoxylin & eosin, and Alcian blue confirmed chondrocyte morphology and matrix formation. Interestingly, regulation of the collagen type II gene was particularly sensitive to the flow conditions. The understanding of the cell response to encapsulation and flow could be used to identify the appropriate culture conditions necessary to design and develop hydrogel carriers to promote the formation of extracellular matrix as well as to further our knowledge of chondrocyte mechanobiology. (C) 2006 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 Natl Inst Stand & Technol, Div Polymers, Gaithersburg, MD 20899 USA. NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Univ Colorado, Dept Chem & Biol Engn, Howard Hughes Med Inst, Boulder, CO 80309 USA. RP Cooper, JA (reprint author), Natl Inst Stand & Technol, Div Polymers, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM Dr.JCooper@gmail.com; wash-burn@andrew.cmu.edu RI Li, Wan-Ju/A-7002-2008 NR 36 TC 17 Z9 19 U1 2 U2 14 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD JAN PY 2007 VL 3 IS 1 BP 13 EP 21 DI 10.1016/j.actbio.2006.08.010 PG 9 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 121SX UT WOS:000243178400002 PM 17097360 ER PT J AU Dror, O Lasker, K Nussinov, R Wolfson, H AF Dror, Oranit Lasker, Keren Nussinov, Ruth Wolfson, Haim TI EMatch: an efficient method for aligning atomic resolution subunits into intermediate-resolution cryo-EM maps of large macromolecular assemblies SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID STRUCTURAL-INFORMATICS APPROACH; ELECTRON-DENSITY MAPS; CRYOELECTRON MICROSCOPY; ANGSTROM RESOLUTION; PROTEIN STRUCTURES; BETA-SHEETS; MODELS; CRYOMICROSCOPY; COMPLEXES; MACHINES AB Structural analysis of biological machines is essential for inferring their function and mechanism. Nevertheless, owing to their large size and instability, deciphering the atomic structure of macromolecular assemblies is still considered as a challenging task that cannot keep up with the rapid advances in the protein- identification process. In contrast, structural data at lower resolution is becoming more and more available owing to recent advances in cryo- electron microscopy (cryoEM) techniques. Once a cryo- EM map is acquired, one of the basic questions asked is what are the folds of the components in the assembly and what is their configuration. Here, a novel knowledge- based computational method, named EMatch, towards tackling this task for cryo- EM maps at 6-10 angstrom resolution is presented. The method recognizes and locates possible atomic resolution structural homologues of protein domains in the assembly. The strengths of EMatch are demonstrated on a cryo- EM map of native GroEL at 6 angstrom resolution. C1 Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. NCI, Basic Res Program, SAIC Frederick, Canc Res Ctr, Frederick, MD 21702 USA. RP Dror, O (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM oranit@post.tau.ac.il; ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 37 TC 16 Z9 16 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2007 VL 63 BP 42 EP 49 DI 10.1107/S0907444906041059 PN 1 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 116IN UT WOS:000242796000006 PM 17164525 ER PT J AU Kubon, C Sivertsen, A Vindenes, HA Abyholm, F Wilcox, A Lie, RT AF Kubon, Christer Sivertsen, Ase Vindenes, Hallvard Andreas Abyholm, Frank Wilcox, Allen Lie, Rolv Terje TI Completeness of registration of oral clefts in a medical birth registry: a population-based study SO ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA LA English DT Article DE oral cleft; ascertainment; birth registry ID PALATE; LIP AB Background. Epidemiological surveillance and research on birth defects require accurate diagnosis and adequate registration. In this regard, the performance of national birth registries is not well described. Methods. We linked clinical data from all 3,616 cleft cases treated in Norway between 1967 and 1998 with data from the Medical Birth Registry of Norway, and calculated the proportion of clinically verified cases reported to the Registry, stratified by severity. Results. The cleft type most completely ascertained was cleft lip and palate (CLP), of which 94% were reported. Ascertainment was less complete for cleft lip alone (83% recorded), and cleft palate only (CPO) (57% recorded). For each of the three types of clefts, completeness of reporting depended on severity of the cleft. For example, 71% of cases with severe CPO were reported, while only 11% of cases with mild CPO were reported. Conclusions. Ascertainment was strongly related to cleft type and severity. To the degree that severity of birth defects may be related to their cause, these patterns of registration have implications for surveillance of birth defects as well as the conduct of etiologic studies. The large proportion of cleft palate cases unrecorded at birth suggests that clinical examination of the newborn palate is often inadequate. C1 Univ Bergen, Dept Publ Hlth & Primary Hlth Care, NO-5018 Bergen, Norway. Haukeland Hosp, Dept Plast Surg, N-5021 Bergen, Norway. Univ Oslo, Rikshosp, Dept Plast Surg, N-0027 Oslo, Norway. NIEHS, Epidemiol Branch, Durham, NC USA. RP Kubon, C (reprint author), Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Kalfarveien 31, NO-5018 Bergen, Norway. EM ckubon@hotmail.com OI Wilcox, Allen/0000-0002-3376-1311 NR 12 TC 28 Z9 28 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA PO BOX 12 POSTHUSET, NO-0051 OSLO, NORWAY SN 0001-6349 J9 ACTA OBSTET GYN SCAN JI Acta Obstet. Gynecol. Scand. PY 2007 VL 86 IS 12 BP 1453 EP 1457 DI 10.1080/08037050701645090 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 237UE UT WOS:000251401100009 PM 17851803 ER PT J AU Aziz, NM AF Aziz, Noreen M. TI Cancer survivorship research: State of knowledge, challenges and opportunities SO ACTA ONCOLOGICA LA English DT Review ID LONG-TERM SURVIVORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; QUALITY-OF-LIFE; STANDARD-DOSE CHEMOTHERAPY; BREAST-CARCINOMA SURVIVORS; CHILDHOOD-CANCER; HODGKINS-DISEASE; FOLLOW-UP; CRANIAL IRRADIATION; COGNITIVE FUNCTION AB Introduction. Seminal advances in early detection of and treatment strategies for cancer have led to burgeoning numbers of cancer survivors. While most therapeutic modalities for cancer are beneficial and lifesaving, they are associated with adverse long-term and late sequelae. Materials and Methods. Literature review using MEDLINE to identify studies examining adverse medical outcomes and post-treatment follow-up care among long-term survivors. Emerging concepts in survivorship research such as definitional issues, research paradigms and methodologic concerns were also examined. Results. Long- term or late adverse sequelae are more prevalent, serious, and persistent than expected in survivors of pediatric and adult cancer, but remain understudied especially among those diagnosed as adults. Follow-up care relevant to survivorship outcomes is neither standardized nor guideline or evidence based for most adult cancers, and optimal practices have yet to be defined. Discussion. Adverse sequelae contribute to burden of illness, health care costs, and decreased length and quality of survival. To-date, very