FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Yedavalli, V Zhang, N Cai, H Jeang, KT Hosmane, R AF Yedavalli, Venkat Zhang, Ning Cai, Hongyi Jeang, Kuan-Teh Hosmane, Ramachandra TI Ring-expanded nucleosides (RENs) exhibit potent ATP-dependent helicase activity of RNA helicase DDX3 with little or no toxicity in ex vivo cell culture or in vivo in mice SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 21st International Conference on Antiviral Research CY APR 13-17, 2008 CL Montreal, CANADA SP Int Soc Antiviral Res C1 [Zhang, Ning; Cai, Hongyi; Hosmane, Ramachandra] Univ Maryland UMBC, Dept Chem & Biochem, Lab Drug Design & Synth, Baltimore, MD USA. [Yedavalli, Venkat; Jeang, Kuan-Teh] NIAID, Mol Microbiol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RI Jeang, Kuan-Teh/A-2424-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2008 VL 78 IS 2 MA 136 BP A68 EP A68 DI 10.1016/j.antiviral.2008.01.150 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 295PN UT WOS:000255486500125 ER PT J AU Ingvarsen, S Engelholm, LH Madsen, DH Hillig, T Lund, LR Holmbeck, K Behrendt, N AF Ingvarsen, Signe Engelholm, Lars H. Madsen, Daniel H. Hillig, Thore Lund, Leif R. Holmbeck, Kenn Behrendt, Niels TI Dimerization of endogenous MT1-MMP is a regulatory step in the activation of the 72 kDa gelatinase, MMP-2, on fibroblasts and fibrosarcoma cells SO APMIS LA English DT Meeting Abstract C1 [Ingvarsen, Signe; Engelholm, Lars H.; Madsen, Daniel H.; Hillig, Thore; Lund, Leif R.; Behrendt, Niels] Rigshosp, Finsen Lab, DK-2100 Copenhagen N, Denmark. [Engelholm, Lars H.] Rigshosp, Bartholin Inst, DK-2100 Copenhagen N, Denmark. [Holmbeck, Kenn] Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0903-4641 J9 APMIS JI APMIS PD MAY PY 2008 VL 116 IS 5 BP 433 EP 434 PG 2 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 295RC UT WOS:000255490600056 ER PT J AU Madsen, DH Engelholm, LH Hillig, T Ingvarsen, S Wagenaar-Miller, R Kjoller, L Gardsvoll, H Hoyer-Hansen, G Holmbeck, K Bugge, TH Behrendt, N AF Madsen, Daniel H. Engelholm, Lars H. Hillig, Thore Ingvarsen, Signe Wagenaar-Miller, Rebecca Kjoller, Lars Gardsvoll, Henrik Hoyer-Hansen, Gunilla Holmbeck, Kenn Bugge, Thomas H. Behrendt, Niels TI The endocytic collagen receptor, uPARAP/Endo180 in matrix turnover and cancer invasion SO APMIS LA English DT Meeting Abstract C1 [Madsen, Daniel H.; Engelholm, Lars H.; Hillig, Thore; Ingvarsen, Signe; Kjoller, Lars; Gardsvoll, Henrik; Hoyer-Hansen, Gunilla; Behrendt, Niels] Rigshosp, Finsen Lab, DK-2200 Copenhagen N, Denmark. [Wagenaar-Miller, Rebecca; Holmbeck, Kenn; Bugge, Thomas H.] Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0903-4641 J9 APMIS JI APMIS PD MAY PY 2008 VL 116 IS 5 BP 438 EP 439 PG 2 WC Immunology; Microbiology; Pathology SC Immunology; Microbiology; Pathology GA 295RC UT WOS:000255490600067 ER PT J AU Russell, KM Maraj, MS Wilson, LR Shedd-Steele, R Champion, VL AF Russell, Kathleen M. Maraj, Maltie S. Wilson, Lisa R. Shedd-Steele, Rivienne Champion, Victoria L. TI Barriers to recruiting urban African American women into research studies in community settings SO APPLIED NURSING RESEARCH LA English DT Article ID FOCUS GROUP INTERVIEW; MEDICAL-RESEARCH; CANCER PREVENTION; TREATMENT TRIALS; CLINICAL-TRIALS; PARTICIPATION; PROMOTION; DISTRUST; SURVIVAL; US AB This qualitative study identified barriers to African American women's participation in a community-based behavioral intervention trial to increase mammography screening. Four themes emerged from focus group discussions with community agency providers and research team members. These themes were (1) going to the gatekeepers; (2) knowing the culture; (3) location is everything; and (4) protocols, policies, and possibilities. A checklist of actions that nurse researchers could consider to increase African American women's participation in community trials is provided. (C) 2008 Elsevier Inc. All rights reserved. C1 [Russell, Kathleen M.; Wilson, Lisa R.; Champion, Victoria L.] Indiana Univ, Sch Nursing, Indianapolis, IN 46202 USA. [Maraj, Maltie S.] Sponsored Res Serv, Indianapolis, IN 46202 USA. [Shedd-Steele, Rivienne] Indiana Univ, Ctr Canc, Natl Canc Inst, Canc Informat Serv, Indianapolis, IN 46202 USA. RP Russell, KM (reprint author), Indiana Univ, Sch Nursing, Indianapolis, IN 46202 USA. EM katrusse@iupui.edu; msmaraj@iupui.edu; lwilson3@iupui.edu; rsheddst@iupui.edu; vchampio@iupui.edu FU NCI NIH HHS [5 R01 CA 77736-04] NR 36 TC 25 Z9 25 U1 3 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0897-1897 J9 APPL NURS RES JI Appl. Nurs. Res. PD MAY PY 2008 VL 21 IS 2 BP 90 EP 97 DI 10.1016/j.apnr.2006.05.001 PG 8 WC Nursing SC Nursing GA 302TZ UT WOS:000255993900007 PM 18457748 ER PT J AU Hasler, G Fromm, S Carlson, PJ Luckenbaugh, DA Waldeciz, T Geraci, M Roiser, JP Neumeister, A Meyers, N Charney, DS Drevets, WC AF Hasler, Gregor Fromm, Stephen Carlson, Paul J. Luckenbaugh, David A. Waldeciz, Tracy Geraci, Marilla Roiser, Jonathan P. Neumeister, Alexander Meyers, Noah Charney, Dennis S. Drevets, Wayne C. TI Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID MEDIAL PREFRONTAL CORTEX; METHYL-PARA-TYROSINE; PARKINSONS-DISEASE; TRYPTOPHAN DEPLETION; DOPAMINE RELEASE; MOOD-DISORDERS; NOREPINEPHRINE; HUMANS; COMORBIDITY; METABOLISM AB Context: The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD). Objectives: To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD. Design: Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial. Setting: Psychiatric outpatient clinic. Participants: Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls. Intervention: Induction of CD by oral administration of alpha-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose. Main Outcome Measures: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia). Results: Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms. Conclusions: This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. it demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry. C1 [Hasler, Gregor] Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. [Fromm, Stephen; Carlson, Paul J.; Luckenbaugh, David A.; Waldeciz, Tracy; Geraci, Marilla; Roiser, Jonathan P.; Meyers, Noah; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, Sect Neuroimaging Mood & Anxiety Disorders, Natl Inst Hlth, Bethesda, MD 20892 USA. [Neumeister, Alexander] Yale Univ, Sch Med, Mol Imaging Program, Clin Neurosci Div, West Haven, CT 06516 USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Pharmacol, New York, NY USA. [Charney, Dennis S.] Mt Sinai Sch Med, Dept Biol Chem, New York, NY USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Roiser, Jonathan/A-1791-2010; Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 FU Intramural NIH HHS [Z01 MH002812-05] NR 50 TC 93 Z9 97 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2008 VL 65 IS 5 BP 521 EP 531 DI 10.1001/archpsyc.65.5.521 PG 11 WC Psychiatry SC Psychiatry GA 296NY UT WOS:000255554300006 PM 18458204 ER PT J AU Monk, CS Telzer, EH Mogg, K Bradley, BP Mai, XQ Louro, HMC Chen, G McClure-Tone, EB Ernst, M Pine, DS AF Monk, Christopher S. Telzer, Eva H. Mogg, Karin Bradley, Brendan P. Mai, Xiaoqin Louro, Hugo M. C. Chen, Gang McClure-Tone, Erin B. Ernst, Monique Pine, Daniel S. TI Amygdala and ventrolateral prefrontal cortex activation to masked angry faces in children and adolescents with generalized anxiety disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; EMOTIONAL FACIAL EXPRESSIONS; EVENT-RELATED FMRI; RECEPTOR SUBUNIT EXPRESSION; ATTENTIONAL BIAS; SOCIAL PHOBIA; FEARFUL FACES; BRAIN; PERCEPTION; MODULATION AB Context: Vigilance for threat is a key feature of generalized anxiety disorder (GAD). The amygdala and the ventrolateral prefrontal cortex constitute a neural circuit that is responsible for detection of threats. Disturbed interactions between these structures may underlie pediatric anxiety. To date, no study has selectively examined responses to briefly presented threats in GAD or in pediatric anxiety. Objective: To investigate amygdala and ventrolateral prefrontal cortex activation during processing of briefly presented threats in pediatric GAD. Design: Case-control study. Setting: Government clinical research institute. Participants: Youth volunteers, 17 with GAD and 12 without a psychiatric diagnosis. Main Outcome Measures: We used functional magnetic resonance imaging to measure blood oxygenation level-dependent signal. During imaging, subjects performed an attention-orienting task with rapidly presented (17 milliseconds) masked emotional (angry or happy) and neutral faces. Results: When viewing masked angry faces, youth with GAD relative to comparison subjects showed greater right amygdala activation that positively correlated with anxiety disorder severity. Moreover, in a functional connectivity (psychophysiological interaction) analysis, the right amygdala and the right ventrolateral prefrontal cortex showed strong negative coupling specifically to masked angry faces. This negative coupling tended to be weaker in youth with GAD than in comparison subjects. Conclusions: Youth with GAD have hyperactivation of the amygdala to briefly presented masked threats. The presence of threat-related negative connectivity between the right ventrolateral prefrontal cortex and the amygdala suggests that the prefrontal cortex modulates the amygdala response to threat. in pediatric GAD, amygdala hyperresponse occurs in the absence of a compensatory increase in modulation by the ventrolateral prefrontal cortex. C1 [Monk, Christopher S.; Louro, Hugo M. C.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Monk, Christopher S.] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Monk, Christopher S.; Mai, Xiaoqin] Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. [Telzer, Eva H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Mogg, Karin; Bradley, Brendan P.] Univ Southampton, Sch Psychol, Southampton, Hants, England. [Chen, Gang] NIMH, Sci Statist Comp Core, Natl Inst Hlth, Bethesda, MD 20892 USA. [Ernst, Monique; Pine, Daniel S.] NIMH, Mood & Anxiety Disorders Program, Natl Inst Hlth, Bethesda, MD 20892 USA. [McClure-Tone, Erin B.] Georgia State Univ, Dept Psychol, Atlanta, GA 30303 USA. RP Monk, CS (reprint author), Univ Michigan, Dept Psychol, 530 Church St, Ann Arbor, MI 48109 USA. EM csmonk@umich.edu RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; Monk, Christopher/J-1805-2014; OI Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271 FU Intramural NIH HHS; NIMH NIH HHS [K22 MH068017-02, K22 MH068017]; Wellcome Trust NR 50 TC 287 Z9 296 U1 12 U2 60 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2008 VL 65 IS 5 BP 568 EP 576 DI 10.1001/archpsyc.65.5.568 PG 9 WC Psychiatry SC Psychiatry GA 296NY UT WOS:000255554300010 PM 18458208 ER PT J AU Finger, EC Marsh, AA Mitchell, DG Reid, ME Sims, C Budhani, S Kosson, DS Chen, G Towbin, KE Leibenluft, E Pine, DS Blair, JR AF Finger, Elizabeth C. Marsh, Abigail A. Mitchell, Derek G. Reid, Marguerite E. Sims, Courtney Budhani, Salitna Kosson, David S. Chen, Gang Towbin, Kenneth E. Leibenluft, Ellen Pine, Daniel S. Blair, James R. TI Abnormal ventromedial prefrontal cortex function in children with psychopathic traits during reversal learning SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; DEFICIT HYPERACTIVITY DISORDER; ANTISOCIAL PERSONALITY-DISORDER; CALLOUS-UNEMOTIONAL TRAITS; COMMON STEREOTACTIC SPACE; DECISION-MAKING COGNITION; CONDUCT PROBLEMS; ORBITOFRONTAL CORTEX; JUVENILE PSYCHOPATHY; SELECTIVE ATTENTION AB Context: Children and adults with psychopathic traits and conduct or oppositional defiant disorder demonstrate poor decision making and are impaired in reversal learning. However, the neural basis of this impairment has not previously been investigated. Furthermore, despite high comorbidity of psychopathic traits and attention-deficit/hyperactivity disorder, to our knowledge, no research has attempted to distinguish neural correlates of childhood psychopathic traits and attentiondeficit/hyperactivity disorder. Objective: To determine the neural regions that underlie the reversal learning impairments in children with psychopathic traits plus conduct or oppositional defiant disorder. Design: Case-control study. Setting: Government clinical research institute. Participants: Forty-two adolescents aged 10 to 17 years: 14 with psychopathic traits and oppositional defiant disorder or conduct disorder, 14 with attention-cleficit/hyperactivity disorder only, and 14 healthy controls. Main Outcome Measure: Blood oxygenation level-dependent signal as measured via functional magnetic resonance imaging during a probabilistic reversal task. Results: Children with psychopathic traits showed abnormal responses within the ventromedial prefrontal cortex (Brodmann area 10) during punished reversal errors compared with children with attention-deficit/hyperactivity disorder and healthy children (P<.05 corrected for multiple comparisons). Conclusions: To our knowledge, this study provides the first evidence of abnormal ventromedial prefrontal cortex responsiveness in children with psychopathic traits and demonstrates this dysfunction was not attributable to comorbid attention-deficit/hyperactivity disorder. These findings suggest that reversal learning impairments in patients with developmental psychopathic traits relate to abnormal processing of reinforcement information. C1 [Finger, Elizabeth C.] Univ Western Ontario Hosp, Dept Clin Neurol Sci, London, ON N6A 5A5, Canada. [Finger, Elizabeth C.; Marsh, Abigail A.; Reid, Marguerite E.; Sims, Courtney; Budhani, Salitna; Chen, Gang; Towbin, Kenneth E.; Leibenluft, Ellen; Pine, Daniel S.; Blair, James R.] NIMH, Natl Inst Hlth, Bethesda, MD 20892 USA. [Finger, Elizabeth C.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. [Mitchell, Derek G.] Univ Western Ontario, Dept Psychiat, London, ON N6A 3K7, Canada. [Mitchell, Derek G.] Univ Western Ontario, Dept Anat, London, ON, Canada. [Mitchell, Derek G.] Univ Western Ontario, Dept Cell Biol, London, ON, Canada. [Kosson, David S.] Rosalind Franklin Univ Med & Sci, Dept Psychol, N Chicago, IL USA. RP Finger, EC (reprint author), Univ Western Ontario Hosp, Dept Clin Neurol Sci, Room B10-004, London, ON N6A 5A5, Canada. EM elizabeth.finger@lhsc.on.ca RI Finger, Elizabeth/B-6453-2015 FU Intramural NIH HHS [ZIA MH002860-05]; NIMH NIH HHS [R01 MH057714, R01 MH057714-01A1, R01 MH057714-02, R01 MH057714-03, R01 MH057714-04] NR 79 TC 157 Z9 159 U1 6 U2 21 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2008 VL 65 IS 5 BP 586 EP 594 DI 10.1001/archpsyc.65.5.586 PG 9 WC Psychiatry SC Psychiatry GA 296NY UT WOS:000255554300012 PM 18458210 ER PT J AU Wong, WT Yeh, S Chan, CC Kalina, RE Kinyoun, JL Folk, JC Coleman, HR Chew, EY AF Wong, Wai T. Yeh, Steven Chan, Chi-Chao Kalina, Robert E. Kinyoun, James L. Folk, James C. Coleman, Hanna R. Chew, Emily Y. TI Retinal vascular proliferation as an ocular manifestation of von Hippel-Lindau disease SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CANCER AB Objectives: To describe the features, natural history, and management of an unusual manifestation of ocular von Hippel-Lindau disease in the form of fine vascular proliferation. Methods: Case series of 14 patients with definite or presumed von Hippel-Lindau disease. Results: Retinal vascular proliferation consisting of fine superficial vessels was found in 16 eyes of 14 patients with von Hippel-Lindau disease. The lesion was often found in a juxtapapillary location and associated with a fibrovascular component and/or a macular epiretinal membrane. In cases with follow-up ( 12 patients; mean [SD] follow-up, 10.9 [7.5] years), the lesion was stable in 7 of 13 eyes but showed growth and progression resulting in vision loss in the remainder. In 5 eyes, surgical intervention with pars plana vitrectomy, membrane peel, and excision of the fibrovascular lesion resulted in visual improvement in all of the cases. Conclusions: Ocular von Hippel-Lindau disease can uncommonly manifest as vascular proliferation that consists of fine, superficial, juxtapapillary vessels that are often associated with fibrovascular proliferation and epiretinal membrane formation. The natural history of this lesion is variable and can result in vision loss from tractional effects in progressive cases. Vision-threatening cases may be successfully managed by surgical excision. C1 [Coleman, Hanna R.; Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, Natl Inst Hlth, Clin Res Ctr, Bethesda, MD 20892 USA. [Wong, Wai T.] NEI, Off Sci Director, Natl Inst Hlth, Bethesda, MD 20892 USA. [Yeh, Steven; Chan, Chi-Chao] NEI, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kalina, Robert E.; Kinyoun, James L.] Univ Washington, Dept Ophthalmol, Seattle, WA 98195 USA. [Folk, James C.] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, Natl Inst Hlth, Clin Res Ctr, Bldg 10,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [Z01 EY000222-22, Z99 EY999999, ZIE EY000487-01] NR 13 TC 8 Z9 9 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 2008 VL 126 IS 5 BP 637 EP 643 DI 10.1001/archopht.126.5.637 PG 7 WC Ophthalmology SC Ophthalmology GA 299UO UT WOS:000255780700005 PM 18474773 ER PT J AU Mueller, MB Tuan, RS AF Mueller, Michael B. Tuan, Rocky S. TI Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells SO ARTHRITIS AND RHEUMATISM LA English DT Article ID 3-DIMENSIONAL NANOFIBROUS SCAFFOLD; HUMAN OSTEOARTHRITIC CARTILAGE; IN-VITRO CHONDROGENESIS; GROWTH-FACTOR-BETA; BONE-MARROW; CHONDROCYTE HYPERTROPHY; PROGENITOR CELLS; THYROID-HORMONE; MOLECULAR EVENTS; GENE-EXPRESSION AB Objective. Mesenchymal stem cells (MSCs) are promising candidate cells for cartilage tissue engineering. Expression of cartilage hypertrophy markers (e.g., type X collagen) by MSCs undergoing chondrogenesis raises concern for a tissue engineering application for MSCs, because hypertrophy would result in apoptosis and ossification. To analyze the biologic basis of MSC hypertrophy, we examined the response of chondrifying MSCs to culture conditions known to influence chondrocyte hypertrophy, using an array of hypertrophy-associated markers. Methods. Human MSC pellet cultures were pre-differentiated for 2 weeks in a chondrogenic medium, and hypertrophy was induced by withdrawing transforming growth factor beta (TGF beta), reducing the concentration of dexamethasone, and adding thyroid hormone (T3). Cultures were characterized by histologic, immunohistochemical, and biochemical methods, and gene expression was assessed using quantitative reverse transcription-polymerase chain reaction. Results. The combination of TGF beta withdrawal, a reduction in the level of dexamethasone, and the addition of T3 was essential for hypertrophy induction. Cytomorphologic changes were accompanied by increased alkaline phosphatase activity, matrix mineralization, and changes in various markers of hypertrophy, including type X collagen, fibroblast growth factor receptors 1-3, parathyroid hormone-related protein receptor, retinoic acid receptor gamma, matrix metalloproteinase 13, Indian hedgehog, osteocalcin, and the proapoptotic gene p53. However, hypertrophy was not induced uniformly throughout the pellet culture, and distinct regions of dedifferentiation were observed. Conclusion. Chondrogenically differentiating MSCs behave in a manner functionally similar to that of growth plate chondrocytes, expressing a very similar hypertrophic phenotype. Under the in vitro culture conditions used here, MSC-derived chondrocytes underwent a differentiation program analogous to that observed during endochondral embryonic skeletal development, with the potential for terminal differentiation. This culture system is applicable for the screening of hypertrophy-inhibitory conditions and agents that may be useful to enhance MSC performance in cartilage tissue engineering. C1 [Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. [Mueller, Michael B.] Univ Regensburg, Med Ctr, Regensburg, Germany. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Room 1523,Mail Stop Code 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural NIH HHS [ZIA AR041177-02]; NIAMS NIH HHS [Z01 AR041131, Z01-AR-41131] NR 50 TC 171 Z9 177 U1 5 U2 28 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2008 VL 58 IS 5 BP 1377 EP 1388 DI 10.1002/art.23370 PG 12 WC Rheumatology SC Rheumatology GA 300TP UT WOS:000255848400021 PM 18438858 ER PT J AU Tejero, ME Ebbesson, SEO Lopez-Alvarenga, JC Ebbesson, L Howard, BV Fabsitz, R Comuzzie, AG AF Tejero, M. E. Ebbesson, S. E. O. Lopez-Alvarenga, J. C. Ebbesson, L. Howard, B. V. Fabsitz, R. Comuzzie, A. G. TI ASSOCIATIONS AMONG FATTY ACIDS IN RED BLOOD CELLS AND COMPONENTS OF THE METABOLIC SYNDROME SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract C1 [Tejero, M. E.; Lopez-Alvarenga, J. C.; Comuzzie, A. G.] SFBR, San Antonio, TX USA. [Ebbesson, S. E. O.] Norton Sound Hlth Corp, Nome, AK USA. [Ebbesson, L.] Univ Bergen, Bergen, Norway. [Howard, B. V.] Medstar Res Inst, Hyattsville, MD USA. [Fabsitz, R.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD MAY PY 2008 VL 9 IS 1 BP 11 EP 12 DI 10.1016/S1567-5688(08)70042-4 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA V12PI UT WOS:000207610700043 ER PT J AU Eiriksdottir, G Aspelund, T Smith, AV Launer, LJ Harris, TB Gudnason, V AF Eiriksdottir, G. Aspelund, T. Smith, A. V. Launer, L. J. Harris, T. B. Gudnason, V. TI C-REACTIVE PROTEIN (CRP) POLYMORPHISM MODIFIES THE ASSOCIATION OF ADIPOSITY AND CRP LEVELS: AGE GENE/ENVIRONMENT SUSCEPTIBILITY - REYKJAVIK STUDY SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract C1 [Launer, L. J.; Harris, T. B.] NIA, NIH, Bethesda, MD 20892 USA. RI Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD MAY PY 2008 VL 9 IS 1 BP 32 EP 32 DI 10.1016/S1567-5688(08)70121-1 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA V12PI UT WOS:000207610700122 ER PT J AU Berkane, A Tranchida, F Pietri, S Culcasi, M Nguyen, H Merlin, D de la Porte, PL Deyris, V Tchiakpe, L Jourdheuil-Rahmani, D Waheed, A Hiol, A AF Berkane, A. Tranchida, F. Pietri, S. Culcasi, M. Nguyen, H. Merlin, D. de la Porte, P. Lechene Deyris, V. Tchiakpe, L. Jourdheuil-Rahmani, D. Waheed, A. Hiol, A. TI HIGH ENERGY FRUCTOSE DIET INDUCED TYPE 2 DIABETES IN RATS SO ATHEROSCLEROSIS SUPPLEMENTS LA English DT Meeting Abstract C1 [Berkane, A.; Tranchida, F.; Deyris, V.; Hiol, A.] Univ Paul Cezanne, FST St Jerome, Inst Mediterraneen Rech Nutr IMRN, UMR INRA 1111, F-13397 Marseille 20, France. [Pietri, S.; Culcasi, M.] CNRS, Lab Struct & Reactivite Especes Paramagnet, UMR 6517, Marseille, France. [Nguyen, H.; Merlin, D.] Emory Univ, Sch Med, Dept Med, Div Digest Dis, Atlanta, GA 30322 USA. [de la Porte, P. Lechene; Tchiakpe, L.; Jourdheuil-Rahmani, D.] INSERM, Nutr Humaine & Lipides U476, F-13385 Marseille, France. [Waheed, A.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 3 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1567-5688 J9 ATHEROSCLEROSIS SUPP JI Atheroscler. Suppl. PD MAY PY 2008 VL 9 IS 1 BP 71 EP 71 DI 10.1016/S1567-5688(08)70285-X PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA V12PI UT WOS:000207610701004 ER PT J AU Lissek, S Biggs, AL Rabin, SJ Cornwell, BR Alvarez, RP Pine, DS Grillon, C AF Lissek, Shmuel Biggs, Arter L. Rabin, Stephanie J. Cornwell, Brian R. Alvarez, Ruben P. Pine, Daniel S. Grillon, Christian TI Generalization of conditioned fear-potentiated startle in humans: Experimental validation and clinical relevance SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE fear-potentiated startle; stimulus generalization; fear-conditioning; anxiety disorders ID STIMULUS-GENERALIZATION; ANXIETY DISORDERS; MANIFEST ANXIETY; STRESS-DISORDER; CORTEX; EXTINCTION; PERCEPTION; RESPONSES; PARADIGM; AMYGDALA AB Though generalization of conditioned fear has been implicated as a central feature of pathological anxiety, surprisingly little is known about the psychobiology of this learning phenomenon in humans. Whereas animal work has frequently applied methods to examine generalization gradients to study the gradual weakening of the conditioned-fear response as the test stimulus increasingly differs from the conditioned stimulus (CS), to our knowledge no psychobiological studies of such gradients have been conducted in humans over the last 40 years. The current effort validates an updated generalization paradigm incorporating more recent methods for the objective measurement of anxiety (fear-potentiated startle). The paradigm employs 10, quasi-randomly presented, rings of gradually increasing size with extremes serving as CS+ and CS- The eight rings of intermediary size serve as generalization stimuli (GSs) and create a continuum-ofsimilarity from CS + to CS-. Both startle data and online self-report ratings demonstrate continuous decreases in generalization as the presented stimulus becomes less similar to the CS +. The current paradigm represents an updated and efficacious tool with which to study fear generalization-a central, yet understudied conditioning-correlate of pathologic anxiety. Published by Elsevier Ltd. C1 [Lissek, Shmuel; Biggs, Arter L.; Rabin, Stephanie J.; Cornwell, Brian R.; Alvarez, Ruben P.; Pine, Daniel S.; Grillon, Christian] NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, Bethesda, MD 20892 USA. RP Lissek, S (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, DHHS, 15K N Dr,Rm 200, Bethesda, MD 20892 USA. EM lisseks@mail.nih.gov RI Lissek, Shmuel/B-6577-2008; OI Rabin, Stephanie/0000-0002-8282-0867 FU Intramural NIH HHS [Z99 MH999999] NR 35 TC 122 Z9 124 U1 5 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD MAY PY 2008 VL 46 IS 5 BP 678 EP 687 DI 10.1016/j.brat.2008.02.005 PG 10 WC Psychology, Clinical SC Psychology GA 299YX UT WOS:000255792600010 PM 18394587 ER PT J AU Laco, GS Pommier, Y AF Laco, Gary S. Pommier, Yves TI Role of a tryptophan anchor in human topoisomerase I structure, function and inhibition SO BIOCHEMICAL JOURNAL LA English DT Article DE camptothecin; distributive relaxation; interaction energy score; processive relaxation; topoisomerase I; tryptophan anchor ID N-TERMINAL DOMAIN; FELINE IMMUNODEFICIENCY VIRUS; ACTIVE-SITE; DNA TOPOISOMERASES; CATALYTIC-ACTIVITY; CRYSTAL-STRUCTURES; MECHANISM; PROTEINS; CAMPTOTHECIN; LOCALIZATION AB Human Top I (topoisomerase 1) relaxes supercoiled DNA during cell division and transcription. Top1 is composed of 765 amino acids and contains an unstructured N-terminal domain of 200 amino acids, and a structured functional domain of 565 amino acids that binds and relaxes supercoiled DNA. In the present study we examined the region spanning the junction of the N-terminal domain and functional domain (junction region). Analysis of several published Top1 structures revealed that three tryptophan residues formed a network of aromatic stacking interactions and electrostatic interactions that anchored the N-terminus of the functional domain to sub-domains containing the nose cone and active site. Mutation of the three tryptophan residues (Trp(203)/Trp(205)/Trp(206)) to an alanine residue, either individually or together, in silico revealed that the individual tryptophan residue's contribution to the tryptophan 'anchor' was additive. When the three tryptophan residues were mutated to alanine in vitro, the resulting mutant Top I differed from wild-type Top I in that it lacked processivity, exhibited resistance to camptothecin and was inactivated by urea. The results indicated that the tryptophan anchor stabilized the N-terminus of the functional domain and prevented the loss of Top1 structure and function. C1 [Laco, Gary S.] Lake Erie Coll Osteopath Med, Biochem Lab, Bradenton, FL 34211 USA. [Pommier, Yves] NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Laco, GS (reprint author), Lake Erie Coll Osteopath Med, Biochem Lab, Bradenton, FL 34211 USA. EM glaco@lecom.edu FU Intramural NIH HHS [Z01 BC006161-23] NR 44 TC 12 Z9 12 U1 0 U2 3 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 1 PY 2008 VL 411 BP 523 EP 530 DI 10.1042/BJ20071436 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 298QK UT WOS:000255702000007 PM 18215123 ER PT J AU Yan, R Nanovskaya, TN Zharikova, OL Mattison, DR Hankins, GDV Ahmed, MS AF Yan, Ru Nanovskaya, Tatiana N. Zharikova, Olga L. Mattison, Donald R. Hankins, Gary D. V. Ahmed, Mahmoud S. TI Metabolism of 17 alpha-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE preterm delivery; 17 alpha-hydroxyprogesterone caproate; metabolism; microsomes; human placenta; baboon placenta; human liver; baboon liver ID HUMAN LIVER-MICROSOMES; CYTOCHROMES P450; MEDROXYPROGESTERONE ACETATE; PROGESTERONE; IDENTIFICATION; MONKEY; VITRO; RAT; 3A4 AB Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone caproate (17-HPC), used for treatment of preterm deliveries, during its perfusion across the dually perfused human placental lobule. Previously, we demonstrated that the drug is not hydrolyzed, neither in vivo nor in vitro, to progesterone and caproate. Therefore, the hypothesis for this investigation is that 17-HPC is actively metabolized by human and baboon (Papio cynocephalus) hepatic and placental microsomes. Baboon hepatic and placental microsomes were investigated to validate the nonhuman primate as an animal model for drug use during pregnancy. Data presented here indicate that human and baboon hepatic microsomes formed several mono-, di-, and tri-hydroxylated derivatives of 17-HPC. However, microsomes of human and baboon placentas metabolized 17-HPC to its mono-hydroxylated derivatives only in quantities that were a fraction of those formed by their respective livers, except for two metabolites (M16' and M17') that are unique for placenta and contributed to 25% and 75% of the total metabolites formed by human and baboon, respectively. The amounts of metabolites formed, relative to each other, by human and baboon microsomes were different suggesting that the affinity of 17-HPC to CYP enzymes and their activity could be species-dependent. Published by Elsevier Inc. C1 [Yan, Ru; Nanovskaya, Tatiana N.; Zharikova, Olga L.; Hankins, Gary D. V.; Ahmed, Mahmoud S.] Univ Texas Galveston, Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Mattison, Donald R.] NICHHD, Obstet & Pediat Pharmacol Branch, Rockville, MD 20852 USA. RP Ahmed, MS (reprint author), Univ Texas Galveston, Med Branch, Dept Obstet & Gynecol, 301 Univ Blvd, Galveston, TX 77555 USA. EM maahmed@utmb.edu RI Mattison, Donald/C-2015-2009; Yan, Ru/G-3480-2013; Mattison, Donald/L-4661-2013 OI Yan, Ru/0000-0001-6268-360X; Mattison, Donald/0000-0001-5623-0874 FU NICHD NIH HHS [U10 HD047891, U10 HD047891-05] NR 24 TC 12 Z9 12 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2008 VL 75 IS 9 BP 1848 EP 1857 DI 10.1016/j.bcp.2008.01.013 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 300TZ UT WOS:000255849400016 PM 18329004 ER PT J AU Malone, JH Oliver, B AF Malone, John H. Oliver, Brian TI The sex chromosome that refused to die SO BIOESSAYS LA English DT Article ID BIASED GENE-EXPRESSION; Y-CHROMOSOME; DROSOPHILA-MELANOGASTER; GENOME; EVOLUTION; MIRANDA AB Chromosomes that harbor dominant sex determination loci are predicted to erode over time-losing genes, accumulating transposable elements, degenerating into a functional wasteland and ultimately becoming extinct. The Drosophila melanogaster Y chromosome is fairly far along this path to oblivion. The few genes on largely heterochromatic Y chromosome are required for spermatocyte-specific functions, but have no role in other tissues. Surprisingly, a recent paper shows that divergent Y chromosomes can substantially influence gene expression throughout the D. melanogaster genome.((1)) These results show that variation on Y has an important influence on the deployment of the genome. C1 [Malone, John H.; Oliver, Brian] NIDDKD, NIH, Cellular & Dev Biol Lab, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDKD, NIH, Cellular & Dev Biol Lab, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM oliver@helix.nih.gov FU Intramural NIH HHS [Z01 DK015607-01] NR 17 TC 6 Z9 6 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD MAY PY 2008 VL 30 IS 5 BP 409 EP 411 DI 10.1002/bies.20752 PG 3 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 297MQ UT WOS:000255621200001 PM 18404685 ER PT J AU Wendler, D Grady, C AF Wendler, David Grady, Christine TI What should research participants understand to understand they are participants in research? SO BIOETHICS LA English DT Article DE clinical research; participation; informed consent ID INFORMED-CONSENT; THERAPEUTIC MISCONCEPTION; CLINICAL-TRIALS AB To give valid informed consent to participate in clinical research, potential participants should understand the risks, potential benefits, procedures, and alternatives. Potential participants also should understand that they are being invited to participate in research. Yet it is unclear what potential participants need to understand to satisfy this particular requirement. As a result, it is unclear what additional information investigators should disclose about the research; and it is also unclear when failures of understanding in this respect undermine the validity of potential participants' informed consent. An analysis of individuals' interests suggests that potential participants need to understand three additional facts to understand that they are being invited to participate in research: 1) research contribution: those who enroll in the study will be contributing to a project designed to gather generalizable knowledge to benefit others in the future; 2) research relationship: the investigators will rely on participants' efforts to gather the generalizable knowledge to benefit others; and 3) research impact: the extent to which participating in the study will alter what participants do and what happens to them. C1 [Wendler, David] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Wendler, David] NIH, Dept Bioeth, Unit Vulnerable Populat, Bethesda, MD 20892 USA. [Grady, Christine] NIH, Dept Bioeth, Sect Human Subjects Res, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 19 TC 26 Z9 26 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-9702 J9 BIOETHICS JI Bioethics PD MAY PY 2008 VL 22 IS 4 BP 203 EP 208 DI 10.1111/j.1467-8519.2008.00632.x PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 286OS UT WOS:000254855900003 PM 18405318 ER PT J AU Resnik, DB Zeldin, DC AF Resnik, David B. Zeldin, Darryl C. TI Environmental health research on hazards in the home and the duty to warn SO BIOETHICS LA English DT Article DE hazards in the home; duty to warn; environmental health; ethics ID CLINICAL-RESEARCH AB When environmental health researchers study hazards in the home, they often discover information that may be relevant to protecting the health and safety of the research subjects and occupants. This article describes the ethical and legal basis for a duty to warn research subjects and occupants about hazards in the home and explores the extent of this duty. Investigators should inform research subjects and occupants about the results of tests conducted as part of the research protocol only if the information is likely to be accurate, reliable, and medically useful. Investigators should warn subjects and occupants about hazards they happen to discover while they are in the home, if a reasonable person would warn the subjects and occupants about those hazards. Investigators should not report illegal hazards discovered in the home to the authorities, unless those hazards constitute abuse or neglect of children or mentally disabled people living in the home. When investigators decide to warn research subjects and occupants about hazards in the home, they should take some steps to help them make effective use of this information, such as providing additional counselling or making a referral for remediation or medical treatment. Investigators should discuss these issues with research subjects during the informed consent process. C1 [Resnik, David B.; Zeldin, Darryl C.] NIEHS, NIH, Environm Cardiopulm Dis Sect, Chapel Hill, NC 27516 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Environm Cardiopulm Dis Sect, Mail Drop NH 06 Box 12233, Chapel Hill, NC 27516 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 13 TC 5 Z9 5 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-9702 J9 BIOETHICS JI Bioethics PD MAY PY 2008 VL 22 IS 4 BP 209 EP 217 DI 10.1111/j.1467-8519.2008.00638.x PG 9 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 286OS UT WOS:000254855900004 PM 18405319 ER PT J AU Low, NCP Cui, LH Merikangas, KR AF Low, Nancy C. P. Cui, Lihong Merikangas, Kathleen R. TI Community versus clinic sampling: Effect on the familial aggregation of anxiety disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE familial aggregation; genetics; sampling; selection/ascertainment bias ID NATIONAL-COMORBIDITY-SURVEY; MENTAL-HEALTH SURVEYS; PANIC DISORDER; UNITED-STATES; PSYCHIATRIC-DISORDERS; SURVEY REPLICATION; SOCIAL PHOBIA; DIAGNOSTIC INTERVIEW; EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION AB Background: Most research on the familial aggregation of mental disorders has been based on probands selected from clinics. Sparse research examines the clustering of psychiatric illnesses among families ascertained from the community. Such ascertainment bias limits the generalizability and may compromise the validity of study findings. The objective of this study was to illustrate differences between familial aggregation on the basis of the source of proband ascertainment in a family study of anxiety disorders. Methods: Forty anxiety probands were recruited from clinics; 36 anxiety probands and 60 control subjects were recruited from the community. All probands and their relatives were assessed using standardized psychiatric assessments. Results: Selection of probands with panic and generalized anxiety disorders from clinical settings compared with the same local community settings was associated with greater risk to relatives. In contrast, the familial aggregation of social anxiety was greater in the community sample, and there were no differences in the risk of specific phobia to relatives between probands from clinics versus community. Conclusions: Clinic versus community sampling affects familial clustering of anxiety disorders. in general, the effect of clinic sampling is likely attributable to the greater severity of clinic cases, which may also be associated with increased familial morbidity. Differences observed between the anxiety disorders may be artifactual because of the diagnostic criteria of the anxiety disorders or low power. This study illustrates the importance of establishing standards for case-control selection, especially as complex disorder genetics moves increasingly toward population-based sampling. C1 [Low, Nancy C. P.] McGill Univ, Dept Psychiat, Montreal, PQ H3A 1A1, Canada. [Low, Nancy C. P.; Cui, Lihong; Merikangas, Kathleen R.] NIMH, NIH, Dept Hlth & Human Serv, Intramural Res Program,Mood & Anxiety Disorders P, Bethesda, MD 20892 USA. RP Low, NCP (reprint author), McGill Univ, Dept Psychiat, 1033 Pine Ave W,Room 104, Montreal, PQ H3A 1A1, Canada. EM nancy.low@mcgill.ca FU Intramural NIH HHS NR 42 TC 14 Z9 14 U1 4 U2 6 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 MAY 1 PY 2008 VL 63 IS 9 BP 884 EP 890 DI 10.1016/j.biopsych.2007.08.011 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 287VU UT WOS:000254945400010 PM 17945198 ER PT J AU Sheng, L Cai, F Zhu, Y Pal, A Athanasiou, M Orrison, B Blair, DG Hughes, SH Coffin, JM Lewis, AM Peden, K AF Sheng, Li Cai, Fang Zhu, Yong Pal, Achintya Athanasiou, Meropi Orrison, Brian Blair, Donald G. Hughes, Stephen H. Coffin, John M. Lewis, Andrew M. Peden, Keith TI Oncogenicity of DNA in vivo: Tumor induction with expression plasmids for activated H-ras and c-myc SO BIOLOGICALS LA English DT Article DE DNA oncogenicity; T24-H-ras; c-myc; tumor induction; vaccine cell substrate ID VIRUS EARLY REGION; TRANSGENIC MICE; EMBRYO FIBROBLASTS; CELL-LINE; BK VIRUS; CHROMOSOMAL INSERTION; PROMOTER INSERTION; EPITHELIAL-CELLS; GENE-TRANSFER; FOREIGN DNA AB All vaccines and other biological products contain contaminating residual DNA derived from the production cell substrate. Whether this residual cell-substrate DNA can induce tumors in vaccine recipients and thus represent a risk factor has been debated for over 50 years without resolution. As a first step in resolving this issue, we have generated expression plasmids for the activated human H-ras oncogene and for the murine c-myc proto-oncogene. Their oncogenic activity was confirmed in vitro using the focus-formation transformation assay. Two strains of adult and newborn immune-competent mice were inoculated with different amounts of either plasmid alone or with a combination of the H-ras and c-myc plasmids. Tumors developed only in mice inoculated with both plasmids and only at the highest amount of DNA (12.5 mu g of each plasmid). The NIH Swiss mouse was more sensitive than the C57BL/6 mouse, and newborn animals were more sensitive than adults. Cell lines were established from the tumors. PCR and Southern hybridization analyses demonstrated that both inoculated oncogenes were present in all of the tumor-derived cell lines and that the cells in the tumors were clonal. Western analysis demonstrated that both oncoproteins were expressed in these cell lines. These results demonstrate that cellular oncogenes can induce tumors following subcutaneous inoculation. Such information provides a possible way of evaluating and estimating the theoretical oncogenic risk posed by residual cell-substrate DNA in vaccines. Published by Elsevier Ltd on behalf of The International Association for Biologicals. C1 [Sheng, Li; Cai, Fang; Zhu, Yong; Pal, Achintya; Orrison, Brian; Lewis, Andrew M.; Peden, Keith] US FDA, Div Viral Prod, OVRR, CBER, Bethesda, MD 20892 USA. [Blair, Donald G.; Hughes, Stephen H.; Coffin, John M.] NCI, Frederick Canc Res Facil, Frederick, MD 21701 USA. [Coffin, John M.] Tufts Univ, Dept Microbiol & Mol Biol, Boston, MA 02111 USA. RP Peden, K (reprint author), US FDA, Div Viral Prod, OVRR, CBER, Bldg 29A,Room 3D08 29 Lincoln Dr, Bethesda, MD 20892 USA. EM andrew.lewis@fda.hhs.gov; andrew.lewis@fda.hhs.gov FU NCI NIH HHS [R01 CA089441] NR 56 TC 12 Z9 14 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1045-1056 J9 BIOLOGICALS JI Biologicals PD MAY PY 2008 VL 36 IS 3 BP 184 EP 197 DI 10.1016/j.biologicals.2007.11.003 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 296MF UT WOS:000255548000005 PM 18218323 ER PT J AU Guillery, O Malka, F Landes, T Guillou, E Blackstone, C Lombes, A Belenguer, P Arnoult, D Rojo, M AF Guillery, Olwenn Malka, Florence Landes, Thomas Guillou, Emmanuelle Blackstone, Craig Lombes, Anne Belenguer, Pascale Arnoult, Damien Rojo, Manuel TI Metalloprotease-mediated OPA1 processing is modulated by the mitochondria) membrane potential SO BIOLOGY OF THE CELL LA English DT Article DE apoptosis; ATPase associated with various cellular activities (AAA) protease; mitochondrial fusion; OPA1; YME1 L ID DYNAMIN-RELATED GTPASE; CYTOCHROME-C RELEASE; PROTEIN OPA1; PROTEOLYTIC CLEAVAGE; FUSION; MORPHOLOGY; MITOFUSINS; APOPTOSIS; MGM1P; DYSFUNCTION AB Background information. Human OPA1 (optic atrophy type 1) is a dynamin-related protein of the mitochondrial IMS (intermembrane space) involved in membrane fusion and remodelling. Similarly to its yeast orthologue Mgm1p that exists in two isoforms generated by the serine protease Pcp1p/Rbd1p, OPA1 exists in various isoforms generated by alternative splicing and processing. In the present paper, we focus on protease processing of OPA1. Results. We find that various mammalian cell types display a similar pattern of OPA1 isoforms [two L-OPA1 (long isoforms of OPA1) and three S-OPA1 (short isoforms of OPA1)] and that loss of the inner membrane potential, but not inhibition of oxidative phosphorylation or glycolysis, induces rapid and complete processing of L-OPA1 to S-OPA1. In isolated mitochondria, OPA1 processing was inhibited by heavy-metal chelators, pointing to processing by a mitochondrial metalloprotease. The pattern of OPA1 isoforms and its processing kinetics were normal in mitochondria devoid of the serine protease PARL (presenilins-associated rhomboid-like protein)-the human orthologue of Pcp1/Rbd1 - and in cells from patients carrying homozygous mutations in SPG7 (spastic paraplegia type 7), a gene encoding the matrix-oriented metalloprotease paraplegin. In contrast, OPA1 processing kinetics were delayed upon knock-down of YME1L (human yme1-like protein), an IMS-oriented metal loprotease. OPA1 processing was also stimulated during apoptosis, but inhibition of this processing did not affect apoptotic release of OPA1 and cytochrome c. Finally, we show that all OPA1 isoforms interact with Mfn1 (mitofusin 1) and Mfn2 and that these interactions are not affected by dissipation of Delta Psi m (inner mitochondrial membrane potential) or OPA1 processing. Conclusions. Metalloprotease-mediated processing of OPA1 is modulated by the inner membrane potential and is likely to be mediated by the YME1L protease. C1 [Guillery, Olwenn; Malka, Florence; Lombes, Anne; Rojo, Manuel] INSERM, U582, F-75651 Paris 13, France. [Guillery, Olwenn; Malka, Florence; Lombes, Anne; Rojo, Manuel] UPMC Paris 06, Grp Hosp Pitie Salpetriere, Inst Mycol, F-75651 Paris 13, France. [Landes, Thomas; Guillou, Emmanuelle; Belenguer, Pascale] Univ Toulouse 3, CNRS, LBCMCP, UMR 5088, F-31062 Toulouse, France. [Blackstone, Craig] Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, Bethesda, MD 20892 USA. [Arnoult, Damien] INSERM, U542, F-94807 Villejuif, France. [Arnoult, Damien] Univ Paris Sud, Hop Paul Brousse, F-94807 Villejuif, France. RP Rojo, M (reprint author), Univ Victor Segalen, CNRS, IBGC, Bordeaux, France. EM manuel.rojo@ibgc.u-bordeaux2.fr RI Lombes, Anne/G-4684-2014 FU Intramural NIH HHS NR 31 TC 90 Z9 95 U1 0 U2 10 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD MAY PY 2008 VL 100 IS 5 BP 315 EP 325 DI 10.1042/BC20070110 PG 11 WC Cell Biology SC Cell Biology GA 295AS UT WOS:000255448000005 PM 18076378 ER PT J AU Melman, A Gao, ZG Kumar, D Wan, TC Gizewski, E Auchampach, JA Jacobson, KA AF Melman, Artem Gao, Zhan-Guo Kumar, Deepmala Wan, Tina C. Gizewski, Elizabeth Auchampach, John A. Jacobson, Kenneth A. TI Design of (N)-methanocarba adenosine 5 '-uronamides as species-independent A(3) receptor-selective agonists SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE nucleoside; G protein-coupled receptor; mouse; adenosine receptor; radioligand binding ID HIGHLY POTENT; FUNCTIONALIZED CONGENERS; ADENINE NUCLEOSIDES; HIGH-AFFINITY; DERIVATIVES; ACTIVATION; CELLS; A(1); EFFICACY; ANALOGS AB 2-Chloro-5'-N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo[3.1.0] hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A(3) adenosine receptor ( AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A(1)AR. Therefore, we varied substituents at the N-6 and C2 positions in search of compounds that have improved A(3)AR selectivity and are species independent. An N-6-methyl analogue was balanced in affinity at mouse A(1)/A(3)ARs, with high selectivity in comparison to the A(2A)AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A(3)AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A3AR selectivity more effectively than similar chains attached at the 3-position of the N-6-benzyl group. Published by Elsevier Ltd. C1 [Melman, Artem; Gao, Zhan-Guo; Kumar, Deepmala; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. [Wan, Tina C.; Gizewski, Elizabeth; Auchampach, John A.] Med Coll Wisconsin, Dept Pharmacol, Milwaukee, WI 53226 USA. RP Jacobson, KA (reprint author), NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bldg 8A,Room B1 A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20]; NHLBI NIH HHS [R01 HL077707-04, R01 HL077707] NR 35 TC 30 Z9 31 U1 0 U2 3 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 MAY 1 PY 2008 VL 18 IS 9 BP 2813 EP 2819 DI 10.1016/j.bmcl.2008.04.001 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 294ZH UT WOS:000255444300010 PM 18424135 ER PT J AU Risbood, PA Kane, CT Hossain, MT Vadapalli, S Chadda, SK AF Risbood, Prabhakar A. Kane, Charles T., Jr. Hossain, Md. Tafazzal Vadapalli, Sudhakarrao Chadda, Satish K. TI Synthesis of gemcitabine triphosphate (dFdCTP) as a tris(triethylammonium) salt SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE gemcitabine triphosphate (dFdCTP) AB First synthesis of gemcitabine triphosphate (dFdCTP) as a tris(triethylammonium) salt is reported. Published by Elsevier Ltd. C1 [Risbood, Prabhakar A.] NIH, Drug Synth & Chem Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,Natl Canc Inst, Bethesda, MD 20892 USA. [Kane, Charles T., Jr.; Hossain, Md. Tafazzal; Vadapalli, Sudhakarrao; Chadda, Satish K.] Starks Associates Inc, Buffalo, NY 14213 USA. RP Risbood, PA (reprint author), NIH, Drug Synth & Chem Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis,Natl Canc Inst, Bldg 10, Bethesda, MD 20892 USA. EM risboodp@mail.nih.gov FU NCI NIH HHS [N02 CM52209, N02CM52209, N02-CM-52209] NR 5 TC 12 Z9 12 U1 0 U2 3 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 MAY 1 PY 2008 VL 18 IS 9 BP 2957 EP 2958 DI 10.1016/j.bmcl.2008.03.063 PG 2 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 294ZH UT WOS:000255444300039 PM 18396042 ER PT J AU Balasubramanian, R Raghavan, B Steele, JC Sackett, DL Fecik, RA AF Balasubramanian, Ranganathan Raghavan, Bhooma Steele, Jaeson C. Sackett, Dan L. Fecik, Robert A. TI Tubulysin analogs incorporating desmethyl and dimethyl tubuphenylalanine derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE tubulysin; tubulin; anticancer agents; cytotoxicity; natural products ID BIOLOGICAL-PROPERTIES; MYXOBACTERIA; POLYMERIZATION; TUBULIN AB A series of tubulysin analogs in which one of the stereogenic centers of tubuphenylalanine was eliminated were synthesized. All compounds were tested for antiproliferative activity towards ovarian cancer cells and for inhibition of tubulin polymerization. The dimethyl analogs were generally more active than the desmethyl analogs, and four analogs have tubulin polymerization IC50 values similar to combretastatin A4 and the hemiasterlin analog HTI-286. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Balasubramanian, Ranganathan; Raghavan, Bhooma; Steele, Jaeson C.; Fecik, Robert A.] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA. [Sackett, Dan L.] NIH, Lab Integrat & Med Biophys, Natl Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Fecik, RA (reprint author), Univ Minnesota, Dept Med Chem, 308 Harvad St SE,8-101 weaver Densford Hall, Minneapolis, MN 55455 USA. EM fecik001@umn.edu FU Intramural NIH HHS NR 14 TC 25 Z9 25 U1 0 U2 7 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 MAY 1 PY 2008 VL 18 IS 9 BP 2996 EP 2999 DI 10.1016/j.bmcl.2008.03.046 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 294ZH UT WOS:000255444300047 PM 18411048 ER PT J AU Yogurtcu, ON Erdemli, SB Nussinov, R Turkay, M Keskin, O AF Yogurtcu, Osman N. Erdemli, S. Bora Nussinov, Ruth Turkay, Metin Keskin, Ozlem TI Restricted mobility of conserved residues in protein-protein interfaces in molecular simulations SO BIOPHYSICAL JOURNAL LA English DT Article ID HOT-SPOTS; DYNAMICS; BINDING; RECOGNITION; ENTROPY; DOCKING; IDENTIFICATION; ARCHITECTURE; FLEXIBILITY; NETWORK AB Conserved residues in protein-protein interfaces correlate with residue hot-spots. To obtain insight into their roles, we have studied their mobility. We have performed 39 explicit solvent simulations of 15 complexes and their monomers, with the interfaces varying in size, shape, and function. The dynamic behavior of conserved residues in unbound monomers illustrates significantly lower. exibility as compared to their environment, suggesting that already before binding they are constrained in a boundlike con. guration. To understand this behavior, we have analyzed the inter-and intrachain hydrogen- bond residence-time in the interfaces. We find that conserved residues are not involved significantly in hydrogen bonds across the interface as compared to nonconserved. However, the monomer simulations reveal that conserved residues contribute dominantly to hydrogen- bond formation before binding. Packing of conserved residues across the trajectories is significantly higher before and after the binding, rationalizing their lower mobility. Backbone torsional angle distributions show that conserved residues assume restricted regions of space and the most visited conformations in the bound and unbound trajectories are similar, suggesting that conserved residues are preorganized. Combined with previous studies, we conclude that conserved residues, hot spots, anchor, and interface-buried residues may be similar residues, fulfilling similar roles. C1 [Nussinov, Ruth] Natl Canc Inst, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Tel Aviv, Israel. [Yogurtcu, Osman N.; Erdemli, S. Bora; Turkay, Metin; Keskin, Ozlem] Kochi Univ, Ctr Computat Biol & Bioinformat, Istanbul, Turkey. [Yogurtcu, Osman N.; Erdemli, S. Bora; Turkay, Metin; Keskin, Ozlem] Coll Engn Rumelifeneri Yolu, Istanbul, Turkey. RP Nussinov, R (reprint author), Natl Canc Inst, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD USA. EM ruthn@ncifcrf.gov RI Turkay, Metin/F-9769-2011 OI Turkay, Metin/0000-0003-4769-6714 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 39 TC 45 Z9 45 U1 0 U2 4 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 1 PY 2008 VL 94 IS 9 BP 3475 EP 3485 DI 10.1529/biophysj.107.114835 PG 11 WC Biophysics SC Biophysics GA 286EW UT WOS:000254829700011 PM 18227135 ER PT J AU Gohon, Y Dahmane, T Ruigrok, RWH Schuck, P Charvolin, D Rappaport, F Timmins, P Engelman, DM Tribet, C Popot, JL Ebel, C AF Gohon, Yann Dahmane, Tassadite Ruigrok, Rob W. H. Schuck, Peter Charvolin, Delphine Rappaport, Fabrice Timmins, Peter Engelman, Donald M. Tribet, Christophe Popot, Jean-Luc Ebel, Christine TI Bacteriorhodopsin/amphipol complexes: Structural and functional properties SO BIOPHYSICAL JOURNAL LA English DT Article ID INTEGRAL MEMBRANE-PROTEINS; PURPLE MEMBRANE; ACETYLCHOLINE-RECEPTOR; ELECTRON-MICROSCOPY; NEUTRON-SCATTERING; SARCOPLASMIC-RETICULUM; AMPHIPATHIC POLYMERS; AMPHIPOL A8-35; DETERGENT; RESOLUTION AB The membrane protein bacteriorhodopsin ( BR) can be kept soluble in its native state for months in the absence of detergent by amphipol (APol) A8-35, an amphiphilic polymer. After an actinic. ash, A8-35-complexed BR undergoes a complete photocycle, with kinetics intermediate between that in detergent solution and that in its native membrane. BR/APol complexes form well defined, globular particles comprising a monomer of BR, a complete set of purple membrane lipids, and, in a peripheral distribution, similar to 2 g APol/g BR, arranged in a compact layer. In the absence of free APol, BR/APol particles can autoassociate into small or large ordered fibrils. C1 [Ebel, Christine] Univ Grenoble 1, F-38027 Grenoble, France. [Ebel, Christine] IBS, CNRS, Mol Biophys Lab, CEA,DSV, F-38027 Grenoble, France. [Gohon, Yann; Dahmane, Tassadite; Popot, Jean-Luc] Univ Paris 07, Inst Biol Phys Chim, F-75005 Paris, France. [Gohon, Yann; Dahmane, Tassadite; Popot, Jean-Luc] CNRS, Lab Phys Chim Mol Membranes Biol, F-75005 Paris, France. [Ruigrok, Rob W. H.] Unit Virus Host Cell Interact, Grenoble, France. [Ebel, Christine] NIH, PBR, DBPS, ORS, Bethesda, MD USA. [Rappaport, Fabrice] CNRS, Paris, France. [Rappaport, Fabrice] Univ Paris 06, Inst Biol Phys Chim, Paris, France. [Timmins, Peter] Inst Max Von Laue Paul Langevin, Large Scale Struct Grp, Grenoble, France. [Engelman, Donald M.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA. [Tribet, Christophe] CNRS, Lab Phys Chim Polymeres & Milieux Disperses, Paris, France. RP Ebel, C (reprint author), IBS, CNRS, Mol Biophys Lab, CEA,DSV, 41 Rue Jules Horowitz, F-38027 Grenoble, France. EM jean-luc.popot@ibpc.fr; christine.ebel@ibs.fr RI TRIBET, christophe/C-2868-2008; OI Schuck, Peter/0000-0002-8859-6966; Rappaport, Fabrice/0000-0001-9377-4934 NR 49 TC 66 Z9 66 U1 4 U2 22 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 1 PY 2008 VL 94 IS 9 BP 3523 EP 3537 DI 10.1529/biophysj.107.121848 PG 15 WC Biophysics SC Biophysics GA 286EW UT WOS:000254829700015 PM 18192360 ER PT J AU Qasba, PK Boeggeman, E Ramakrishnan, B AF Qasba, Pradman K. Boeggeman, Elizabeth Ramakrishnan, Boopathy TI Site-specific linking of biomolecules via glycan residues using Glycosyltransferases SO BIOTECHNOLOGY PROGRESS LA English DT Article; Proceedings Paper CT 234th National Meeting of the American-Chemical-Society CY AUG 19-23, 2007 CL Boston, MA SP Amer Chem Soc ID CANCER THERAPEUTICS; DONOR SPECIFICITY; GLYCOSYLATION; PROTEINS; ANTIBODIES; MUTATION; BETA-1,4-GALACTOSYLTRANSFERASE-I; GALACTOSYLTRANSFERASE; GALACTOSYLATION; IMMUNOGLOBULINS AB The structural information on glycosyltransferases has revealed that the sugar-donor specificity of these enzymes can be broadened to include modified sugars with a chemical handle that can be utilized for conjugation chemistry. Substitution of Tyr289 to Leu in the catalytic pocket of bovine beta-1,4-galactosyltransferase generates a novel glycosyltransferase that can transfer not only Gal but also Ga1NAc or a C. modified galactose that has a chemical handle, from the corresponding UDP-derivatives, to the non-reducing end G1cNAc residue of a glycoconjugate. Similarly, the wild-type polypeptide-N-acetyl-galactosaminyltransferase, which naturally transfers Ga1NAc from UDP-Ga1NAc, can also transfer C2-modified galactose with a chemical handle from its UDP-derivative to the Ser/Thr residue of a polypeptide acceptor substrate that is tagged as a fusion peptide to a non-glycoprotein. The potential of wild-type and mutant glycosyltransferases to produce glycoconjugates carrying sugar moieties with chemical handle makes it possible to conjugate biomolecules with orthogonal reacting groups at specific sites. This methodology assists in the assembly of bio-nanoparticles that are useful for developing targeted drug-delivery systems and contrast agents for magnetic resonance imaging. C1 [Qasba, Pradman K.; Boeggeman, Elizabeth; Ramakrishnan, Boopathy] NCI, Struct Glycobiol Sect, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. [Boeggeman, Elizabeth; Ramakrishnan, Boopathy] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Struct Glycobiol Sect, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU Intramural NIH HHS [Z01 BC009304-12, Z01 BC010742-01]; NCI NIH HHS [N01CO12400, N01-CO-12400] NR 36 TC 13 Z9 13 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD MAY-JUN PY 2008 VL 24 IS 3 BP 520 EP 526 DI 10.1021/bp0704034 PG 7 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 311IG UT WOS:000256593300006 PM 18426242 ER PT J AU Euling, SY Makris, S Sen, B White, L Benson, R Gaido, KW Kim, AS Hester, S Wilson, VS Keshava, C Keshava, N Foster, PM Androulakis, IP Ovacik, M Ierapetritou, MG Gray, LE Thompson, C Chiu, W AF Euling, S. Y. Makris, S. Sen, B. White, L. Benson, R. Gaido, K. W. Kim, A. S. Hester, S. Wilson, V. S. Keshava, C. Keshava, N. Foster, P. M. Androulakis, I. P. Ovacik, M. Ierapetritou, M. G. Gray, L. E., Jr. Thompson, C. Chiu, W. TI An approach to using genomics data in risk assessment: Dibutyl phthalate (DBP) case study SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Euling, S. Y.; Makris, S.; Kim, A. S.; Keshava, C.; Keshava, N.; Thompson, C.; Chiu, W.] US EPA, NCEA, Washington, DC 20460 USA. [Sen, B.; White, L.] US EPA, NCEA, Res Triangle Pk, NC 27711 USA. [Benson, R.] US EPA, Reg 8, Denver, CO USA. [Gaido, K. W.] Hamner Inst, Res Triangle Pk, NC USA. [Hester, S.; Wilson, V. S.; Gray, L. E., Jr.] US EPA, NHEERL, Res Triangle Pk, NC 27711 USA. [Foster, P. M.] NIEHS, Res Triangle Pk, NC 27709 USA. [Androulakis, I. P.; Ovacik, M.; Ierapetritou, M. G.] Rutgers UMDNJ, ebCTC, Piscataway, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2008 VL 82 IS 5 BP 296 EP 296 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 312FR UT WOS:000256655000023 ER PT J AU Von Ehrenstein, OS Mikolajczyk, RT Zhang, J AF Von Ehrenstein, O. S. Mikolajczyk, R. T. Zhang, J. TI Intrauterine growth during different time windows in relation to mental development at 13 months postpartum SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Von Ehrenstein, O. S.; Mikolajczyk, R. T.; Zhang, J.] NICHHD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2008 VL 82 IS 5 BP 302 EP 302 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 312FR UT WOS:000256655000034 ER PT J AU Johnson, K Davis, J Ryan, L Moser, G AF Johnson, K. Davis, J. Ryan, L. Moser, G. TI Application of micro-computed tomography in rat teratology studies SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Johnson, K.] NIEHS, Res Triangle Pk, NC 27709 USA. [Davis, J.; Moser, G.] Integrated Lab Inc, Durham, NC USA. [Ryan, L.] HistoMax, Durham, NC USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2008 VL 82 IS 5 BP 311 EP 311 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 312FR UT WOS:000256655000052 ER PT J AU Foster, PMD AF Foster, P. M. D. TI Keeping a multi-generation protocol SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Foster, P. M. D.] NIEHS, NTP, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2008 VL 82 IS 5 BP 344 EP 344 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 312FR UT WOS:000256655000107 ER PT J AU Yamada, S Lee, ES Samtani, RR Uwabe, C Shiota, K Anderson, SA Lo, CW AF Yamada, S. Lee, E. S. Samtani, R. R. Uwabe, C. Shiota, K. Anderson, S. A. Lo, C. W. TI A digital Atlas of Human Embryonic Development using episcopic fluorescence image capture SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Meeting Abstract C1 [Yamada, S.; Uwabe, C.; Shiota, K.] Kyoto Univ, Grad Sch Med, Congential Anomaly Res Ctr, Kyoto, Japan. [Yamada, S.; Lee, E. S.; Samtani, R. R.; Lo, C. W.] NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. [Shiota, K.] Kyoto Univ, Grad Sch Med, Dept Anat & Dev Biol, Kyoto, Japan. [Anderson, S. A.] NHLBI, Anim MRI Imaging Core, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD MAY PY 2008 VL 82 IS 5 BP 355 EP 355 PG 1 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 312FR UT WOS:000256655000126 ER PT J AU Calado, RT Young, NS AF Calado, Rodrigo T. Young, Neal S. TI Telomere maintenance and human bone marrow failure SO BLOOD LA English DT Review ID LINKED DYSKERATOSIS-CONGENITA; SHWACHMAN-DIAMOND-SYNDROME; ACQUIRED APLASTIC-ANEMIA; HEMATOPOIETIC STEM-CELLS; BREAST-CANCER CELLS; REVERSE-TRANSCRIPTASE; FANCONI-ANEMIA; IN-VIVO; FUNCTIONAL-CHARACTERIZATION; HEMATOLOGIC DISORDERS AB Acquired and congenital aplastic anemias recently have been linked molecularly and pathophysiologically by abnormal telomere maintenance. Telomeres are repeated nucleotide sequences that cap the ends of chromosomes and protect them from damage. Telomeres are eroded with cell division, but in hematopoietic stem cells, maintenance of their length is mediated by telomerase. Accelerated telomere shortening is virtually universal in dyskeratosis congenita, caused by mutations in genes encoding components of telomerase or telomere-binding protein (TERT, TERC, DKC1, NOP10, or TINF2). About one-third of patients with acquired aplastic anemia also have short telomeres, which in some cases associate with TERT or TERC mutations. These mutations cause low telomerase activity, accelerated telomere shortening, and diminished proliferative capacity of hematopoietic progenitors. As in other genetic diseases, additional environmental, genetic, and epigenetic modifiers must contribute to telomere erosion and ultimately to disease phenotype. Short telomeres also may cause genomic instability and malignant progression in these marrow failure syndromes. Identification of short telomeres has potential clinical implications: it may be useful in dyskeratosis congenita diagnosis, in suggesting mutations in patients with acquired aplastic anemia, and for selection of suitable hematopoietic stem cell family donors for transplantation in telomerase-deficient patients. C1 [Calado, Rodrigo T.; Young, Neal S.] NHLBI, Natl Inst Hlth, Hematol Branch, Bethesda, MD 20892 USA. RP Calado, RT (reprint author), 10 Ctr Dr,Bldg 10-CRC,Rm 3E-5140, Bethesda, MD 20892 USA. EM calador@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU Intramural NIH HHS NR 102 TC 115 Z9 123 U1 2 U2 13 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 MAY 1 PY 2008 VL 111 IS 9 BP 4446 EP 4455 DI 10.1182/blood-2007-08-019729 PG 10 WC Hematology SC Hematology GA 294EO UT WOS:000255387400011 PM 18239083 ER PT J AU Bolinger, B Krebs, P Tian, YH Engeler, D Scandella, E Miller, S Palmer, DC Restifo, NP Clavien, PA Ludewig, B AF Bolinger, Beatrice Krebs, Philippe Tian, Yinghua Engeler, Daniel Scandella, Elke Miller, Simone Palmer, Douglas C. Restifo, Nicholas P. Clavien, Pierre-Alain Ludewig, Burkhard TI Immunologic ignorance of vascular endothelial cells expressing minor histocompatibility antigen SO BLOOD LA English DT Article ID CD8(+) T-CELLS; VERSUS-HOST-DISEASE; CROSS-PRESENTATION; SELF-ANTIGENS; GRAFT-REJECTION; TRANSGENIC MICE; IN-VIVO; TOLERANCE; LYMPHOCYTES; TRANSPLANTATION AB Endothelial cells (ECs) presenting minor histocompatibility antigen (mhAg) are major target cells for alloreactive effector CD8(+) T cells during chronic transplant rejection and graft-versus-host disease (GVHD). The contribution of ECs to T-cell activation, however, is still a controversial issue. In this study, we have assessed the antigen-presenting capacity of ECs in vivo using a transgenic mouse model with beta-galactosidase (beta-gal) expression confined to the vascular endo-thelium (Tie2-LacZ mice). In a GVHD-like setting with adoptive transfer of beta-gal-specific T-cell receptor-transgenic T cells, beta-gal expression by ECs was not sufficient to either activate or tolerize CD8(+) T cells. Likewise, transplantation of fully vascularized heart or liver grafts from Tie2-LacZ mice into nontransgenic recipients did not suffice to activate beta-gal-specific CD8+ T cells, indicating that CD8+ T-cell responses against mhAg cannot be initiated by ECs. Moreover, we could show that spontaneous activation of beta-gal-specific CD8+ T cells in Tie2-LacZ mice was exclusively dependent on CD11c(+) dendritic cells (DCs), demonstrating that mhAgs presented by ECs remain immunologically ignored unless presentation by DCs is granted. C1 [Bolinger, Beatrice; Krebs, Philippe; Engeler, Daniel; Scandella, Elke; Miller, Simone; Ludewig, Burkhard] Kantonal Hosp, Res Dept, CH-9007 St Gallen, Switzerland. [Tian, Yinghua; Clavien, Pierre-Alain] Univ Zurich Hosp, Dept Visceral Surg, CH-8091 Zurich, Switzerland. [Palmer, Douglas C.; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. RP Ludewig, B (reprint author), Kantonal Hosp, Res Dept, CH-9007 St Gallen, Switzerland. EM burkhard.ludewiu@kssu.ch RI Palmer, Douglas/B-9454-2008; Restifo, Nicholas/A-5713-2008; Krebs, Philippe/A-3449-2012; OI Palmer, Douglas/0000-0001-5018-5734; Krebs, Philippe/0000-0003-4918-6654; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 49 TC 12 Z9 12 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 MAY 1 PY 2008 VL 111 IS 9 BP 4588 EP 4595 DI 10.1182/blood-2007-09-114769 PG 8 WC Hematology SC Hematology GA 294EO UT WOS:000255387400027 PM 18195091 ER PT J AU Rosinski, KV Fujii, N Mito, JK Koo, KKW Xuereb, SM Sala-Torra, O Gibbs, JS Radich, JP Akatsuka, Y Van den Eynde, BJ Riddell, SR Warren, EH AF Rosinski, Kellie V. Fujii, Nobuharu Mito, Jeffrey K. Koo, Kevin K. W. Xuereb, Suzanne M. Sala-Torra, Olga Gibbs, James S. Radich, Jerald P. Akatsuka, Yoshiki Van den Eynde, Benoit J. Riddell, Stanley R. Warren, Edus H. TI DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells SO BLOOD LA English DT Article ID MINOR HISTOCOMPATIBILITY ANTIGEN; VERSUS-HOST-DISEASE; T-CELLS; TRANSPLANTATION ANTIGEN; GRAFT-REJECTION; FEMALE DONORS; GENE CODES; B-CELL; CHROMOSOME; IDENTIFICATION AB The Y chromosome encodes male-specific minor histocompatibility (H-Y) antigens that stimulate T- and B-lymphocyte responses after sex-mismatched allogeneic hematopoietic cell transplantation (HCT). A CD8(+) cytotoxic T lymphocyte (CTL) clone that recognizes a novel HLA-B*2705-restricted H-Y antigen encoded by the DDX3Y gene was isolated from a male who had received a hematopoietic cell graft from his human leukocyte antigen (HLA)-identical sister. The antigenic peptide is a decamer that differs from the homologous DDX3X-encoded peptide at 4 positions. Expression of DDX3Y and of the H-Y epitope that it encodes was examined by quantitative polymerase chain reaction (PCR) and by CTL recognition assays. Expression of DDX3Y is detected in all myeloid and lymphoid leukemic cells that carry an intact Y chromosome. Moreover, the DDX3Y-encoded H-Y epitope is presented on the surface of both myeloid and lymphoid leukemic cells from male HLA-B*2705(+) patients. DDX3Y-specific CTLs prevent engraftment of human acute leukemia in nonobese diabetic/severe combined immune deficient mice, demonstrating that the DDX3Y-encoded H-Y antigen is also expressed in leukemic stem cells. These results demonstrate that CD8+ T-cell responses against DDX3Y have the potential to contribute to graft-versus-leukemia (GVL) activity after female into male allogeneic HCT. This study is registered at http://clinicaltrials.gov as NCT00107354. C1 [Rosinski, Kellie V.; Fujii, Nobuharu; Mito, Jeffrey K.; Koo, Kevin K. W.; Xuereb, Suzanne M.; Sala-Torra, Olga; Radich, Jerald P.; Riddell, Stanley R.; Warren, Edus H.] Fred Hutchinson Canc Res Ctr, Program Immunol, Div Clin Res, Seattle, WA 98109 USA. [Gibbs, James S.