few studies have compared survivor outcomes pre- and post diagnosis. It is critical to examine under- researched questions and understudied survivor groups. Regular follow- up care and monitoring of health status post cancer treatment should 1) permit the timely diagnosis and treatment of adverse outcomes; 2) enable timely diagnosis and treatment of recurrences; 3) facilitate screening and early detection of second cancer( s); 4) allow for detection and management of co-morbidities; and 5) provide the opportunity for preventive strategies such as lifestyle changes. Research findings to- date underscore the need for continued cancer survivorship research that will: inform our understanding of the mechanisms underlying adverse sequelae; lead to the design of less toxic treatments; test the effectiveness of interventions - medical, pharmacologic, and behavioral - that reduce adverse outcomes; test models of post-treatment follow-up care; develop an evidence base for optimal follow-up care practices; and inform survivor and provider decision making. C1 NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. RP Aziz, NM (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, 6130 Execut Blvd, Bethesda, MD 20852 USA. EM na45f@nih.gov NR 104 TC 116 Z9 117 U1 0 U2 9 PU TAYLOR & FRANCIS AS PI OSLO PA PO BOX 12 POSTHUSET, NO-0051 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2007 VL 46 IS 4 BP 417 EP 432 DI 10.1080/02841860701367878 PG 16 WC Oncology SC Oncology GA 171FC UT WOS:000246719300001 PM 17497308 ER PT J AU Nord, C Ganz, PA Aziz, N Fossa, SD AF Nord, Carina Ganz, Patricia A. Aziz, Noreen Fossa, Sophie D. TI Follow-up of long-term cancer survivors in the Nordic countries SO ACTA ONCOLOGICA LA English DT Article ID CHILDHOOD-CANCER; TESTICULAR-CANCER; METABOLIC SYNDROME; 5-YEAR SURVIVORS; 2ND CANCERS; CHEMOTHERAPY; RISK; CARE; RADIOTHERAPY; STRATEGIES AB Cancer survivors are at increased risk of developing different co-morbid conditions. With an increasing number of long-term cancer survivors in the Nordic countries, the need for recommendations for long-term follow-up has become necessary. However, at present there are no general guidelines for follow- up in the Nordic countries. Three steps of follow- up should be distinguished and the objectives associated with each: 1) Follow-up research done as clinical studies in cancer survivors and as registry-based epidemiological investigations. Whenever possible these approaches should be combined with translational research relating clinical observations with findings from biological material for increased understanding of pathophysiology and aetiology. Such investigation has to provide evidence- based knowledge of late effects associated with the malignancy itself and its treatment. The Nordic countries have excellent possibilities for conducting such follow-up research; 2) Creation of guidelines, in an attempt to put results from research into clinical practice, should take the local situation and resources into consideration. Provision of an individualized Survivorship Care Plan is a first step; 3) Implementation of guidelines into daily health care. Guidelines have little influence on long-term cancer care if they do not reach the practitioners and convince them to comply. There is a need for well-planned follow-up to manage and reduce possible treatment-related morbidity and mortality in cancer survivors. The Nordic countries provide excellent possibilities for relevant research, but lack, so far evidence-based guidelines. In agreement with the initiatives of ASCO the development of Survivor Care Plans is the first step to improve on this situation. C1 Karolinska Univ Hosp, Radiumhemmet, Dept Hematol & Oncol, S-17677 Stockholm, Sweden. Univ Calif Los Angeles, Sch Med, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Div Canc Prevent & Control Res, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. NCI, Off Canc Survivorshop, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. Natl Hosp Norway, Radium Hosp Med Ctr, Dept Clin Canc Res, Sect Long Term Studies, N-0310 Oslo, Norway. RP Nord, C (reprint author), Karolinska Univ Hosp, Radiumhemmet, Dept Hematol & Oncol, S-17677 Stockholm, Sweden. EM carina.nord@karolinska.se NR 61 TC 11 Z9 11 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA PO BOX 12 POSTHUSET, NO-0051 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2007 VL 46 IS 4 BP 433 EP 440 DI 10.1080/02841860701203552 PG 8 WC Oncology SC Oncology GA 171FC UT WOS:000246719300002 PM 17497309 ER PT J AU Furie, KL Lev, MH Koroshetz, WJ Greer, DM AF Furie, Karen L. Lev, Michael H. Koroshetz, Walter J. Greer, David M. BE Greer, DM TI EVALUATION OF ACUTE STROKE ETIOLOGIES SO ACUTE ISCHEMIC STROKE: AN EVIDENCE-BASED APPROACH LA English DT Article; Book Chapter ID CAROTID-ARTERY STENOSIS; ACUTE ISCHEMIC-STROKE; MAGNETIC-RESONANCE ANGIOGRAPHY; DIFFUSION-WEIGHTED MRI; DIGITAL-SUBTRACTION-ANGIOGRAPHY; DOPPLER ULTRASOUND CRITERIA; CARDIOGENIC BRAIN EMBOLISM; EARLY CLINICAL-DIAGNOSIS; PERTH-COMMUNITY-STROKE; LONG-TERM PROGNOSIS C1 [Furie, Karen L.; Lev, Michael H.; Greer, David M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Koroshetz, Walter J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Furie, KL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 80 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE PUBL PI OXFORD PA OSNEY MEAD, OXFORD OX2 0EL, ENGLAND BN 978-0-470-18339-7 PY 2007 BP 197 EP 212 DI 10.1002/9780470183397.ch9 D2 10.1002/9780470183397 PG 16 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA BCJ20 UT WOS:000310276000010 ER PT S AU Sawitzke, JA Thomason, LC Costantino, N Bubunenko, M Datta, S Court, DL AF Sawitzke, James A. Thomason, Lynn C. Costantino, Nina Bubunenko, Mikhail Datta, Simanti Court, Donald L. BE Hughes, KT Maloy, SR TI Recombineering: In vivo genetic engineering in E-coli, S-enterica, and beyond SO ADVANCED BACTERIAL GENETICS: USE OF TRANSPOSONS AND PHAGE FOR GENOMIC ENGIEERING SE Methods in Enzymology LA English DT Review; Book Chapter ID BACTERIAL ARTIFICIAL CHROMOSOMES; GRAM-NEGATIVE BACTERIA; PHAGE-LAMBDA; BETA-PROTEIN; HOMOLOGOUS RECOMBINATION; RED-PATHWAY; MEDIATED RECOMBINATION; SALMONELLA-TYPHIMURIUM; NUCLEOTIDE-SEQUENCE; POSITIVE SELECTION AB "Recombineering," in vivo genetic engineering with short DNA homologies, is changing how constructs are made. The methods are simple, precise, efficient, rapid, and inexpensive. Complicated genetic constructs that can be difficult or even impossible to make with in vitro genetic engineering can be created in days with recombineering. DNA molecules that are too large to manipulate with classical techniques are amenable to recombineering. This technology utilizes the phage lambda homologous recombination functions, proteins that can efficiently catalyze recombination between short homologies. Recombineering can be accomplished with linear PCR products or even single-stranded oligos. In this chapter we discuss methods of and ways to use recombineering. C1 NCI, Frederick, MD 21701 USA. RP Sawitzke, JA (reprint author), NCI, Frederick, MD 21701 USA. FU Intramural NIH HHS NR 72 TC 115 Z9 119 U1 8 U2 32 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0076-6879 BN 978-0-12-373749-6 J9 METHOD ENZYMOL JI Methods Enzymol. PY 2007 VL 421 BP 171 EP 199 DI 10.1016/S0076-6879(06)21015-2 PG 29 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BFX07 UT WOS:000245236000015 PM 17352923 ER PT S AU Nordstrom, RJ AF Nordstrom, Robert J. BE VoDinh, T Grundfest, WS Benaron, DA Cohn, GE Raghavachari, R TI Models for translational research in biomedicine - art. no. 64301V SO Advanced Biomedical and Clinical Diagnostic Systems V SE PROCEEDINGS OF THE SOCIETY OF PHOTO-OPTICAL INSTRUMENTATION ENGINEERS (SPIE) LA English DT Proceedings Paper CT Conference on Advanced Biomedical and Clinical Diagnostic Systems V CY JAN 21-23, 2007 CL San Jose, CA SP SPIE DE translational research; medical device development; standards AB While fundamental research in areas of drug discovery and medical device development will continue to be important, additional emphasis is now being placed on translational research. Here, the scientific discoveries coming from laboratory, clinical, or population studies are being moved into clinical practice. For the most part, this translation is being done with only minimal forethought and planning. This talk will examine models for translational research and the roles and needs of standards in the process. While many of the concepts are valid for all aspects of biomedical research, examples from the optical technology and device area will be highlighted. In particular the NCI Network for Translational Research: Optical Imaging (NTROI) will be mentioned. C1 NCI, Canc Imaging Program, Bethesda, MD 20892 USA. RP Nordstrom, RJ (reprint author), NCI, Canc Imaging Program, 6130 Execut Blvd, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPIE-INT SOC OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98227-0010 USA SN 0277-786X BN 978-0-8194-6543-6 J9 P SOC PHOTO-OPT INS PY 2007 VL 6430 BP V4301 EP V4301 AR 64301V DI 10.1117/12.713352 PG 6 WC Engineering, Biomedical; Optics SC Engineering; Optics GA BGB90 UT WOS:000245947500041 ER PT S AU Mok, SC Elias, KM Wong, KK Ho, K Bonome, T Birrer, MJ AF Mok, Samuel C. Elias, Kevin M. wong, K-Kwok Wong Ho, Kae Bonome, Tomas Birrer, Michael J. BE Hampton, GM Sikora, K TI Biomarker discovery in epithelial ovarian cancer by genomic approaches SO ADVANCES IN CANCER RESEARCH, VOL 96 SE Advances in Cancer Research LA English DT Review; Book Chapter ID DIFFERENTIALLY EXPRESSED GENES; COPY-NUMBER CHANGES; CDNA MICROARRAY; EARLY-STAGE; PROGNOSTIC-SIGNIFICANCE; LOW-GRADE; ADJUVANT CHEMOTHERAPY; BORDERLINE TUMORS; NEOPLASM TRIAL; P53 MUTATIONS AB Ovarian cancer is the fifth most common form of cancer in women in the United States. It is a complex disease composed of different histological grades and histological types. Most of epithelial ovarian cancer cases are detected at an advanced stage. Patients usually respond to primary treatment with surgery and chemotherapy. However, the disease usually recurs and is ultimately fatal. So far, a satisfactory screening procedure and regime to treat the recurrence disease are not available. High-throughput genomic analyses have the potential to change the detection and the treatment of ovarian neoplasms. They can help diagnose subtypes of disease and predict patient survival. New diagnostic and prognostic markers for ovarian cancer are emerging. One day, profiling may influence treatment decisions, informing both which patients should receive chemotherapy and what type of chemotherapeutic agents should be employed. As greater numbers of tumor samples are analyzed, the power of these profiling studies will increase, raising the possibility that novel molecular targets and less toxic therapies will be identified. These powerful techniques hold the potential to unravel the genetic origins of ovarian cancer. Hopefully, this will translate into earlier diagnosis and better patient outcome from disease. (c) 2007 Elsevier Inc. C1 Harvard Univ, Brigham & Womens Hosp,Sch Med, Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Mok, SC (reprint author), Harvard Univ, Brigham & Womens Hosp,Sch Med, Div Gynecol Oncol, Dept Obstet Gynecol & Reprod Biol, 75 Francis St, Boston, MA 02115 USA. OI Wong, Kwong-Kwok/0000-0002-0375-6669 FU NCI NIH HHS [R33CA103595] NR 69 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 0-12-006696-3 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2007 VL 96 BP 1 EP 22 DI 10.1016/S0065-230X(06)96001-1 PG 22 WC Oncology SC Oncology GA BFO38 UT WOS:000243406600001 PM 17161674 ER PT S AU Potter, M AF Potter, Michael BE VandeWoude, GF Klein, G TI The early history of plasma cell tumors in mice, 1954-1976 SO ADVANCES IN CANCER RESEARCH, VOL 98 SE Advances in Cancer Research LA English DT Review; Book Chapter ID IGA MYELOMA PROTEINS; BENCE-JONES PROTEINS; STRAIN C3H MICE; BALB-C MICE; ANTIBODY-FORMATION; GAMMA-GLOBULINS; DIFFUSION-CHAMBERS; TISSUE-CULTURE; MURINE MYELOMA; FORMING CELLS AB Plasma cell tumors (PCTs) in mice became available at an exciting period in immunology when many scientists and laboratories were occupied with how to explain the genetic basis of antibody diversity as well as antibody structure itself. An unlimited Source of PCTs in all inbred strain of mice became a useful adjunct in these efforts. A PCT was a greatly expanded monoclone and a source of a single molecular species of immunoglobulin (Ig) molecule. The PCTs provided not only the components of the Ig-producing cell but also potentially functional secreted products. Many of the monoclonal Igs produced by PCTs in the Mouse and others found in humans were found to have specific antigen-binding activities. These became the prototypes of monoclonal antibodies. This chapter describes the origins of PCTs in mice and attempts to recapture some of the ambience of the day albeit from personal recollection. The great discovery of the hybridoma technology by Cesar Milstein and Georges Kohler in 1975 began a new direction in immunology. (C) 2007 Elsevier Inc. C1 NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Potter, M (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 108 TC 9 Z9 10 U1 2 U2 7 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X BN 978-0-12-373896-7 J9 ADV CANCER RES JI Adv.Cancer Res. PY 2007 VL 98 BP 17 EP 51 DI 10.1016/S0065-2.30X(06)98002-6 PG 35 WC Oncology SC Oncology GA BGB57 UT WOS:000245919700002 PM 17433907 ER PT S AU Patton, JT Vasquez-Del Carpio, R Tortorici, MA Taraporewala, ZF AF Patton, John T. Vasquez-Del Carpio, Rodrigo Tortorici, M. Alejandra Taraporewala, Zenobia F. BE Maramorosch, K Shatkin, AJ TI Coupling of rotavirus genome replication and capsid assembly SO ADVANCES IN VIRUS RESEARCH, VOL 69 SE Advances in Virus Research LA English DT Review; Book Chapter ID DOUBLE-STRANDED-RNA; NONSTRUCTURAL PROTEIN NSP2; VIRUS-LIKE PARTICLES; GROUP-C ROTAVIRUS; L-A VIRUS; MESSENGER-RNA; CONSENSUS SEQUENCE; INFECTED-CELLS; SACCHAROMYCES-CEREVISIAE; CRYOELECTRON MICROSCOPY AB The Reoviridae family represents a diverse collection of viruses with segmented double-stranded (ds)RNA genomes, including some that are significant causes of disease in humans, livestock, and plants. The genome segments of these viruses are never detected free in the infected cell but are transcribed and replicated within viral cores