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. [Radich, Jerald P.; Riddell, Stanley R.; Warren, Edus H.] Univ Washington, Dept Med, Seattle, WA USA. [Akatsuka, Yoshiki] Aichi Canc Ctr, Res Inst, Div Immunol, Nagoya, Aichi 464, Japan. [Van den Eynde, Benoit J.] Ludwig Inst Canc Res, Brussels, Belgium. [Van den Eynde, Benoit J.] Univ Catholique Louvain, Inst Cellular Pathol, Cellular Genet Unit, B-1200 Brussels, Belgium. RP Warren, EH (reprint author), Fred Hutchinson Canc Res Ctr, Program Immunol, Div Clin Res, Seattle, WA 98109 USA. EM ehwarren@u.washington.edu OI Warren, Edus/0000-0002-9570-2755 FU NCI NIH HHS [R01 CA106512, CA106512, CA18029, P01 CA018029]; NIDDK NIH HHS [DK56465, P30 DK056465] NR 50 TC 33 Z9 39 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2008 VL 111 IS 9 BP 4817 EP 4826 DI 10.1182/blood-2007-06-096313 PG 10 WC Hematology SC Hematology GA 294EO UT WOS:000255387400054 PM 18299450 ER PT J AU Rosu-Myles, M Wolff, L AF Rosu-Myles, Michael Wolff, Linda TI p15Ink4b: Dual function in myelopoiesis and inactivation in myeloid disease SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article; Proceedings Paper CT 7th International Workshop on Molecular Aspects of Myeloid Stem Cell Development and Leukemia CY MAY 13-16, 2007 CL Annapolis, MD DE p15Ink4b; myeloid progenitors; AML; MDS; gene silencing ID CELL-CYCLE CONTROL; PROGENITOR CELLS; P15(INK4B) GENE; POOR-PROGNOSIS; MYELODYSPLASTIC SYNDROMES; RETINOBLASTOMA PROTEIN; MYELOBLASTIC-LEUKEMIA; IN-VIVO; METHYLATION; EXPRESSION AB p15Ink4b (p15) is a cyclin-dependent kinase inhibitor (CDKI) that is known for arresting the cell cycle in early G1 phase by inhibiting the activation of cyclin dependent kinases 4 and 6. Loss of p 15 expression has been associated with several cancer types but its silencing is frequent in acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS). Several mechanisms have been identified that are responsible for silencing the gene encoding p15 in myeloid disease, including gene hypermethylation, transcription factor deregulation and direct inhibition by translocation products. The effect of p15 loss during disease may be attributed to the dual role of this protein as a mediator of cell cycle arrest in late stage myeloid progenitors and as a regulator of differentiation in early common myeloid progenitors (CMP). Here we outline the mechanisms by which p15 is silenced and the functions of this CDKI in myelopoiesis as well as discuss the implications of these findings to myeloid disease. Published by Elsevier Inc. C1 [Rosu-Myles, Michael; Wolff, Linda] NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wolff, L (reprint author), NCI, NIH, Ctr Canc Res, Bldg 37,Room 4124A,37 Convent Dr MSC 4263, Bethesda, MD 20892 USA. EM lwolff@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 15 Z9 19 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAY-JUN PY 2008 VL 40 IS 3 BP 406 EP 409 DI 10.1016/j.bcmd.2007.09.005 PG 4 WC Hematology SC Hematology GA 293EH UT WOS:000255317500019 PM 18029205 ER PT J AU Brown, EE Zhang, MD Zarin-Pass, R Bernig, T Tseng, FC Xiao, NQ Yeager, M Edlin, BR Chanock, SJ O'Brien, TR AF Brown, Elizabeth E. Zhang, Mingdong Zarin-Pass, Rebecca Bernig, Toralf Tseng, Fan-Chen Xiao, Nianqing Yeager, Meredith Edlin, Brian R. Chanock, Stephen J. O'Brien, Thomas R. TI MBL2 and hepatitis C virus infection among injection drug users SO BMC INFECTIOUS DISEASES LA English DT Article ID MANNOSE-BINDING LECTIN; GENETIC-VARIATION; PROTEIN; SUSCEPTIBILITY; VARIANTS; REVEALS; HOST AB Background: Genetic variations in MBL2 that reduce circulating levels and alter functional properties of the mannose binding lectin (MBL) have been associated with many autoimmune and infectious diseases. We examined whether MBL2 variants influence the outcome of hepatitis C virus (HCV) infection. Methods: Participants were enrolled in the Urban Health Study of San Francisco Bay area injection drug users (IDU) during 1998 through 2000. Study subjects who had a positive test for HCV antibody were eligible for the current study. Participants who were positive for HCV RNA were frequency matched to those who were negative for HCV RNA on the basis of ethnicity and duration of IDU. Genotyping was performed for 15 single nucleotide polymorphisms in MBL2. Statistical analyses of European American and African American participants were conducted separately. Results: The analysis included 198 study subjects who were positive for HCV antibody, but negative for HCV RNA, and 654 IDUs who were positive for both antibody and virus. There was no significant association between any of the genetic variants that cause MBL deficiency and the presence of HCV RNA. Unexpectedly, the MBL2 - 289X promoter genotype, which causes MBL deficiency, was over-represented among European Americans who were HCV RNA negative (OR = 1.65, 95% CI 1.05-2.58), although not among the African Americans. Conclusion: This study found no association between genetic variants that cause MBL deficiency and the presence of HCV RNA. The observation that MBL2 - 289X was associated with the absence of HCV RNA in European Americans requires validation. C1 [Brown, Elizabeth E.; Zhang, Mingdong; Zarin-Pass, Rebecca; Tseng, Fan-Chen; Chanock, Stephen J.; O'Brien, Thomas R.] NCI, Div Canc Epidemiol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bernig, Toralf; Chanock, Stephen J.] NCI, Canc Res Ctr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Xiao, Nianqing; Yeager, Meredith] NCI, SAIC Frederick Inc, Core Genotyping Facil, Adv Technol Ctr, Gaithersburg, MD USA. [Edlin, Brian R.] Cornell Univ, Weill Med Coll, Ctr Study Hepatitis C, New York, NY 10021 USA. [Edlin, Brian R.] Univ Calif San Francisco, Urban Hlth Study, San Francisco, CA 94143 USA. RP O'Brien, TR (reprint author), NCI, Div Canc Epidemiol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ebrown@ms.soph.uab.edu; mingdong.zhang@fda.hhs.gov; Pass-rzpass@stanford.edu; bernigt@mail.nih.gov; 950119@nhri.org.tw; xiaon@mail.nih.gov; yeagerm@mail.nih.gov; bre2002@med.cornell.edu; chanocks@mail.nih.gov; obrient@exchange.nih.gov RI Tseng, Fan-Chen/D-2097-2010; OI Edlin, Brian/0000-0001-8172-8797 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA009532, R01 DA016159, R01DA16159, R01 DA013245, R01-DA13245, R01-DA09532] NR 27 TC 5 Z9 5 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD MAY 1 PY 2008 VL 8 AR 57 DI 10.1186/1471-2334-8-57 PG 8 WC Infectious Diseases SC Infectious Diseases GA 311LW UT WOS:000256602700001 PM 18452612 ER PT J AU Schmidt, J Barthel, K Wrede, A Salajegheh, M Bahr, M Dalakas, MC AF Schmidt, Jens Barthel, Konstanze Wrede, Arne Salajegheh, Mohammad Baehr, Mathias Dalakas, Marinos C. TI Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle SO BRAIN LA English DT Article DE muscle inflammation; protein aggregation; autoimmunity; beta-amyloid; chemokines and cytokines ID INCLUSION-BODY MYOSITIS; TRANSGENIC MICE; EXPRESSION PROFILE; INTERFERON-GAMMA; A-BETA; MYOPATHIES; PROTEIN; CHEMOKINES; ALPHA; CELLS AB Distinct interrelationships between inflammation and beta-amyloid-associated degeneration, the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis (sIBM), have remained elusive. Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM, polymyositis (PM), dermatomyositis (DM), dystrophic and non-myopathic muscle as controls, and cultured human myotubes. By quantitative PCR, a higher upregulation was noted for the mRNA-expression of CXCL-9, CCL-3, CCL-4, IFN-gamma, TNF-alpha and IL-1 beta in sIBM muscle compared to PM, DM and controls. All inflammatory myopathies displayed overexpression of degeneration-associated markers, yet only in sIBM, expression of the mRNA of amyloid precursor protein (APP) significantly and consistently correlated with inflammation in the muscle and mRNA-levels of chemokines and IFN-gamma. Only in sIBM, immunohistochemical analysis revealed that inflammatory mediators including IL-1 beta co-localized to beta-amyloid depositions within myofibres. In human myotubes, exposure to IL-1 beta caused upregulation of APP with subsequent intracellular aggregation of beta-amyloid. Our data suggest that, in sIBM muscle, production of high amounts of pro-inflammatory mediators specifically induces beta-amyloid-associated degeneration. The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle. C1 [Schmidt, Jens; Barthel, Konstanze; Baehr, Mathias] Univ Gottingen, Dept Neurol, D-37073 Gottingen, Germany. [Schmidt, Jens; Barthel, Konstanze; Baehr, Mathias] Univ Gottingen, Dept Expt & Clin Neuroimmunol, D-37073 Gottingen, Germany. [Dalakas, Marinos C.] Thomas Jefferson Univ, Neuromuscular Div, Philadelphia, PA 19107 USA. [Schmidt, Jens; Salajegheh, Mohammad; Dalakas, Marinos C.] Natl Inst Neurol Disorders & Stroke, Neuromuscular Dis Sect, NIH, Bethesda, MD USA. RP Schmidt, J (reprint author), Univ Gottingen, Dept Neurol, Waldweg 33, D-37073 Gottingen, Germany. EM j.schmidt@gmx.org; marinos.dalakas@jefferson.edu RI Baehr, Mathias/K-2188-2014; Schmidt, Jens/B-5791-2013 FU Intramural NIH HHS NR 41 TC 100 Z9 101 U1 2 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2008 VL 131 BP 1228 EP 1240 DI 10.1093/brain/awn053 PN 5 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 296DN UT WOS:000255523800010 PM 18420712 ER PT J AU Pantazopoulos, H Murray, EA Berretta, S AF Pantazopoulos, Harry Murray, Elisabeth A. Berretta, Sabina TI Total number, distribution, and phenotype of cells expressing chondroitin sulfate proteoglycans in the normal human amygdala SO BRAIN RESEARCH LA English DT Article DE astrocyte; perineuronal net; glial fibrillary acidic protein; dual fluorescence microscopy; postmortem; wisteria floribunda agglutinin ID PARVALBUMIN-CONTAINING NEURONS; BRAIN EXTRACELLULAR-MATRIX; PERINEURONAL NETS; ENTORHINAL CORTEX; NERVOUS-SYSTEM; VISUAL-CORTEX; ADULT-RAT; SYNAPTIC PLASTICITY; REACTIVE ASTROCYTES; NEURITE OUTGROWTH AB Chondroitin sulfate proteoglycans (CSPGs) are a key structural component of the brain extracellular matrix. They are involved in critical neurodevelopmental functions and are one of the main components of pericellular aggregates known as perineuronal nets. As a step toward investigating their functional and pathophysiological roles in the human amygdala, we assessed the pattern of CSPG expression in the normal human amygdala using wisteria floribunda agglutinin (WFA) lectin histochemistry. Total numbers of WFA-labeled elements were measured in the lateral (LN), basal (BN), accessory basal (ABN) and cortical (CO) nuclei of the amygdala from 15 normal adult human subjects. For interspecies qualitative comparison, we also investigated the pattern of WFA labeling in the amygdala of naive rats (n=32) and rhesus monkeys (Macaca mulatta; n=6). In human amygdala, WFA lectin histochemistry resulted in labeling of perineuronal nets and cells with clear glial morphology, while neurons did not show WFA labeling. Total numbers of WFA-labeled glial cells showed high interindividual variability. These cells aggregated in clusters with a consistent between-subjects spatial distribution. In a subset of human subjects (n = 5), dual color fluorescence using an antibody raised against glial fibrillary acidic protein (GFAP) and WFA showed that the majority (93.7%) of WFA-labeled glial cells correspond to astrocytes. In rat and monkey amygdala, WFA histochemistry labeled perineuronal nets, but not glial cells. These results suggest that astrocytes are the main cell type expressing CSPGs in the adult human amygdala. Their highly segregated distribution pattern suggests that these cells serve specialized functions within human amygdalar nuclei. (C) 2008 Elsevier B.V. All rights reserved. C1 [Pantazopoulos, Harry; Berretta, Sabina] McLean Hosp, Translat Neurosci Lab, Belmont, MA 02478 USA. [Murray, Elisabeth A.] NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. [Berretta, Sabina] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Berretta, S (reprint author), McLean Hosp, Translat Neurosci Lab, 115 Mill St, Belmont, MA 02478 USA. EM s.berretta@mclean.harvard.edu RI Pantazopoulos, Harry/M-1435-2016; OI Pantazopoulos, Harry/0000-0002-0540-1589; Murray, Elisabeth/0000-0003-1450-1642 FU NIMH NIH HHS [MH063215, MH066280, R01 MH066280, R01 MH066280-01A2, R01 MH066955, R01 MH066955-01A1, R24 MH068855, R24MH068855] NR 91 TC 18 Z9 18 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 1 PY 2008 VL 1207 BP 84 EP 95 DI 10.1016/j.brainres.2008.02.036 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 299AW UT WOS:000255729200009 PM 18374308 ER PT J AU Samimi, G Colditz, GA Baer, HJ Tamimi, RM AF Samimi, Goli Colditz, Graham A. Baer, Heather J. Tamimi, Rulla M. TI Measures of energy balance and mammographic density in the Nurses' Health Study SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; energy balance; mammographic density; physical activity; body fatness ID BREAST-CANCER RISK; RECREATIONAL PHYSICAL-ACTIVITY; BODY-MASS INDEX; POSTMENOPAUSAL WOMEN; UNITED-STATES; WEIGHT-GAIN; QUANTITATIVE-ANALYSIS; PARENCHYMAL PATTERNS; PREMENOPAUSAL WOMEN; PROSPECTIVE COHORT AB Mammographic density is a strong risk factor for breast cancer; however the mechanism that underlies this association is unclear. We hypothesized that measures of energy balance early in life and in adulthood may be associated with mammographic density. We conducted a cross-sectional analysis of 1,398 women in the Nurses' Health Study to examine associations between physical activity, childhood and current body fatness, weight gain from age 18 years to present and mammographic density. Percent mammographic density was measured from digitized mammograms by a computer-assisted method. Demographic and lifestyle data were obtained from prospectively collected questionnaires. For all analyses, subjects were stratified into three groups: premenopausal women, postmenopausal women not currently taking hormones, and postmenopausal women currently taking hormones. Childhood body fatness was inversely associated with mammographic density. The correlations ranged from -0.15 to -0.19 in the three strata of women (P <= 0.001). The difference in mean percent mammographic density between the leanest and heaviest body types ranged from 6.2 to 9.9%. Similarly, adult body fatness was inversely associated with percent mammographic density. The correlations ranged from -0.41 to -0.48 in the three strata of women (P<0.0001). The difference in mean percent mammographic density between the leanest and heaviest body types ranged from 22.3 to 35.1%. Weight gain from age 18 was also inversely associated with mammographic density. There was no association between recent physical activity and mammographic density. These findings indicate that childhood and adult body fatness and weight change from age 18 are inversely associated with mammographic density. C1 [Samimi, Goli; Baer, Heather J.; Tamimi, Rulla M.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Samimi, Goli; Baer, Heather J.; Tamimi, Rulla M.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Samimi, Goli] NCI, Canc Prevent Fellowship Program, DCP, NIH, Bethesda, MD 20892 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Baer, Heather J.; Tamimi, Rulla M.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Tamimi, RM (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM rulla.tamimi@channing.harvard.edu RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [CA075016, CA087969, CA089393] NR 57 TC 35 Z9 36 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD MAY PY 2008 VL 109 IS 1 BP 113 EP 122 DI 10.1007/s10549-007-9631-7 PG 10 WC Oncology SC Oncology GA 289BW UT WOS:000255031000012 PM 17592770 ER PT J AU Choi, HJ Song, BJ Gong, YD Gwak, WJ Soh, Y AF Choi, H. J. Song, B-J Gong, Y-D Gwak, W. J. Soh, Y. TI Rapid degradation of hypoxia-inducible factor-1 alpha by KRH102053, a new activator of prolyl hydroxylase 2 SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE hypoxia-inducible factor; KRH102053; prolyl hydroxylase; hypoxia; invasion; vascular endothelial growth factor ID HYPOXIA-INDUCIBLE FACTOR; TUMOR-SUPPRESSOR PROTEIN; FACTOR-I; GENE-TRANSCRIPTION; UBIQUITIN LIGASE; HIF; ANGIOGENESIS; LOCALIZATION; CARCINOMA; FACTOR-1 AB Background and purpose: Hypoxia-inducible factor (HIF) is a transcription factor induced by hypoxia and degraded by ubiquitin-dependent proteasomes in normoxic conditions. Under hypoxic conditions, hydroxylation of HIF-1 alpha subunit by prolyl hydroxylase (PHD) is suppressed, thus leading to increased levels of HIF. Although PHD2 plays a key role in regulating the levels of HIF, chemical activators of PHD2 are relatively unknown. The aim of this study was to identify small molecule activators of PHD2 that could be used, eventually, to suppress the level of HIF-1 alpha. Experimental approach: By using the overproduced PHD2 as a target, a molecular library consisting of more than 600 small molecules with a benzopyran structure was screened with an HPLC assay method. Key results: We found a potent activator of PHD2, KRH102053 (2-amino-4-methylsulphanyl-butylic acid-4-methoxy-6-(4-methoxy- benzylamino)-2,2-dimethyl-chroman-3-yl ester). The effects of KRH102053 on controlling HIF were studied in human HOS osteosarcoma, rat PC12 phaeochromocytoma and human HepG2 hepatoma cells. Under our experimental conditions, KRH102053 decreased the protein level of HIF-1 alpha and the mRNA levels of HIF-regulated downstream target genes, such as vascular endothelial growth factor, aldolase A, enolase 1 and monocarboxylate transporter 4. Consistent with these results, KRH102053 also inhibited the rates of HIF-related migration and invasion of HOS cells as well as the degree of tube formation in human umbilical vein endothelium cells. Conclusions and implications: These results suggest that KRH102053 and its structural analogues have the potential for use as therapeutic agents against various diseases associated with HIF. C1 [Choi, H. J.; Soh, Y.] Chonbuk Natl Univ, Dept Dent Pharmacol, Sch Dent, Jeon Ju 561756, South Korea. [Choi, H. J.] Chonbuk Natl Univ, Inst Oral Biosci, Jeon Ju, South Korea. [Song, B-J] NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. [Gong, Y-D] Korea Res Inst Chem Technol, Ctr High Throughput Synth Platform Technol, Taejon 305606, South Korea. [Gwak, W. J.] SK Chem Inc, Life Sci R&D Ctr, Suwon, South Korea. RP Soh, Y (reprint author), Chonbuk Natl Univ, Dept Dent Pharmacol, Sch Dent, Jeon Ju 561756, South Korea. EM ysoh@chonbuk.ac.kr NR 43 TC 29 Z9 32 U1 1 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2008 VL 154 IS 1 BP 114 EP 125 DI 10.1038/bjp.2008.70 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 293ZT UT WOS:000255374600013 PM 18332861 ER PT J AU Thomas, MJ Kalivas, PW Shaham, Y AF Thomas, M. J. Kalivas, P. W. Shaham, Y. TI Neuroplasticity in the mesolimbic dopamine system and cocaine addiction SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE actin cycling; dopamine; extracellular signal-regulated kinase; long-term depression; long-term potentiation; glutamate; psychomotor sensitization; reinstatement; relapse; synaptic plasticity ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS NEURONS; LONG-TERM DEPRESSION; MEDIAL PREFRONTAL CORTEX; PSYCHOMOTOR STIMULANT-DRUGS; GLUTAMATE-RECEPTOR SUBUNITS; ERK SIGNALING PATHWAY; MAP KINASE CASCADE; NEUROTROPHIC FACTOR; BEHAVIORAL SENSITIZATION AB The main characteristics of cocaine addiction are compulsive drug use despite adverse consequences and high rates of relapse during periods of abstinence. A current popular hypothesis is that compulsive cocaine use and cocaine relapse is due to drug-induced neuroadaptations in reward-related learning and memory processes, which cause hypersensitivity to cocaine-associated Here, we review results from studies on the effect of cocaine exposure on selected signalling cascades, growth factors and physiological processes previously implicated in neuroplasticity underlying normal learning and memory. These include the extracellular signal-regulated kinase (ERK) signalling pathway, brain-derived neurotrophic factor (BDNF), glutamate transmission, and synaptic plasticity (primarily in the form of long-term potentiation and depression, LTP and LTD). We also discuss the degree to which these cocaine-induced neuroplasticity changes in the mesolimbic dopamine system mediate cocaine psychomotor sensitization and cocaine-seeking behaviours, as assessed in animal models of drug addiction. Finally, we speculate on how these factors may interact to initiate and sustain cocaine psychomotor sensitization and cocaine seeking. C1 [Thomas, M. J.] Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. [Thomas, M. J.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Kalivas, P. W.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Shaham, Y.] DHHS, NIDA, NIH, IRP,Behav Neurosci Branch, Baltimore, MD USA. RP Thomas, MJ (reprint author), Univ Minnesota, Dept Neurosci, 6-145 Jackson Hall,321 Church St SE, Minneapolis, MN 55455 USA. EM tmhomas@umn.edu RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA003906, DA015369, DA019666, DA03906, DA12513, P50 DA015369, R01 DA012513, R01 DA019666, R37 DA003906] NR 169 TC 238 Z9 244 U1 6 U2 45 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2008 VL 154 IS 2 BP 327 EP 342 DI 10.1038/bjp.2008.77 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 299LA UT WOS:000255755900007 PM 18345022 ER PT J AU Solinas, M Goldberg, SR Piomelli, D AF Solinas, M. Goldberg, S. R. Piomelli, D. TI The endocannabinoid system in brain reward processes SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Review DE addiction; anandamide; 2-arachidonoylglycerol; dopamine; FAAH; cannabinoid receptors; endocannabinoid transport; food; drugs ID CANNABINOID CB1 RECEPTOR; ACID AMIDE HYDROLASE; CONDITIONED PLACE PREFERENCE; VENTRAL TEGMENTAL AREA; INTRACRANIAL SELF-STIMULATION; NUCLEUS-ACCUMBENS SHELL; PREFERRING SP RATS; ETHANOL-SEEKING BEHAVIOR; INDUCED DOPAMINE RELEASE; CENTRAL-NERVOUS-SYSTEM AB Food, drugs and brain stimulation can serve as strong rewarding stimuli and are all believed to activate common brain circuits that evolved in mammals to favour fitness and survival. For decades, endogenous dopaminergic and opioid systems have been considered the most important systems in mediating brain reward processes. Recent evidence suggests that the endogenous cannabinoid (endocannabinoid) system also has an important role in signalling of rewarding events. First, CB(1) receptors are found in brain areas involved in reward processes, such as the dopaminergic mesolimbic system. Second, activation of CB(1) receptors by plant-derived, synthetic or endogenous CB(1) receptor agonists stimulates dopaminergic neurotransmission, produces rewarding effects and increases rewarding effects of abused drugs and food. Third, pharmacological or genetic blockade of CB(1) receptors prevents activation of dopaminergic neurotransmission by several addictive drugs and reduces rewarding effects of food and these drugs. Fourth, brain levels of the endocannabinoids anandamide and 2-arachidonoylglycerol are altered by activation of reward processes. However, the intrinsic activity of the endocannabinoid system does not appear to play a facilitatory role in brain stimulation reward and some evidence suggests it may even oppose it. The influence of the endocannabinoid system on brain reward processes may depend on the degree of activation of the different brain areas involved and might represent a mechanism for fine-tuning dopaminergic activity. Although involvement of the various components of the endocannabinoid system may differ depending on the type of rewarding event investigated, this system appears to play a major role in modulating reward processes. C1 [Solinas, M.] Univ Poitiers, Inst Physiol & Biol Cellulaires, CNRS, F-86022 Poitiers, France. [Goldberg, S. R.] Natl Inst Drug Abuse, NIH, Dept Hlth & Human Serv, Behav Neurosci Res Branch,Preclin Pharmacol Sect, Baltimore, MD USA. [Piomelli, D.] Univ Calif Irvine, Ctr Drug Discovery, Dept Pharmacol, Irvine, CA USA. RP Solinas, M (reprint author), Univ Poitiers, Inst Physiol & Biol Cellulaires, CNRS, 40 Ave Recteur Pineau, F-86022 Poitiers, France. EM marcello.solinas@univ-poitiers.fr RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU Intramural NIH HHS; NIDA NIH HHS [DA07318, DA12413, DA14447, F31 DA014447, R01 DA012413, R01 DA012447, T32 DA007318] NR 210 TC 133 Z9 138 U1 4 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2008 VL 154 IS 2 BP 369 EP 383 DI 10.1038/bjp.2008.130 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 299LA UT WOS:000255755900010 PM 18414385 ER PT J AU Nair, SG Golden, SA Shaham, Y AF Nair, S. G. Golden, S. A. Shaham, Y. TI Differential effects of the hypocretin 1 receptor antagonist SB 334867 on high-fat food self-administration and reinstatement of food seeking in rats SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE hypocretin; hypocretin 1 receptor; SB 334867; yohimbine; food priming; self-administration; reinstatement; relapse; orexin ID ANXIOGENIC DRUG YOHIMBINE; DEPRIVATION-INDUCED REINSTATEMENT; STRESS-INDUCED REINSTATEMENT; HYPOTHALAMIC OREXIN NEURONS; CUE-INDUCED REINSTATEMENT; EXCESSIVE SUGAR INTAKE; D1 DOPAMINE-RECEPTORS; COCAINE-SEEKING; ALCOHOL-SEEKING; PALATABLE FOOD AB Background and purpose: Many studies have demonstrated a role of hypocretin 1 (orexin 1) receptors in home-cage food consumption in rodents. However, the role of these receptors in operant food self-administration or relapse to food seeking in animal models is unknown. Experimental approach: In Experiment 1, we trained food-restricted rats (16-20 g per day) to lever press for high-fat (35%) pellets (3-6 h per day, every other day). We then tested the effect of the hypocretin 1 receptor antagonist SB 334867 (10, 20 mg kg(-1), i.p) on pellet self-administration. In Experiment 2, we trained rats to self-administer the food pellets, and following extinction of the food-reinforced responding, we tested the effect of hypocretin 1 (3 and 6 mu g, i.c.v) on reinstatement of food-seeking and the effect of SB 334867 on this reinstatement. In Experiment 3, we tested the effect of SB 334867 on reinstatement induced by non-contingent pellet exposure (pellet-priming) or the pharmacological stressor yohimbine (2 mg kg(-1), i.p). Key results: SB 334867 attenuated high-fat pellet self-administration. In contrast, SB 334867 had no effect on reinstatement of lever presses induced by hypocretin 1, pellet-priming or yohimbine. Conclusions and implications: These data indicate that during dieting, hypocretin 1 receptors contribute to operant high-fat pellet self-administration, but not to relapse to food seeking induced by acute re-exposure to the food itself or by the induction of a stress-like state. C1 [Nair, S. G.; Golden, S. A.; Shaham, Y.] NIDA, NIH, IRP, Behav Neurosci Branch, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, NIH, IRP, Behav Neurosci Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Golden, Sam/0000-0002-2104-2272 FU Intramural NIH HHS NR 66 TC 83 Z9 83 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1188 EI 1476-5381 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD MAY PY 2008 VL 154 IS 2 BP 406 EP 416 DI 10.1038/bjp.2008.3 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 299LA UT WOS:000255755900013 PM 18223663 ER PT J AU Alabran, JL Cheuk, A Liby, K Sporn, M Khan, J Letterio, J Leskov, KS AF Alabran, Jennifer L. Cheuk, Adam Liby, Karen Sporn, Michael Khan, Javed Letterio, John Leskov, Konstantin S. TI Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO SO CANCER BIOLOGY & THERAPY LA English DT Article DE triterpenoid; CDDO; Bax; apoptosis; neuroblastoma ID NITRIC-OXIDE PRODUCTION; ACUTE MYELOGENOUS LEUKEMIA; HIGHLY-ACTIVE INHIBITORS; BREAST-CANCER CELLS; 2-CYANO-3,12-DIOXOOLEANA-1,9-DIEN-28-OIC ACID; 2-CYANO-3,12-DIOXOOLEAN-1,9-DIEN-28-OIC ACID; MOUSE MACROPHAGES; INDUCE APOPTOSIS; MITOCHONDRIAL-MEMBRANE; RECEPTOR-GAMMA AB Synthetic triterpenoids, such as 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its derivatives, are an extremely potent class of new anti-cancer therapeutic agents, characterized by high anti-tumor potency and low toxicity to normal tissues. This report is the first to investigate the effects of C-28 derivatives of CDDO on 22 pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. We determined IC(50)s in the range of 5-170 nM for inhibition of colony formation and DNA synthesis, and 110-630 nM for metabolic cell death and decrease in cell number, using the C-28 CDDO analogs, CDDO methyl ester (CDDO-Me), CDDO imidazolide (CDDO-Im), CDDO ethyl amide (CDDO-EA), CDDO trifluoroethyl amide (CDDO-TFEA), and CDDO diethylamide (CDDO-DE). After treatment of human neuroblastoma cells with CDDO-Me, cell cycle studies show depletion of the S-phase, while apoptosis studies show conformational activation and mitochondrial translocation of Bax protein, as well as activation of caspases-3 and -8. These data demonstrate the potential utility of CDDO analogs as promising novel therapeutic agents for high-risk pediatric solid tumors. C1 [Alabran, Jennifer L.; Letterio, John; Leskov, Konstantin S.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Pediat, Cleveland, OH 44106 USA. [Cheuk, Adam; Khan, Javed] NCI, Pediat Oncol Branch, Oncogenom Sect, NIH, Bethesda, MD 20892 USA. [Liby, Karen; Sporn, Michael] Dartmouth Med Sch, Dept Pharmacol, Hanover, NH USA. RP Leskov, KS (reprint author), Case Western Reserve Univ, Case Comprehens Canc Ctr, Dept Pediat, Wolstein Reserve Bldg,2103 Cornell Ave, Cleveland, OH 44106 USA. EM ksl9@case.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU Intramural NIH HHS [Z01 BC010594-04]; NCI NIH HHS [R01 CA78814, P30 CA023108, R01 CA078814] NR 50 TC 12 Z9 13 U1 1 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAY PY 2008 VL 7 IS 5 BP 709 EP 717 DI 10.4161/cbt.7.5.5713 PG 9 WC Oncology SC Oncology GA 322SC UT WOS:000257394600015 PM 18277094 ER PT J AU Trichopoulos, D Cole, P Cook, EF Feinleib, M Hoover, R Hsieh, CC Hunter, D Monson, R Mueller, N Rahu, M Rimm, E Rothman, K Stampfer, M Weiss, N Willett, W Adami, HO AF Trichopoulos, D. Cole, P. Cook, E. F. Feinleib, M. Hoover, R. Hsieh, C. -C. Hunter, D. Monson, R. Mueller, N. Rahu, M. Rimm, E. Rothman, K. Stampfer, M. Weiss, N. Willett, W. Adami, H. O. TI Brian MacMahon (1923-2007): founder of modern epidemiology SO CANCER CAUSES & CONTROL LA English DT Biographical-Item DE Brian MacMahon; epidemiology; tribute; biography AB Brian MacMahon was born in Sheffield, UK in 1923. He served as chair of the Department of Epidemiology at Harvard School of Public Health for more than 30 years. He was admired as a noble and generous man and respected for his shining intellect, scientific integrity, and broad culture. He set the pace for modern epidemiology and led the way for a whole school of epidemiologists who are now spread around the nation and the world. He made major scientific contributions, received several distinguished prizes and awards, and continued to publish insightful papers until the very end. Brian MacMahon was the first editor-in-chief of Cancer Causes and Control. C1 [Trichopoulos, D.; Cook, E. F.; Hsieh, C. -C.; Hunter, D.; Monson, R.; Mueller, N.; Rimm, E.; Stampfer, M.; Willett, W.; Adami, H. O.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Cole, P.] Univ Alabama, Sch Publ Hlth, Birmingham, AL 35294 USA. [Feinleib, M.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Hoover, R.] NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Rahu, M.] Natl Inst Hlth Dev, Tallinn, Estonia. [Rothman, K.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Weiss, N.] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. RP Trichopoulos, D (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM dtrichop@hsph.harvard.edu RI Rahu, Mati/A-9981-2008; OI Rothman, Kenneth/0000-0003-2398-1705 NR 1 TC 0 Z9 0 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2008 VL 19 IS 4 BP 329 EP 337 DI 10.1007/s10552-008-9156-3 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 289YP UT WOS:000255090100001 PM 18415024 ER PT J AU Weissman, AM AF Weissman, Allan M. TI How much REST is enough? SO CANCER CELL LA English DT Editorial Material ID BETA-TRCP; DEGRADATION; CANCER; CDC25A; GENES AB Recent papers published in Nature by Guardavaccaro et al. and Westbrook et al. describe a nexus of two masters of negative regulation of protein levels. Both of these studies establish that the transcriptional repressor REST/NRSF is regulated by the highly versatile ubiquitin protein ligase (E3) SCF beta-TrCP, adding a new dimension to the relationship between the ubiquitin-proteasome system and epigenetic regulation of transcription. These studies elucidate a critical means of regulation for REST, with implications for neuronal stem cell differentiation and the dual roles of this protein as a tumor suppressor and oncogene. These findings and their significance are discussed herein. C1 NCI, Lab Protein Dynam & Signaling, Ctr Canc Res, Frederick, MD 20712 USA. RP Weissman, AM (reprint author), NCI, Lab Protein Dynam & Signaling, Ctr Canc Res, Frederick, MD 20712 USA. EM amw@nih.gov NR 12 TC 23 Z9 24 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAY PY 2008 VL 13 IS 5 BP 381 EP 383 DI 10.1016/j.ccr.2008.04.011 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 296TP UT WOS:000255569000004 PM 18455121 ER PT J AU Lee, KM Kang, D Clapper, ML Ingelman-Sundberg, M Ono-Kihara, M Kiyohara, C Min, S Lan, Q Le Marchand, L Lin, PP Lung, ML Pinarbasi, H Pisani, P Srivatanakul, P Seow, A Sugimura, H Tokudome, S Yokota, J Taioli, E AF Lee, Kyoung-Mu Kang, Daehee Clapper, Margie L. Ingelman-Sundberg, Magnus Ono-Kihara, Masko Kiyohara, Chikako Min, Shen Lan, Qing Le Marchand, Loic Lin, Pinpin Lung, Maria Li Pinarbasi, Hatice Pisani, Paola Srivatanakul, Petcharin Seow, Adeline Sugimura, Haruhiko Tokudome, Shinkan Yokota, Jun Taioli, Emanuela TI CYP1A1, GSTM1, and GSTT1 polymorphisms, smoking, and lung cancer risk in a pooled analysis among Asian populations SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ARYL-HYDROCARBON HYDROXYLASE; ADENOCARCINOMA SUSCEPTIBILITY; GENETIC SUSCEPTIBILITY; JAPANESE POPULATION; DNA-ADDUCTS; ASSOCIATION; GENOTYPES; METAANALYSIS; CARCINOGENS; EXPRESSION AB evaluate the roles of CYP1A1 polymorphisms [Ile (462)Val and (TC)-C-6235 (MspI)] and deletion of GSTM1 and and GSTT1 in lung cancer development in Asian populations, a pooled analysis was conducted on 13 existing studies included in Genetic Susceptibility to Environmental Carcinogenesis database. This pooled analysis included 1,971 cases and 2,130 controls. Lung cancer risk was estimated as odds ratios (OR) and 95% confidence intervals (95% CD using unconditional logistic regression model adjusting for age, sex, and pack-year. The CYP1A1 C-6235 variant was associated with squamous cell lung cancer (TC versus TT: OR, 1.42; 95% CI, 0.96-2.09; CC versus TT: OR, 1.97; 95% CI, 1.26-3.07; P-trend = 0.003). In haplotype analysis, (462)Val-T-6235 and Ile-C haplotypes were associated with lung cancer risk with reference to the Ile-T haplotype (OR, 3.41; 95% CI, 1.78-6.53 and OR, 1.39; 95% CI, 1.12-1.71, respectively). The GSTM1-null genotype increased squamous cell lung cancer risk (OR, 1.36; 95% CI, 1.05-1.77). When the interaction was evaluated with smoking, increasing trend of lung cancer risk as pack-year increased was stronger among those with the CYP1A1 6235 TC/CC genotype compared with those with IT genotype (P-interaction = 0.001) and with the GSTM1-null genotype compared with the present type (Pinteraction 0.08, when no genotype effect with no exposure was assumed). These results suggest that genetic polymorphisms in CYP1A1 and GSTM1 are associated with lung cancer risk in Asian populations. However, further investigation is warranted considering the relatively small sample size when subgroup analyses were done and the lack of environmental exposure data other than smoking. C1 [Lee, Kyoung-Mu; Kang, Daehee] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea. [Clapper, Margie L.] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Ingelman-Sundberg, Magnus] Karolinska Inst, Dept Physiol Chem, S-10401 Stockholm, Sweden. [Ono-Kihara, Masko] Kyoto Univ, Dept Global Hlth & Socioepidemiol, Sch Publ Hlth, Kyoto, Japan. [Kiyohara, Chikako] Kyushu Univ, Grad Sch Med Sci, Fukuoka 812, Japan. [Lee, Kyoung-Mu; Min, Shen; Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Lin, Pinpin] Natl Hlth Res Inst, Zhunan, Taiwan. [Lung, Maria Li] Hong Kong Univ Sci & Technol, Dept Biol, Kowloon, Hong Kong, Peoples R China. [Lung, Maria Li] Hong Kong Univ Sci & Technol, Ctr Canc Res, Kowloon, Hong Kong, Peoples R China. [Pinarbasi, Hatice] Cumhuriyet Univ, Dept Biochem, Fac Med, Sivas, Turkey. [Pisani, Paola] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Srivatanakul, Petcharin] Natl Canc Inst, Canc Control Unit, Bangkok, Thailand. [Seow, Adeline] Natl Univ Singapore, Dept Community Occupat & Family Med, Singapore 117548, Singapore. [Sugimura, Haruhiko] Hamamatsu Univ Sch Med, Dept Pathol, Shizuoka, Japan. [Tokudome, Shinkan] Nagoya City Univ, Dept Hlth Promot & Prevent Med, Grad Sch Med Sci, Nagoya, Aichi, Japan. [Yokota, Jun] Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan. [Taioli, Emanuela] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. RP Kang, D (reprint author), Seoul Natl Univ, Coll Med, Dept Prevent Med, 28 Yongon Dong, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Kang, Dae Hee/E-8631-2012; Lin, Pinpin/B-2668-2010 FU NCI NIH HHS [P30CA047904-19S1, 2P50CA090440-06] NR 43 TC 40 Z9 47 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1120 EP 1126 DI 10.1158/1055-9965.EPI-07-2786 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800016 PM 18463401 ER PT J AU Peters, U Chatterjee, N Hayes, RB Schoen, RE Wang, YH Chanock, SJ Foster, CB AF Peters, Ulrike Chatterjee, Nilanjan Hayes, Richard B. Schoen, Robert E. Wang, Yinghui Chanock, Stephen J. Foster, Charles B. TI Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HYDROPEROXIDE GLUTATHIONE-PEROXIDASE; HUMAN SELENOPROTEIN-P; PLASMA SELENIUM CONCENTRATION; THIOREDOXIN REDUCTASE; BREAST-CANCER; COLON-CANCER; GI-GPX; EXTRACELLULAR-SUPEROXIDE; HYDROGEN-PEROXIDE; OXIDATIVE DAMAGE AB Background: Epidemiologic and animal studies provide evidence for a chemopreventive effect of selenium on colorectal cancer, which may be mediated by the antioxidative and anti-inflammatory properties of selenoenzymes. We therefore investigated whether genetic variants in selenoenzymes abundantly expressed in the colon are associated with advanced colorectal adenoma, a cancer precursor. Methods: Cases with a left-sided advanced adenoma (n = 772) and matched controls (n = 777) screen negative for polyps based on sigmoidoscopy examination were randomly selected from participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The underlying genetic variation was determined by resequencing. We genotyped 44 tagging single nucleotide polymorphisms (SNP) in six genes [glutathione peroxidase 1-4 (GPX1, GPX2, GPX3, and GPX4), selenoprotein P (SEPP1), and thioredoxin reductase 1 (TXNRD1)] to efficiently predict common variation across these genes. Results: Four variants in SEPP1 were significantly associated with advanced adenoma risk. A rare variant in the 5' region of SEPP1 (-4166C>G) was present in nine cases but in none of the controls (exact P = 0.002). Three SNPs located in the 3' region of SEPP1, which is overlapping with the promoter region of an antisense transcript, were significantly associated with adenoma risk: homozygotes at two SEPP1 loci (31,174 bp 3' of STP A>G and 43,881 bp 3' of STP G>A) were associated with increased adenoma risk [odds ratio (OR), 1.48; 95% confidence interval (95% CI), 1.00-2.19 and OR, 1.53; 95% CI, 1.05-2.22, respectively] and the variant SEPP1 44,321 bp 3' of STP C>T was associated with a reduced adenoma risk (CT versus CC OR, 0.85; 95% CI, 0.63-1.15). Furthermore, we observed a significant 80% reduction for advanced colorectal adenoma risk for carriers of the variant allele at TXNRD1 IVS1-181C>G (OR, 0.20; 95% CI, 0.07-0.55; P-trend = 0.004). Consistent with the individual SNP results, we observed a significant overall association with adenoma risk for SEPP1 and TXNRD1 (global P = 0.02 and 0.008, respectively) but not for the four GPX genes. Conclusion: Our study suggests that genetic variants at or near the SEPP1 and TXNRD1 loci may be associated with advanced colorectal adenoma. As this is the first study to comprehensively investigate this hypothesis, confirmation in independent study populations is needed. C1 [Peters, Ulrike; Wang, Yinghui] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Peters, Ulrike] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Chatterjee, Nilanjan; Hayes, Richard B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Schoen, Robert E.] Univ Pittsburgh, Pittsburgh, PA USA. [Chanock, Stephen J.] NCI, Core Genotype Facil, NIH, Dept Hlth & Human Serv, Gaithersburg, MD USA. [Foster, Charles B.] Cleveland Clin, Div Pediat, Cleveland, OH 44106 USA. RP Peters, U (reprint author), Fred Hutchinson Canc Res Ctr, POB 19024,1100 Fairview Ave N,M4-B402, Seattle, WA 98109 USA. EM upeters@fhcre.org OI Hayes, Richard/0000-0002-0918-661X NR 77 TC 63 Z9 69 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1144 EP 1154 DI 10.1158/1055-9965.EPI-07-2947 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800019 PM 18483336 ER PT J AU de Martel, C Llosa, AE Friedmana, GD Vogelman, JH Orentreich, N Stolzenberg-Solomon, RZ Parsonnet, J AF de Martel, Catherine Llosa, Augusto E. Friedmana, Gary D. Vogelman, Joseph H. Orentreich, Norman Stolzenberg-Solomon, Rachael Z. Parsonnet, Julie TI Helicobacter pylori infection and development of pancreatic cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PHYSICAL-ACTIVITY; RISK; OBESITY; ADENOCARCINOMA; METAANALYSIS AB Background: Infection with Helicobacter pylori is an established risk factor for gastric cancer. Results from two studies suggest that it may also be a risk factor for pancreatic cancer. Methods: We conducted a nested case control study among 128,992 adult subscribers to the Kaiser Permanente Medical Care Program who had been enrolled in a multiphasic health checkup from 1964 to 1969. Serum collected during the checkup was maintained frozen, and subjects were followed for cancer. Cases consisted of 104 randomly selected subjects among 507 who developed pancreatic cancer in the cohort. Controls consisted of 262 pancreatic cancer-free subjects from a pool of 730 controls previously tested for studies conducted on this cohort. Controls were individually matched to cases on age, gender, race, site, and date of multiphasic health checkup. Control sera were compared with cases for antibodies to H. pylori and the CagA protein. The effects of smoking, alcohol consumption, obesity, and years of education were also investigated. Results: Neither H. pylori [odds ratio (OR), 0.85; 95% confidence interval (95% CI), 0.49-1.48] nor its CagA protein (OR, 0.96; 95% CI, 0.48-1.92) was associated with subsequent development of pancreatic cancer. Smoking (OR, 2.09; 95% CI, 1.17-3.74) and greater number of years of education (OR, 2.13; 95% CI, 1.23-3.69) were risk factors for pancreatic cancer, whereas alcohol consumption and obesity were not. Conclusion: Our results suggest that H. pylori infection is not associated with development of pancreatic cancer. C1 [de Martel, Catherine; Llosa, Augusto E.; Parsonnet, Julie] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [de Martel, Catherine; Parsonnet, Julie] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. [Friedmana, Gary D.] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. [Vogelman, Joseph H.; Orentreich, Norman] Orentreich Fdn Advancement Sci Inc, Cold Spring Harbor, NY USA. [Stolzenberg-Solomon, Rachael Z.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Stolzenberg-Solomon, Rachael Z.] NCI, Genet & Canc Prevent Studies Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP de Martel, C (reprint author), Stanford Univ, Sch Med, Dept Hlth Res & Policy, 300 Pasteur Rd, Stanford, CA 94305 USA. EM prosper@stanford.edu RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 NR 29 TC 40 Z9 40 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1188 EP 1194 DI 10.1158/1055-9965.EPI-08-0185 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800024 PM 18483341 ER PT J AU Salinas, CA Kwon, E Carlson, CS Koopmeiners, JS Feng, Z Karyadi, DM Ostrander, EA Stanford, JL AF Salinas, Claudia A. Kwon, Erika Carlson, Christopher S. Koopmeiners, Joseph S. Feng, Ziding Karyadi, Danielle M. Ostrander, Elaine A. Stanford, Janet L. TI Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID AFRICAN-AMERICAN MEN; CHROMOSOME 8Q24; BREAST-CANCER; LOCUS; PATHOPHYSIOLOGY; AMPLIFICATION; EPIDEMIOLOGY; CONFIRMATION; METAANALYSIS; EXPRESSION AB Recently, the 8q24 region has been identified as a prostate cancer susceptibility locus in a genome-wide scan of prostate cancer families in Iceland and an admixture scan of African Americans. Further investigations of variants at 8q24 have shown the existence of additional single nucleotide polymorphisms (SNPs) that enhance prostate cancer risk, suggesting the possibility of multiple regions harboring variants for the disease. In the present population-based study of Caucasians (1,308 cases and 1,266 controls) and African Americans (149 cases and 85 controls), we tested the association between prostate cancer and 23 SNPs in the 8q24 region. Fourteen SNPs in Caucasians and 5 SNPs in African Americans were significantly associated with risk of prostate cancer after adjusting for multiple comparisons; of these, 5 SNPs in Caucasians and 3 in African Americans were independently associated with risk. The strongest association was for rs6983561 (carriers of any C allele) with an odds ratio of 1.6 (95% confidence interval, 1.1-2.1) in Caucasians; variants in rs979200, rs1016343, rs7837328, and rs10090154 were also independently associated with risk. In African Americans, the strongest association was for rs7000448 (carriers of any T allele) with an odds ratio of 3.4 (95% confidence interval, 1.3-8.7). In addition, two SNPs that extend the boundaries of the 8q24 region were significantly associated with risk: rs979200 at the centromeric boundary and rs3891248, located in the first intron of the c-MYC gene (IVS1-355), which identifies a new telomeric boundary. C1 [Salinas, Claudia A.; Carlson, Christopher S.; Koopmeiners, Joseph S.; Feng, Ziding; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Salinas, Claudia A.; Stanford, Janet L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Koopmeiners, Joseph S.] Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. [Kwon, Erika; Karyadi, Danielle M.; Ostrander, Elaine A.] NHGRI, Canc Gene Branch, NIH, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, M4-B874,POB 19024, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU NCI NIH HHS [CA56678, CA92579, CA97189, N01-PC-35142] NR 36 TC 43 Z9 45 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1203 EP 1213 DI 10.1158/1055-9965.EPI-07-2811 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800026 PM 18483343 ER PT J AU Koebnick, C Michaud, D Moore, SC Park, Y Hollenbeck, A Ballard-Barbash, R Schatzkin, A Leitzmann, MF AF Koebnick, Corinna Michaud, Dominique Moore, Steven C. Park, Yikyung Hollenbeck, Albert Ballard-Barbash, Rachel Schatzkin, Arthur Leitzmann, Michael F. TI Body mass index, physical activity, and bladder cancer in a large prospective study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GROWTH-FACTOR-I; URINARY-BLADDER; PLASMA-LEVELS; RISK-FACTORS; LARGE COHORT; OBESITY; MORTALITY; WOMEN; MEN; ASSOCIATION AB Increased body size and lack of physical activity are associated with increased risk of several cancers, but the relations of body mass index (BMI) and physical activity to bladder cancer are poorly understood. We investigated the associations between BMI, physical activity, and bladder cancer in the NIH-AARP Diet and Health Study, a prospective cohort of 471,760 U.S. men and women, followed from 1995 to 2003. During 3,404,642 person-years of follow-up, we documented 1,719 incident cases of bladder cancer. Compared with normal weight, obesity was associated with an up to 28% increased risk for bladder cancer. The multivariate relative risks of bladder cancer for BMI values of 18.5 to 24.9 (reference), 25.0 to 29.9. 30.0 to 34.9. and >= 35 kg/m(2) were 1.0, 1.15, 1.22, and 1.28 (95% confidence interval, 1.02-1.61; P-trend = 0.028). The association between BMI and bladder cancer was consistent among subgroups defined by gender, education, smoking status, and other potential effect modifiers. In contrast, physical activity showed no statistically significant relation with bladder cancer. After multivariate adjustment, including BMI, the relative risks of bladder cancer for increasing frequency of physical activity [0 (reference), < 1, 1-2, 3-4, and >= 5 times a week] were 1.0, 0.85, 0.89, 0.91, and 0.87 (95% confidence interval, 0.74-1.02; P-trend = 0.358), respectively. In conclusion, these findings provide support for a modest adverse effect of adiposity on risk for bladder cancer. In contrast, our results do not suggest a relation between physical activity and bladder cancer. C1 [Koebnick, Corinna; Moore, Steven C.; Park, Yikyung; Schatzkin, Arthur; Leitzmann, Michael F.] Natl Canc Inst, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Ballard-Barbash, Rachel] Natl Canc Inst, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Koebnick, Corinna] Kaiser Permanente So Cali, Dept Res & Evaluat, Pasadena, CA USA. [Michaud, Dominique] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. RP Leitzmann, MF (reprint author), 6120 Execut Blvd, Bethesda, MD 20892 USA. EM leitzmann@mail.nih.gov RI Michaud, Dominique/I-5231-2014; Koebnick, Corinna/P-4767-2016; Moore, Steven/D-8760-2016; OI Koebnick, Corinna/0000-0001-8274-0309; Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS NR 46 TC 50 Z9 52 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1214 EP 1221 DI 10.1158/1055-9965.EPI-08-0026 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800027 PM 18483344 ER PT J AU Gravitt, PE Schiffman, M Solomon, D Wheeler, CM Castle, PE AF Gravitt, Patti E. Schiffman, Mark Solomon, Diane Wheeler, Cosette M. Castle, Philip E. TI A comparison of Linear Array and Hybrid Capture 2 for detection of carcinogenic human papillomavirus and cervical precancer in ASCUS-LSIL triage study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS INTRAEPITHELIAL LESIONS; HYBRID CAPTURE 2; CYTOLOGICALLY NORMAL WOMEN; HIGH-RISK; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; FOLLOW-UP; MANAGEMENT STRATEGIES; UNIVERSITY-STUDENTS; NEOPLASIA GRADE-2 AB Background: We were interested in comparing the performance of Linear Array (LA; Roche Molecular Systems) to Hybrid Capture 2 (hc2; Digene) for the detection of carcinogenic human papillomavirus (HPV) and cervical precancer. Methods: LA and hc2 results were compared on baseline specimens collected from women with an atypical squamous cells of undetermined significance (ASCUS) Pap referred into ASCUS and Low-Grade Squamous Intraepithelial Lesion Triage Study (n=3,488). hc2 was conducted at the time of the study on liquid cytology specimens. LA was conducted retrospectively on aliquots from a second, stored cervical specimen masked to the hc2 results and clinical data. Paired LA and hc2 results (n=3,289; 94%) were compared for the detection of carcinogenic HPV (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and 2-year cumulative cervical intraepithelial neoplasia (CIN) grade : 3 as diagnosed by the quality-control pathology review. Results: LA was more likely to test positive for carcinogenic HPV than hc2 (55% versus 53%; P=0.001). For 2-year cumulative >= CIN3, LA and hc2 had similar sensitivities (93.3% versus 92.6%, respectively; P=1), and LA was marginally less specific than hc2 (48.1% versus 50.6%, respectively; P=0.05). LA and hc2 had similar negative predictive values (98.70% versus 98.64% respectively; P=0.4), and LA had a slightly lower positive predictive value than hc2 (14.6% versus 15.1%, respectively; P < 0.0001). Conclusion: We observed that LA and hc2 performed similarly in the detection of carcinogenic HPV and identification of CIN3 among women with an ASCUS Pap. C1 [Gravitt, Patti E.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Gravitt, Patti E.