by RNA-dependent RNA polymerase (RdRP). Insight into the replication mechanism has been provided from studies on Rotavirus, a member of the Reoviridae whose RdRP can specifically recognize viral plus (+) strand RNAs and catalyze their replication to dsRNAs in vitro. These analyses have revealed that although the rotavirus RdRP can interact with recognition signals in (+) strand RNAs in the absence of other proteins, the conversion of this complex to one that can support initiation of dsRNA synthesis requires the presence and partial assembly of the core capsid protein. By this mechanism, the viral polymerase can carry out dsRNA synthesis only when capsid protein is available to package its newly made product. By preventing the accumulation of naked dsRNA within the cell, the virus avoids triggering dsRNA-dependent interferon signaling pathways that can induce expression and activation of antiviral host proteins. C1 Natl Inst Allergy & Infect Dis, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), Natl Inst Allergy & Infect Dis, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. RI Patton, John/P-1390-2014 FU Intramural NIH HHS NR 120 TC 27 Z9 28 U1 3 U2 8 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-3527 BN 978-0-12-373712-0 J9 ADV VIRUS RES JI Adv.Virus Res. PY 2007 VL 69 BP 167 EP 201 DI 10.1016/S0065-3527(06)69004-0 PG 35 WC Virology SC Virology GA BFR60 UT WOS:000244034500004 PM 17222694 ER PT J AU Semba, RD Varadhan, R Bartali, B Ferrucci, L Ricks, MO Blaum, C Fried, LP AF Semba, Richard D. Varadhan, Ravi Bartali, Benedetta Ferrucci, Luigi Ricks, Michelle O. Blaum, Caroline Fried, Linda P. TI Low serum carotenoids and development of severe walking disability among older women living in the community: the Women's Health and Aging Study I SO AGE AND AGEING LA English DT Article DE ageing; carotenoids; disability; risk factors; women; elderly ID HUMAN SKELETAL-MUSCLE; GROWTH-FACTOR-I; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; MEDITERRANEAN DIET; OXIDATIVE STRESS; VEGETABLE INTAKE; SARCOPENIA; FRUIT; INFLAMMATION AB Objective: to determine whether low serum carotenoid levels, an indicator of low intake of fruits and vegetables, are associated with the progression of disability in older women. Design: longitudinal analysis in a population-based cohort. Setting: moderately-severely disabled women, >= 65 years, living in the community in Baltimore, Maryland (the Women's Health and Aging Study 1). Participants: 554 women without severe walking disability (inability to walk or walking speed < 0.4 m/s) at baseline. Main outcome measure: incidence of severe walking disability assessed every 6 months over 3 years. Results: 155 women (27.9%) developed severe walking disability during follow-up. Rates of development of severe walking disability per 100 person-years among women in the lowest and in the three upper quartiles of total carotenoids were, respectively, 13.8 versus 10.9 (P = 0.0017). Adjusting for confounders, women in the lowest quartile of total carotenoids were more likely to develop severe walking disability (hazards ratio 1.57, 95% confidence interval 1.24-2.00, P = 0.0002) compared with women in the three upper quartiles. Conclusion: low serum carotenoid levels, an indicator of low intake of fruits and vegetables, are independent predictors of the progression towards severe walking disability among older women living in the community. C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. NIA, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. RP Semba, RD (reprint author), Johns Hopkins Med Inst, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000722]; NIA NIH HHS [N01 AG012112, N01 AG12112, R01 AG011703, R01 AG027012, R01 AG11703-01A1, R37 AG019905]; NIAID NIH HHS [R01 AI041956, R01 AI41956] NR 30 TC 34 Z9 35 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD JAN PY 2007 VL 36 IS 1 BP 62 EP 67 DI 10.1093/ageing/afl122 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 138MF UT WOS:000244366000014 PM 17114201 ER PT J AU Schottenbauer, MA Hommer, D Weingartner, H AF Schottenbauer, Michele A. Hommer, Daniel Weingartner, Herbert TI Memory deficits among alcoholics: Performance on a selective reminding task SO AGING NEUROPSYCHOLOGY AND COGNITION LA English DT Article ID PSYCHIATRIC COMORBIDITY; IMPAIRMENTS; ABSTINENCE; ETHANOL; INTELLIGENCE; TEMAZEPAM AB This article compared alcoholics and healthy controls on the Buschke Selective Reminding Task. Alcoholics demonstrated deficits in memory and learning when compared to healthy controls, even when controlling for age. Examination of the alcoholic sample initially showed that age predicted memory deficits; however, age was no longer a significant predictor once the number of years of heavy drinking was entered into the regression equation. Findings suggest a direct link or mechanism of action between alcohol use and memory impairments, above and beyond effects of age or education. C1 NIAAA, Bethesda, MD 20892 USA. RP Schottenbauer, MA (reprint author), Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. EM maschotten@aol.com NR 38 TC 7 Z9 7 U1 1 U2 3 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1382-5585 J9 AGING NEUROPSYCHOL C JI Aging Neuropsychol. Cogn. PY 2007 VL 14 IS 5 BP 505 EP 516 DI 10.1080/13825580600681305 PG 12 WC Psychology, Developmental; Psychology, Experimental SC Psychology GA 221SJ UT WOS:000250247300004 ER PT J AU Minor, RK Smith, CI De Cabo, R Ingram, DK AF Minor, Robin K. Smith, Carolina I. De Cabo, Rafael Ingram, Donald K. TI Food for life: maximising lifespan through the diet SO AGRO FOOD INDUSTRY HI-TECH LA English DT Article ID FATTY-ACID-COMPOSITION; AGE-ASSOCIATED CHANGES; CALORIE RESTRICTION; OXIDATIVE STRESS; GREEN TEA; CARDIOVASCULAR-DISEASE; CELLULAR GLUTATHIONE; COFFEE CONSUMPTION; MEDITERRANEAN DIET; COGNITIVE FUNCTION AB The intense industrialisation and modernisation of food production and commerce has put the food industry in a position needing to remain competitive in a market glutted with calorie-rich products. This market position is ironic when we consider that the only reliable dietary intervention known to increase lifespan in mammals is the consistent, controlled and micronutrient-sufficient reduction in calories known as calorie restriction. Actually, calorie restriction is not proven in humans, though it is expected to be at least somewhat effective at enhancing human longevity (1-3). That said, the educated guess of some gerontologists who study calorie restriction is that humans will prefer not to calorie restrict in the presence of a sufficient food supply so long as alternatives, or mimetics, to calorie restriction may be identified. Calorie restriction is associated with a vast array of physiological changes in experimental models, and the mechanisms regulating these changes are still debated; however, a number of candidates are regarded as probable contributors including enhanced stress resistance and reduced oxidative damage accumulation (4-7). Foods or food components that can evoke synonymous adaptations are candidate calorie restriction mimetics and warrant investigation for their anti-ageing potential (8, 9). With this pursuit in mind, we discuss in this review foods, food components and whole-diet patterns with reasonable, research supported claims to increase lifespan with a focus on human data where possible. C1 NIA, Intramural Res Program, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. Univ Florida, Dept Food Sci & Human Nutr, Gainesville, FL 32611 USA. Louisiana State Univ, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Minor, RK (reprint author), NIA, Intramural Res Program, Lab Expt Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI de Cabo, Rafael/E-7996-2010; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 69 TC 0 Z9 0 U1 0 U2 3 PU TEKNOSCIENZE PUBL PI MILAN PA VIA AURELIO SAFFI 23, 20123 MILAN, ITALY SN 1722-6996 J9 AGRO FOOD IND HI TEC JI Agro Food Ind. Hi-Tech PD JAN-FEB PY 2007 VL 18 IS 1 BP 36 EP 39 PG 4 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 159RY UT WOS:000245885200010 ER PT J AU Braithwaite, RS Conigliaro, J Roberts, MS Shechter, S Schaefer, A McGinnis, K Rodriguez, MC Rabeneck, L Bryant, K Justice, AC AF Braithwaite, R. S. Conigliaro, J. Roberts, M. S. Shechter, S. Schaefer, A. McGinnis, K. Rodriguez, M. C. Rabeneck, L. Bryant, K. Justice, A. C. TI Estimating the impact of alcohol consumption on survival for HIV plus individuals SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID ANTIRETROVIRAL THERAPY ADHERENCE; REVERSE-TRANSCRIPTASE INHIBITORS; BRIEF PHYSICIAN ADVICE; INFECTED DRUG-USERS; MITOCHONDRIAL TOXICITY; HIV-1-INFECTED PATIENTS; MEDICATION ADHERENCE; REPORTED ADHERENCE; COST-EFFECTIVENESS; VIRAL SUPPRESSION AB Alcohol consumption is associated with decreased antiretroviral adherence, and decreased adherence results in poorer outcomes. However the magnitude of alcohol's impact on survival is unknown. Our objective was to use a calibrated and validated simulation of HIV disease to estimate the impact of alcohol on survival. We incorporated clinical data describing the temporal and dose- response relationships between alcohol consumption and adherence in a large observational cohort ( N = 2,702). Individuals were categorized as nondrinkers ( no alcohol consumption), hazardous drinkers ( consume >= 5 standard drinks on drinking days), and nonhazardous drinkers ( consume <5 standard drinks on drinking days). Our results showed that nonhazardous alcohol consumption decreased survival by more than 1 year if the frequency of consumption was once per week or greater, and by 3.3 years ( from 21.7 years to 18.4 years) with daily consumption. Hazardous alcohol consumption decreased overall survival by more than 3 years if frequency of consumption was once per week or greater, and by 6.4 years ( From 16.1 years to 9.7 years) with daily consumption. Our results suggest that alcohol is an underappreciated yet modifiable risk factor for poor survival among individuals with HIV. C1 Yale Univ, Sch Med, Gen Internal Med Sect, W Haven VA CT Healthcare Syst,VACS 11 ACSL G, West Haven, CT 06516 USA. Vet Adm Med Ctr, Houston, TX 77211 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Toronto, Toronto, ON, Canada. NIAAA, NIH, Bethesda, MD USA. RP Braithwaite, RS (reprint author), Yale Univ, Sch Med, Gen Internal Med Sect, W Haven VA CT Healthcare Syst,VACS 11 ACSL G, 950 Campbell Ave, West Haven, CT 06516 USA. FU NCATS NIH HHS [UL1 TR000005]; NIAAA NIH HHS [K23 AA014483, U24 AA020794, 1 K23 AA14483-01] NR 38 TC 59 Z9 61 U1 1 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PY 2007 VL 19 IS 4 BP 459 EP 466 DI 10.1080/09540120601095734 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 167UV UT WOS:000246478900002 PM 17453583 ER PT J AU Brogly, S Read, JS Shapiro, D Stek, A Tuomala, R AF Brogly, Susan Read, Jennifer S. Shapiro, David Stek, Alice Tuomala, Ruth TI Participation of HIV-infected pregnant women in research in the United States SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CLINICAL-TRIALS; COHORT AB Previous studies suggested that some groups of HIV-infected women were underrepresented in studies of antiretrovirals (ARVs). We assessed rates of and reasons for nonenrollment in a U. S. prospective cohort study ( protocol P1025), and differences in the characteristics of HIV-infected pregnant women who were and were not enrolled. Forty-one percent of women invited to participate were not enrolled. Clinic-related reasons for nonenrollment included staffing or site resources (26.7% of women) and clinician refusal because of the woman's nonadherence to prenatal care and/or poor research candidacy (10.8%). Patient-related reasons for nonenrollment included unavailability of women for enrollment ( e. g., difficulty enrolling during labor/delivery, loss of clinic contact) (20.3%), refusal because of mistrust (10.1%), refusal because of time requirements (8.3%), refusal because of distance to the clinic (4.7%), and spontaneous abortion (4.7%). P1025 participants (N = 530) were significantly more likely to be Hispanic (32.1% vs. 19.8%), and less likely to be non-Hispanic black), to present in the first or second trimester for prenatal care (91.5% vs. 77.6%), and to be ARV-naive (32.8% vs. 23.0%) than nonparticipants (N = 2222). This high rate of nonenrollment can bias study results and generate findings that are applicable only to particular groups of women. Efforts should be taken to design protocols that facilitate enrollment of HIV-infected pregnant women. C1 Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Natl Inst Child Hlth & Dev, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20814 USA. Univ So Calif, Sch Med, Los Angeles Cty Med Ctr, Los Angeles, CA 90033 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Brogly, S (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. EM sbrogly@sdac.harvard.edu NR 8 TC 9 Z9 9 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JAN PY 2007 VL 23 IS 1 BP 51 EP 53 DI 10.1089/aid.2006.0045 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 133EM UT WOS:000243995300007 PM 17263632 ER PT J AU Modi, AA Feld, JJ AF Modi, Apurva A. Feld, Jordan J. TI Viral hepatitis and HIV in Africa SO AIDS REVIEWS LA English DT Review DE hepatitis B; hepatitis C; HIV; Africa; coinfection ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CHRONIC LIVER-DISEASE; C/HEPATITIS G VIRUS; B CORE ANTIGEN; TENOFOVIR DISOPROXIL FUMARATE; TREPONEMA-PALLIDUM INFECTIONS; ALPHA-2A PLUS RIBAVIRIN; DAR-ES-SALAAM; C VIRUS AB With increasing access to antiretroviral therapy across sub-Saharan Africa, progress is finally being made in combating the devastating HIV epidemic. As HIV-infected individuals live longer, the effects of coinfection with chronic hepatitis 8 and C will likely become an increasingly relevant issue. Indeed, HIV adversely affects the natural history of HBV and HCV, both of which are endemic across the African continent. Issues ranging from appropriate diagnostic testing to prevention and treatment are affected by HIV coinfection, particularly in resource-limited settings. In addition, some of the more complex problems such as occult infection, immune reconstitution, and antiretroviral hepatotoxicity are becoming increasingly important considerations. In this review, we present the available data on coinfection in Africa with a major emphasis on prevalence, routes of transmission, prevention and treatment strategies. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Feld, JJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr MSC 1800, Bethesda, MD 20892 USA. EM feldj@niddk.nih.gov FU Intramural NIH HHS NR 149 TC 61 Z9 61 U1 0 U2 0 PU PERMANYER PUBLICATIONS PI BARCELONA PA MALLORCA, 310, BARCELONA, SPAIN SN 1139-6121 J9 AIDS REV JI Aids Rev. PD JAN-MAR PY 2007 VL 9 IS 1 BP 25 EP 39 PG 15 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 160AP UT WOS:000245909500003 PM 17474311 ER PT J AU Brown, AK George, DT Fujita, M Liow, JS Ichise, M Hibbeln, J Ghose, S Sangare, J Hommer, D Innis, RB AF Brown, Amira K. George, David T. Fujita, Masahiro Liow, Jeih-San Ichise, Masanori Hibbeln, Joseph Ghose, Subroto Sangare, Janet Hommer, Daniel Innis, Robert B. TI PET [C-11]DASB imaging of serotonin transporters in patients with alcoholism SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE positron emission tomography; aggression; parametric imaging; [C-11]DASB; serotonin transporter; alcoholism ID POSITRON-EMISSION-TOMOGRAPHY; HUMAN BRAIN; AVAILABILITY; SPECT; AGGRESSION; DOPAMINE; GENOTYPE; BEHAVIOR; BINDING AB Objective: Alcoholism and aggression have each been associated with neurochemical measurements suggestive of decreased serotonin synaptic transmission. We measured densities of the serotonin transporter (SERT) in a moderate-sized sample of alcoholic patients who were assessed for aggressive characteristics. Methods: Thirty alcoholic inpatients and 18 healthy controls received a PET scan with [C-11]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile. The alcoholic inpatients were classified as aggressive or nonaggressive based on a comparison between the top third and bottom third scores on the Buss - Durkee Hostility Index. Results: Using a pixel-wise comparison, no brain region showed significant alterations in SERT binding among the 3 groups of subjects (aggressive alcoholic subjects, nonaggressive alcoholic subjects, and healthy controls) or between the combined alcoholic group and healthy controls. None of the clinical measures (including measures of aggression) correlated with SERT binding in the alcoholic subjects. Conclusion: Contrary to prior imaging reports using the nonselective ligand [I-123]beta-CIT, we found no significant alterations of SERT density in alcoholic patients. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NIAAA, NIH, Bethesda, MD USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Columbia Univ, Dept Radiol, New York, NY USA. RP Brown, AK (reprint author), NIMH, Mol Imaging Branch, 1 Ctr Dr,Rm B3-10, Bethesda, MD 20892 USA. EM amirabrown@mail.nih.gov RI Ghose, Subroto/J-6732-2016 FU Intramural NIH HHS NR 27 TC 30 Z9 32 U1 3 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2007 VL 31 IS 1 BP 28 EP 32 DI 10.1111/j.1530-0277.2006.00261.x PG 5 WC Substance Abuse SC Substance Abuse GA 119OS UT WOS:000243022200004 PM 17207098 ER PT J AU Dawson, DA Grant, BF Li, TK AF Dawson, Deborah A. Grant, Bridget F. Li, Ting-Kai TI Impact of age at first drink on stress-reactive drinking SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE age at first drink; stress; consumption; early-onset drinking ID NATIONAL EPIDEMIOLOGIC SURVEY; ALCOHOL-USE; TENSION-REDUCTION; SUBSTANCE USE; ETHANOL EXPOSURE; ADOLESCENCE; DISORDERS; BEHAVIOR; VULNERABILITY; ASSOCIATION AB Background: Although recent data from animal models indicate that adolescent ethanol exposure increases self-administered ethanol intake in adult rats, the impact of age at first drink on the association between stress and drinking has not been studied in humans. Methods: Data collected in the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were used to estimate the extent to which age at first drink modified the association between stress and average daily volume (ADV) of ethanol intake in a sample of 26,946 past-year drinkers. Successive models estimated the magnitude and significance of the interaction between age at first drink (ages 14 or younger, 15-17, and 18 or older) and number of stressors (out of 12 past-year negative life events) after (1) adjusting for sociodemographic characteristics, ( 2) additionally adjusting for family history of alcoholism, comorbid psychopathology, adolescent, and past-year tobacco and illicit drug use, and (3) additionally adjusting for all other significant interactions with number of stressors. Results: Even after adjusting for a wide range of confounders and their interactions with stress, initiation of drinking at ages 14 and younger increased the association between the number of stressors and ADV of ethanol consumption by 8% (p = 0.014), when considering the full range of 12 potential stressors. In fact, the positive association between stress and consumption was significant only for this group of drinkers with early adolescent exposure to ethanol. Within this group, ADV of consumption increased by an average of 7% with each additional stressor experienced, although the exact percentage increase varied as a function of other covariates that had significant interactions with stress. When a reduced set of 4 stressors was considered, the magnitudes of the associations were mostly unchanged, but the modifying effect of age at first drink fell short of statistical significance (p = 0.309) in the fully adjusted model. Conclusions: The findings of this study are consistent with the argument that early-onset drinking may increase stress-reactive ethanol consumption; however, these findings need to be replicated in an experimental human study in order to control fully the direction of the relationship between stress and consumption. C1 NIAAA, NIH, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, NIH, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, LEB Room 3093,5635 Fishers Lane MSC 9304, Bethesda, MD 20892 USA. EM ddawson@mail.nih.gov FU Intramural NIH HHS NR 47 TC 49 Z9 49 U1 2 U2 8 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JAN PY 2007 VL 31 IS 1 BP 69 EP 77 DI 10.1111/j.1530-0277.2006.00265.x PG 9 WC Substance Abuse SC Substance Abuse GA 119OS UT WOS:000243022200010 PM 17207104 ER PT S AU Jeong, JK Berman, P Przytycka, TM AF Jeong, Jieun K. Berman, Piotr Przytycka, Teresa M. BE Giancarlo, R Hannenhalli, S TI Bringing folding pathways into strand pairing prediction SO Algorithms in Bioinformatics, Proceedings SE LECTURE NOTES IN BIOINFORMATICS LA English DT Proceedings Paper CT 7th International Workshop on Algorithms in Bioinformatics (WABI 2007) CY SEP 08-09, 2007 CL Philadelphia, PA ID BETA-SHEET TOPOLOGY; GLOBULAR-PROTEINS; LOCAL-STRUCTURE; SEQUENCE; ORGANIZATION; RECOGNITION; POTENTIALS; DOMAINS AB The topology of beta-sheets is defined by the pattern of hydrogen-bonded strand pairing. Therefore, predicting hydrogen bonded strand partners is a fundamental step towards predicting beta-sheet topology. In this work we report a new strand pairing algorithm. Our algorithm attempts to mimic elements of the folding process. Namely, in addition to ensuring that the predicted hydrogen bonded strand pairs satisfy basic global consistency constraints, it takes into account hypothetical folding pathways. Consistently with this view, introducing hydrogen bonds between a pair of strands changes the probabilities of forming other strand pairs. We demonstrate that this approach provides an improvement over previously proposed algorithms. C1 Penn State Univ, Dept Comp Sci & Engn, University Pk, PA 16802 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Jeong, JK (reprint author), Penn State Univ, Dept Comp Sci & Engn, University Pk, PA 16802 USA. NR 26 TC 2 Z9 2 U1 0 U2 1 PU SPRINGER-VERLAG BERLIN PI BERLIN PA HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY SN 0302-9743 BN 978-3-540-74125-1 J9 LECT N BIOINFORMAT PY 2007 VL 4645 BP 38 EP 48 PG 11 WC Biology; Computer Science, Information Systems SC Life Sciences & Biomedicine - Other Topics; Computer Science GA BGQ41 UT WOS:000249739200004 ER PT J AU Einhorn, PT Davis, BR Massie, BM Cushman, WC Piller, LB Simpson, LM Levy, D Nwachuku, CE Black, HR AF Einhorn, Paula T. Davis, Barry R. Massie, Barry M. Cushman, William C. Piller, Linda B. Simpson, Lara M. Levy, Daniel Nwachuku, Chuke E. Black, Henry R. CA ALLHAT Collaborative Res Grp TI The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT) Heart Failure Validation Study: Diagnosis and prognosis SO AMERICAN HEART JOURNAL LA English DT Article ID MAJOR CARDIOVASCULAR EVENTS; CONVERTING-ENZYME-INHIBITOR; OUTCOMES; SURVIVAL; HYPERTENSION; TRENDS; CHLORTHALIDONE; POPULATION; PREDICTORS; AMLODIPINE C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. Memphis Vet Affairs Med Ctr, Memphis, TN USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL USA. RP Einhorn, PT (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 2 Rockledge Ctr Room 8122,6701 Rockledge Dr MSC 7, Bethesda, MD 20892 USA. EM einhornp@mail.nih.gov FU NHLBI NIH HHS [N01-HC-35130] NR 30 TC 33 Z9 34 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JAN PY 2007 VL 153 IS 1 BP 42 EP + DI 10.1016/j.ahj.2006.10.012 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 129CM UT WOS:000243706000011 PM 17174636 ER PT J AU Resnik, DB AF Resnik, David B. TI Neuroethics, national security and secrecy SO AMERICAN JOURNAL OF BIOETHICS LA English DT Editorial Material C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop NH06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-01] NR 8 TC 1 Z9 1 U1 0 U2 3 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PY 2007 VL 7 IS 5 BP 14 EP 15 DI 10.1080/15265160701290264 PG 2 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 172UN UT WOS:000246830100003 PM 17497496 ER PT J AU Mudd, SH Brosnan, JT Brosnan, ME Jacobs, RL Stabler, SP Allen, RH Vance, DE Wagner, C AF Mudd, S. Harvey Brosnan, John T. Brosnan, Margaret E. Jacobs, Rene L. Stabler, Sally P. Allen, Robert H. Vance, Dennis E. Wagner, Conrad TI Methyl balance and transmethylation fluxes in humans SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE transmethylation; labile methyl balance; phosphatidylcholine; creatine; sarcosine ID PHOSPHATIDYLETHANOLAMINE N-METHYLTRANSFERASE; PLASMA HOMOCYSTEINE; S-ADENOSYLMETHIONINE; FOLATE-DEFICIENCY; CREATINE; METABOLISM; METHIONINE; BETAINE; RAT; SERUM AB Various questions have been raised about labile methyl balance and total transmethylation fluxes, and further discussion has been encouraged. This report reviews and discusses some of the relevant evidence now available. The fact that, if needed, labile methyl balance is maintained by methylneogenesis appears to be established, but several aspects of transmethylation remain uncertain: definitive measurements of the rate of total trans methylation in humans of both sexes on various diets and at various ages; the extent to which synthesis of phosphatidylcholine has been underestimated; and the relative contributions of the 2 pathways for the formation of sarcosine (ie, N-methylglycine). The available evidence indicates that the quantitatively most important pathways for S-adenosylmethionine-dependent transmethylation in mammals are the syntheses of creatine by guanidinoacetate methyltransferase, of phosphatidylcholine by phosphatidylethanolamine methyltransferase, and of sarcosine by glycine N-methyltransferase. Data presented in this report show that S-adenosylmethionine and methionine accumulate abnormally in the plasma of humans with glycine N-methyltransferase deficiency but not of those with guanidinoacetate N-methyltransferase deficiency or in the plasma or livers of mice devoid of phosphatidylethanolamine N-methyltransferase activity. The absence of such accumulations in the latter 2 conditions may be due to removal of S-adenosylmethionine by synthesis of sarcosine. Steps that may help clarify the remaining issues include the determination of the relative rates of synthesis of sarcosine, creatine, and phosphatidylcholine by rapid measurement of the rates of radiolabel incorporation into these compounds from L-[methyl-H-3]methionine administered intraportally to an experimental animal; clarification of the intracellular hepatic isotope enrichment value during stable-isotope infusion studies to enhance the certainty of methyl flux estimates during such studies; and definitive measurement of the dietary betaine intake from various diets. C1 NIMH, DIRP, Mol Biol Lab, Bethesda, MD 20892 USA. Mem Univ Newfoundland, Dept Biochem, St John, NF A1C 5S7, Canada. Univ Alberta, Canadian Inst Hlth, Res Grp Mol & Cell Biol Lipids, Edmonton, AB T6G 2M7, Canada. Univ Colorado, Hlth Sci Ctr, Div Hematol, Denver, CO 80202 USA. Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. Dept Vet Affairs, Res Serv, Nashville, TN USA. RP Mudd, SH (reprint author), NIMH, DIRP, Mol Biol Lab, Bldg 35,Room 1B1006,35 Lincoln Dr, Bethesda, MD 20892 USA. EM muddh@mail.nih.gov FU NIA NIH HHS [AG-09834]; NIDDK NIH HHS [DK15289] NR 42 TC 82 Z9 83 U1 2 U2 10 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2007 VL 85 IS 1 BP 19 EP 25 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 125CP UT WOS:000243419400004 PM 17209172 ER PT J AU de Jonge, L DeLany, JP Nguyen, T Howard, J Hadley, EC Redman, LM Ravussin, E AF de Jonge, Lilian DeLany, James P. Nguyen, Tuong Howard, Jennyer Hadley, Evan C. Redman, Leanne M. Ravussin, Eric TI Validation study of energy expenditure and intake during calorie restriction using doubly labeled water and changes in body composition SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE doubly labeled water method; DLW; energy intake; body composition; metabolic chamber ID PHYSICAL-ACTIVITY; HUMANS; BALANCE; WEIGHT AB Background: Clinical trials involving calorie restriction (CR) require an assessment of adherence to a prescribed CR with the use of an objective measure of energy intake (EI). Objective: The objective was to validate the use of energy expenditure (EE) measured by doubly labeled water (DLW), in conjunction with precise measures of body composition, to calculate an individual's El during 30% CR. Design: Ten participants underwent 30% CR for 3 wk. During the last week (7 d), 24-h EE was measured in a respiratory chamber and simultaneously by DLW (EEDLW). El was calculated from 7-d EE measured by DLW and from changes in energy stores (ES) (weight and body composition). Calculated El was then compared with the actual El measured in the chamber by using the following equations: calculated El (kcal/d) = EEDLW + Delta ES, where Delta ESFM/FFM (kcal/d) = (9.3 X Delta FM, g/d) + (1.1 X Delta FFM, g/d), FM is fat mass, and FFM is fat-free mass. Results: We found close agreement (R = 0.88) between EE measured in the metabolic chamber and EEDLW during CR. Using the measured respiratory quotient, we found that the mean (+/- SD) EEDLW was 1934 + 377 kcal/d and EE measured in the metabolic chamber was 1906 +/- 327 kcal/d, ie, a 1.3 +/- 8.9% overestimation. El calculated from EEDLW and from changes in ES was 8.7 +/- 36.7% higher than the actual El provided during the chamber stay (1596 +/- 656 kcal/d). Conclusions: DLW methods can accurately estimate 24-h EE during CR. Although the mean difference between actual and calculated EIs for the group was small, we conclude that the interindividual variability was too large to provide an assessment of CR adherence on an individual basis. C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NIA, Bethesda, MD 20892 USA. RP de Jonge, L (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM dejongeh@pbrc.edu FU NIA NIH HHS [U01 AG020478-07, U01 AG020478, U01 AG20478] NR 17 TC 37 Z9 38 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2007 VL 85 IS 1 BP 73 EP 79 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 125CP UT WOS:000243419400012 PM 17209180 ER PT J AU Peters, U Foster, CB Chatterjee, N Schatzkin, A Reding, D Andriole, GL Crawford, ED Sturup, S Chanock, SJ Hayes, RB AF Peters, Ulrike Foster, Charles B. Chatterjee, Nilanjan Schatzkin, Arthur Reding, Douglas Andriole, Gerald L. Crawford, E. David Sturup, Stefan Chanock, Stelhen J. Hayes, Richard B. TI Serum selenium and risk of prostate cancer-a nested case-control study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE selenium; prostate cancer; vitamin E; smoking; serum; nested case-control study ID GLUTATHIONE-PEROXIDASE GENE; VITAMIN-E; OXIDATIVE STRESS; ALPHA-TOCOPHEROL; BETA-CAROTENE; SUBSEQUENT RISK; SELENOPROTEIN-P; METHYLSELENINIC ACID; GAMMA-TOCOPHEROL; PREVENTION TRIAL AB Background: Selenium is a potential chemopreventive agent against prostate cancer, whose chemoprotective effects are possibly mediated through the antioxidative properties of selenoenzymes. Interrelations with other antioxidative agents and oxidative stressors, such as smoking, are poorly understood. Objectives: The aims were to investigate the association between serum selenium and prostate cancer risk and to examine interactions with other antioxidants and tobacco use. Design: A nested case-control study was performed within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Serum selenium in prospectively collected samples was compared between 724 incident prostate cancer case subjects and 879 control subjects, frequency-matched for age, time since initial screen, and year of blood draw. The men were followed for up to 8 y. Results: Overall, serum selenium was not associated with prostate cancer risk (P for trend = 0.70); however, higher serum selenium was associated with lower risks in men reporting a high (more than the median: 28.0 IU/d) vitamin E intake [odds ratio (OR) for the highest compared with the lowest quartile of selenium: 0.58; 95% Cl: 0.37, 0.91; P for trend = 0.05; P for interaction = 0.01] and in multivitamin users (OR for highest compared with the lowest quartile of selenium: 0.61; 95% Cl: 0.36, 1.04; P for trend = 0.06; P for interaction = 0.05). Furthermore, among smokers, high serum selenium concentrations were related to reduced prostate cancer risk (OR for the highest compared with the lowest quartile of selenium: 0.65; 95% CI: 0.44, 0.97; P for trend = 0.09; P for interaction = 0.007). Conclusion: Greater prediagnostic serum selenium concentrations were not associated with prostate cancer risk in this large cohort, although greater concentrations were associated with reduced prostate cancer risks in men who reported a high intake of vitamin E, in multivitamin users, and in smokers. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. Washington Univ, St Louis, MO USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. Danish Univ Pharmaceut Sci, Inst Analyt Chem, Copenhagen, Denmark. NCI, Core Genotype Facil, NIH, Dept Hlth & Human Serv, Gaithersburg, MD USA. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, POB 19024,1100 Fairview Ave N M4-B402, Seattle, WA 98109 USA. EM upeters@fhcrc.org FU Intramural NIH HHS; NCI NIH HHS [K22 CA118421] NR 75 TC 50 Z9 55 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2007 VL 85 IS 1 BP 209 EP 217 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 125CP UT WOS:000243419400030 PM 17209198 ER PT J AU Coates, PM Dwyer, JT Thurn, AL AF Coates, Paul M. Dwyer, Johanna T. Thurn, Anne L. TI Introduction to state-of-the-science conference: Multivitamin/mineral supplements and chronic disease prevention SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 NIH, Off Dietary Supplements, Off Director, Bethesda, MD 20892 USA. RP Thurn, AL (reprint author), NIH, Off Dietary Supplements, Off Director, 6100 Execut Blvd,Room 3B01 MSC 7517, Bethesda, MD 20892 USA. EM thurna@od.nih.gov NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2007 VL 85 IS 1 BP 255S EP 256S PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 125CP UT WOS:000243419400040 ER PT J AU Yetley, EA AF Yetley, Elizabeth A. TI Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Conference on Multiviitamin/Mineral Supplements and Chronic Disease Prevention CY MAY 15-17, 2006 CL Natl Inst Hlth, Bethesda, MD HO Natl Inst Hlth DE vitamin and mineral supplements; bioavailability; bioequivalence; drug interactions; supplement composition; supplement definitions ID MINERAL SUPPLEMENTS; NATIONAL NUTRITION; UNITED-STATES; VITAMIN-E; FORMULATION; NUTRIENTS; CALCIUM; HEALTH; AVAILABILITY; VARIABILITY AB Although multivitamins, multiminerals, and similar terms (eg, multis or multiples) are commonly used, they have no standard scientific, regulatory, or marketplace definitions. Thus, multivitamins-multiminerals refers to products with widely varied compositions and characteristics. Multivitamin-multi mineral composition databases use label values as surrogates for analyzed values. However, actual vitamin and mineral amounts often deviate from label values. Vitamin and mineral bioavailability for dietary supplements also lacks a standard scientific and regulatory definition and validated in vitro and animal models that accurately reflect human bioavailabilities. Systematic information on the bioavailability and bioequivalence of vitamins and minerals in marketed products and on potential drug interactions is scarce. Because of limited information on product characteristics, our ability to directly compare results across studies, estimate changes in usage patterns or intakes over time, and generalize from published results to marketed products is problematic. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Yetley, EA (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01,MSC 7517, Bethesda, MD 20892 USA. EM yetleye@od.nih.gov NR 54 TC 51 Z9 55 U1 2 U2 18 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JAN PY 2007 VL 85 IS 1 BP 269S EP 276S PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 125CP UT WOS:000243419400043 PM 17209208 ER EF