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Sch Med, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Room 5004,EPS MSC 7234,6120 Execut Blvd, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS [Z01 CP010124-12]; NCI NIH HHS [N01 CN055155, N01 CN055105, N01 CN055153, N01 CN055154, N01 CN055156, N01 CN055157, N01 CN055158, N01 CN055159] NR 47 TC 40 Z9 41 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1248 EP 1254 DI 10.1158/1055-9965.EPI-07-2904 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800032 PM 18483347 ER PT J AU Kamangar, F Schantz, MM Abnet, CC Fagundes, RB Dawsey, SM AF Kamangar, Farin Schantz, Michele M. Abnet, Christian C. Fagundes, Renato B. Dawsey, Sanford M. TI High levels of carcinogenic polycyclic aromatic hydrocarbons in mate drinks SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CELL ESOPHAGEAL CANCER; STANDARD REFERENCE MATERIALS; LUNG-CANCER; HIGH-RISK; AERODIGESTIVE TRACT; SOUTHERN BRAZIL; BLADDER-CANCER; HOT BEVERAGES; URUGUAY; TOBACCO AB Background: Drinking mate has been associated with cancers of the esophagus, oropharynx, larynx, lung, kidney, and bladder. We conducted this study to determine whether drinking mate could lead to substantial exposure to polycyclic aromatic hydrocarbons (PAH), including known carcinogens, such as benzo[a]pyrene. Methods: The concentrations of 21 individual PAHs were measured in dry leaves of eight commercial brands of yerba mate and in infusions made with hot (80 degrees C) or cold (5 degrees C) water. Measurements were done using gas chromatography/mass spectrometry, with deuterated PAHs as the surrogates. Infusions were made by adding water to the leaves, removing the resulting infusion after 5 min, and then adding more water to the remaining leaves. This process was repeated 12 times for each infusion temperature. Results: The total concentrations of the 21 PAHs in different brands of yerba mate ranged from 536 to 2,906 ng/g dry leaves. Benzo[a]pyrene concentrations ranged from 8.03 to 53.3 ng/g dry leaves. For the mate infusions prepared using hot water and brand 1, 37% (1,092 of 2,906 ng) of the total measured PAHs and 50% (25.1 of 50 ng) of the benzo[a]pyrene content were released into the 12 infusions. Similar results were obtained for other hot and cold infusions. Conclusion: Very high concentrations of carcinogenic PAHs were found in yerba mate leaves and in hot and cold mate infusions. Our results support the hypothesis that the carcinogenicity of mate may be related to its PAH content. C1 [Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Schantz, Michele M.] Natl Inst Stand & Technol, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Fagundes, Renato B.] Univ Fed Santa Maria, Dept Clin Med, Ctr Ciencias Saude, BR-97119900 Santa Maria, RS, Brazil. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Suite 320, Rockville, MD 20852 USA. EM kamangaf@mail.nih.gov RI Abnet, Christian/C-4111-2015 OI Abnet, Christian/0000-0002-3008-7843 FU Intramural NIH HHS NR 42 TC 45 Z9 46 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2008 VL 17 IS 5 BP 1262 EP 1268 DI 10.1158/1055-9965.EPI-08-0025 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 303AX UT WOS:000256012800034 PM 18483349 ER PT J AU Potocnik, U Glavac, D Dean, M AF Potocnik, Uros Glavac, Damjan Dean, Michael TI Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID MULTIDRUG-RESISTANCE GENE; PRODUCT P-GLYCOPROTEIN; ULCERATIVE-COLITIS; MDR1 GENE; MULTIDRUG-RESISTANCE-1 GENE; EXPRESSION; CELLS; CARCINOMA; APOPTOSIS; DISEASE AB Altered expression of P-glycoprotein (P-gp) encoded by the multidrug resistance (MDR1/ABCB1) gene, as well as somatic mutations and hypermethylation in the MDR1/ABCB1gene, were identified in a proportion of previously untreated colorectal cancers (CRQ exhibiting high microsatellite instability (MSI-H), which suggested that MDR1/ABCB1acts as a candidate gene contributing to the initiation and progression of MSI-H tumors. Here we report germline functional single nucleotide polymorphisms (SNPs) and haplotypes in the MDR1/ABCB1gene, which could contribute to genetic risk or increase susceptibility to MSI-H cancers. We have confirmed disease association by comparing the MDR1/ABCB1 genotype, allele, and haplotype frequencies between healthy controls and patients with MSI-H tumors. In particular, carriers of the T/T genotype in exon 12 (1236 C --> T) SNP and the T/T genotype in exon 21 (2677G-->T) SNP were most significantly associated with a higher risk for developing MSI-H CRC compared to controls (P=0.01, OR=3.182 and P=0.005, OR=3.594, respectively). The most significant MSI-H-associated risk haplotypes include the most frequent haplotype HI (T-C-T-T) defined by SNPs in exon 12, intron 13 (rs2235035), exon 21, and exon 26 (3435 C-T; P=0.004, OR=0.476). Our results suggest that ABCB1/MDR1 is a novel low-penetrance gene for susceptibility to MSI-H tumors. The present study provides additional evidence for the role that the MDR1/ABCB1 gene plays in the initiation and progression of MSI-H CRC development. (C) 2008 Elsevier Inc. All rights reserved. (C) 2008 Elsevier Inc. All rights reserved. C1 [Potocnik, Uros] Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, SLO-2000 Maribor, Slovenia. [Potocnik, Uros] Univ Maribor, Fac Chem & Chem Engn, Lab Biochem Mol Biol & Gen, SLO-2000 Maribor, Slovenia. [Glavac, Damjan] Univ Ljubljana, Fac Med, Inst Pathol, Mol Genet Lab, Ljubljana 1000, Slovenia. [Dean, Michael] NCI, Lab Gen Divers, Frederick, MD 21702 USA. RP Potocnik, U (reprint author), Univ Maribor, Fac Med, Ctr Human Mol Genet & Pharmacogen, SLO-2000 Maribor, Slovenia. EM uros.potocnik@uni-mb.si RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Potocnik, Uros/0000-0003-1624-9428 NR 27 TC 24 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD MAY PY 2008 VL 183 IS 1 BP 28 EP 34 DI 10.1016/j.cancergencyto.2008.01.023 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 305MX UT WOS:000256183600006 PM 18474294 ER PT J AU Freedman, RS Ma, Q Wang, E Gallardo, ST Gordon, IO Shin, JW Jin, P Stroncek, D Marincola, FM AF Freedman, Ralph S. Ma, Qing Wang, Ena Gallardo, Stacie T. Gordon, Ilyssa O. Shin, Jeong Won Jin, Ping Stroncek, David Marincola, Francesco M. TI Migration deficit in monocyte-macrophages in human ovarian cancer SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; FACTOR-I; CARCINOMA; RECEPTOR; EXPRESSION; CHEMOKINES; CELLS; IDENTIFICATION; INFLAMMATION; PERITONEUM AB Purpose To examine the migration responses of monocyte/macrophages (MO/MA) expressing complementary receptors to chemokines produced in the tumor environment of epithelial ovarian cancer (EOC). Methods We examined the expression of the chemokine receptors, CCR1, CCR5, and CXCR4, on EOC associated ascitic and blood MO/MA; their response to complementary chemokines in a MO/MA migration assay and the F-actin content in an actin polymerization assay. A validated cDNA microarray assay was then utilized to examine alterations in pathway genes that can be identified with cell migration. Results Ascitic and EOC blood MO/MA express CCR1, CCR5 and CXCR4, but differently. Cell surface expression levels for CCR1 and CCR5 were higher in ascites than that of normal blood in contrast to CXCR4 levels in ascitic MO/MA which were lower. EOC associated ascitic or blood MO/MA failed to migrate in response to the CC ligand RANTES and to the CXCR4 reactive chemokine, SDF1 (CXCL12). Ascitic and most EOC blood MO/MA also behaved differently from normal blood MO in the polymerization/depolymerization assay. A cDNA gene analysis of purified ascitic MO/MA demonstrated that a number of genes involved with chemokine production, focal adhesion, actin cytoskeletal function and leukocyte transendothelial migration were down-regulated in the ascitic MO/MA when compared to normal blood MO. Moreover, PBMC cDNA from EOC patients' blood also showed gene profiles similar to that of ascitic MO/MA. Conclusions Defective migration and polymerization/depolymerization activity of MO/MA from EOC patients and a significant down-regulation of critical pathway genes suggest that other mechanisms might be involved in the accumulation of systemically derived MO at the tumor site of EOC patients. C1 [Freedman, Ralph S.; Gallardo, Stacie T.; Gordon, Ilyssa O.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77230 USA. [Ma, Qing] Univ Texas Houston, MD Anderson Canc Ctr, Dept Stem Cell Transplantat Res, Houston, TX 77230 USA. [Wang, Ena; Shin, Jeong Won; Jin, Ping; Stroncek, David; Marincola, Francesco M.] NIH, Dept Transfus Med, Immunogenet Sect, Bethesda, MD 20892 USA. RP Freedman, RS (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, POB 301439,Unit 1362, Houston, TX 77230 USA. EM rfreedma@mdanderson.org NR 32 TC 7 Z9 10 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2008 VL 57 IS 5 BP 635 EP 645 DI 10.1007/s00262-007-0401-5 PG 11 WC Oncology; Immunology SC Oncology; Immunology GA 267QP UT WOS:000253524600004 PM 17926037 ER PT J AU Kummar, S Rubinstein, L Kinders, R Parchment, RE Gutierrez, ME Murgo, AJ Ji, J Mroczkowski, B Pickeral, OK Simpson, M Hollingshead, M Yang, SX Helman, L Wiltrout, R Collins, J Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Rubinstein, Larry Kinders, Robert Parchment, Ralph E. Gutierrez, Martin E. Murgo, Anthony J. Ji, Jay Mroczkowski, Barbara Pickeral, Oxana K. Simpson, Mel Hollingshead, Melinda Yang, Sherry X. Helman, Lee Wiltrout, Robert Collins, Jerry Tomaszewski, Joseph E. Doroshow, James H. TI Phase 0 clinical trials: Conceptions and misconceptions SO CANCER JOURNAL LA English DT Article DE phase 0; oncology; clinical trial; exploratory IND; pharmacodynamics ID DRUG DEVELOPMENT; ONCOLOGY; ETHICS; AGENTS; IMPACT; POLYMERASE; BIOPSIES; BENEFITS AB Phase 0 clinical trials, developed in response to the United States Food and Drug Administration (FDA)'s recent exploratory Investigational New Drug (IND) guidance, are intended to expedite the clinical evaluation of new molecular entities. The exploratory IND supports the performance of first-in-human testing of new investigational agents at subtherapeutic doses based on reduced manufacturing and toxicologic requirements, allowing the demonstration of drug-target effects and assessment of pharmacokinetic-pharmacodynamic relationships in humans earlier in clinical development. The objectives of a phase 0 cancer clinical trial are to establish at the very earliest opportunity-before large numbers of patients have been accrued and exposed to potential drug-associated toxicity-whether an agent is modulating its target in a tumor, and consequently whether further clinical development is warranted. We review here the fundamental requirements of clinical studies conducted under an exploratory IND and address some common misconceptions regarding oncologic phase 0 trials. C1 [Doroshow, James H.] NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Kummar, Shivaani; Gutierrez, Martin E.; Helman, Lee; Wiltrout, Robert; Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Kinders, Robert; Parchment, Ralph E.; Ji, Jay; Simpson, Mel] NCI, SAIC Frederick, Lab Human Toxicol & Pharmacol, Frederick, MD 21702 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 27 TC 28 Z9 29 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAY-JUN PY 2008 VL 14 IS 3 BP 133 EP 137 DI 10.1097/PPO.0b013e318172d6f3 PG 5 WC Oncology SC Oncology GA 309TU UT WOS:000256483900001 PM 18536551 ER PT J AU Meoli, E Bossis, I Cazabat, L Mavrakis, M Horvath, A Stergiopoulos, S Shiferaw, ML Fumey, G Perlemoine, K Muchow, M Robinson-White, A Weinberg, F Nesterova, M Patronas, Y Groussin, L Bertherat, J Stratakis, CA AF Meoli, Elise Bossis, Ioannis Cazabat, Laure Mavrakis, Manos Horvath, Anelia Stergiopoulos, Sotiris Shiferaw, Miriam L. Fumey, Glawdys Perlemoine, Karine Muchow, Michael Robinson-White, Audrey Weinberg, Frank Nesterova, Maria Patronas, Yianna Groussin, Lionel Bertherat, Jerome Stratakis, Constantine A. TI Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors SO CANCER RESEARCH LA English DT Article ID ALPHA REGULATORY SUBUNIT; CARNEY COMPLEX; RI-ALPHA; CYCLIC-AMP; I-ALPHA; STRUCTURE REVEALS; LIVING CELLS; CAMP; PKA; GENE AB Most PRKAR1A tumorigenic mutations lead to nonsense mRNA that is decayed; tumor formation has been associated with an increase in type II protein kinase A (PKA) subunits. The IVS6+1G>T PRKAR1A mutation leads to a protein lacking exon 6 sequences [R1 alpha Delta 184-236 (R1 alpha Delta 6)]. We compared in vitro R1 alpha Delta 6 with wild-type (wt) R1 alpha. We assessed PKA activity and subunit expression, phosphorylation of target molecules, and properties of wt-R1 alpha and mutant (mt) R1 alpha; we observed by confocal microscopy R1 alpha tagged with green fluorescent protein and its interactions with Cerulean-tagged catalytic subunit (C alpha). Introduction of the R1 alpha Delta 6 led to aberrant cellular morphology and higher PKA activity but no increase in type II PKA subunits. There was diffuse, cytoplasmic localization of R1 alpha protein in wt-R1 alpha- and R1 alpha Delta 6-transfected cells but the former also exhibited discrete aggregates of R1 alpha that bound Cot; these were absent in R1 alpha Delta 6-transfected cells and did not bind C alpha at baseline or in response to cyclic AMP. Other changes induced by R1 alpha Delta 6 included decreased nuclear C alpha. We conclude that R1 alpha Delta 6 leads to increased PKA activity through the mt-R1 alpha decreased binding to C alpha and does not involve changes in other PKA subunits, suggesting that a switch to type II PKA activity is not necessary for increased kinase activity or tumorigenesis. C1 [Meoli, Elise; Bossis, Ioannis; Horvath, Anelia; Stergiopoulos, Sotiris; Shiferaw, Miriam L.; Muchow, Michael; Robinson-White, Audrey; Weinberg, Frank; Nesterova, Maria; Patronas, Yianna; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Mavrakis, Manos] NICHHD, Sect Organelle Biol, Program Cell Biol & Metab, NIH, Bethesda, MD USA. [Cazabat, Laure; Fumey, Glawdys; Perlemoine, Karine; Groussin, Lionel; Bertherat, Jerome] Inst Cochin, Dept Endocrinol Metab & Canc, Inst Natl Sante & Rech Med U567, Paris, France. [Cazabat, Laure; Fumey, Glawdys; Perlemoine, Karine; Groussin, Lionel; Bertherat, Jerome] CNRS, UMR 8104, Paris, France. [Cazabat, Laure; Fumey, Glawdys; Perlemoine, Karine; Groussin, Lionel; Bertherat, Jerome] Univ Paris 05, Ctr Reference Malad Rares Surrenale, Serv Endocrinol, Hop Cochin, Paris, France. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS [ZIA HD000642-13]; NICHD NIH HHS [Z01 HD000642] NR 44 TC 43 Z9 44 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 MAY 1 PY 2008 VL 68 IS 9 BP 3133 EP 3141 DI 10.1158/0008-5472.CAN-08-0064 PG 9 WC Oncology SC Oncology GA 297FN UT WOS:000255602600011 PM 18451138 ER PT J AU Kumamoto, K Spillare, EA Fujita, K Horikawa, I Yamashita, T Appella, E Nagashima, M Takenoshita, S Yokota, J Harris, CC AF Kumamoto, Kensuke Spillare, Elisa A. Fujita, Kaori Horikawa, Izumi Yamashita, Taro Appella, Ettore Nagashima, Makoto Takenoshita, Seiichi Yokota, Jun Harris, Curtis C. TI Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR NETWORK; REPLICATIVE SENESCENCE; TRANSCRIPTIONAL REPRESSION; ANTAGONIST NUTLIN-3A; HISTONE H3; CYCLIN D1; IN-VIVO; MDM2; APOPTOSIS; CELLS AB Nutlin-3, an MDM2 inhibitor, activates p53, resulting in several types of cancer cells undergoing apoptosis. Although p53 is mutated or deleted in similar to 50%o of all cancers, p53 is still functionally active in the other 50%. Consequently, nutlin-3 and similar drugs could be candidates for neoadjuvant therapy in cancers with a functional p53. Cellular senescence is also a phenotype induced by p53 activation and plays a critical role in protecting against tumor development. In this report, we found that nutlin-3a can induce senescence in normal human fibroblasts. Nutlin-3a activated and repressed a large number of p53-dependent genes, including those encoding microRNAs. mir-34a, mir-34b, and mir-34c, which have recently been shown to be downstream effectors of p53-mediated senescence, were up-regulated, and inhibitor of growth 2 (ING2) expression was suppressed by nutlin-3a treatment. Two candidates for a p53-DNA binding consensus sequence were found in the ING2 promoter regulatory region; thus, we performed chromatin immunoprecipitation and electrophoretic mobility shift assays and confirmed p53 binding directly to those sites. In addition, the luciferase activity of a construct containing the ING2 regulatory region was repressed after p53 activation. Antisense knockdown of ING2 induces p53-independent senescence, whereas overexpression of ING2 induces p53-dependent senescence. Taken together, we conclude that nutlin-3a induces senescence through p53 activation in normal human fibroblasts, and p53-mediated mir34a, mir34b, and mir34c up-regulation and ING2 down-regulation may be involved in the senescence pathway. C1 [Kumamoto, Kensuke; Spillare, Elisa A.; Fujita, Kaori; Horikawa, Izumi; Yamashita, Taro; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Appella, Ettore] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nagashima, Makoto] Toho Univ, Sakura Hosp, Dept Surg, Sakura, Japan. [Kumamoto, Kensuke; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Surg 2, Fukushima, Japan. [Yokota, Jun] Natl Canc Ctr, Res Inst, Div Biol, Tokyo 104, Japan. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM harrisc@mail.nih.gov FU Intramural NIH HHS [Z01 BC005795-13] NR 53 TC 138 Z9 150 U1 0 U2 7 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 MAY 1 PY 2008 VL 68 IS 9 BP 3193 EP 3203 DI 10.1158/0008-5472.CAN-07-2780 PG 11 WC Oncology SC Oncology GA 297FN UT WOS:000255602600018 PM 18451145 ER PT J AU Fichtner-Feigl, S Terabe, M Kitani, A Young, CA Fuss, I Geissler, EK Schlitt, HJ Berzofsky, JA Strober, W AF Fichtner-Feigl, Stefan Terabe, Masaki Kitani, Atsushi Young, Cheryl A. Fuss, Ivan Geissler, Edward K. Schlitt, Hans-Juergen Berzofsky, Jay A. Strober, Warren TI Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha(2) SO CANCER RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; T-CELLS; ANTITUMOR IMMUNITY; IL-13 RECEPTOR; FIBROSIS; GROWTH; CANCER; CYTOTOXICITY; INDUCTION; ARTHRITIS AB In previous studies, we described a "counter-immunosurveiHance" mechanism initiated by tumor-activated, interleukin-13 (IL-13)-producing natural killer T cells that signal Gr-1(+) cells to produce transforming growth factor-beta(1) (TGF-beta(1)), a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8(+) T cells. Here, we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models), this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13R alpha(2), on Gr-1(intermediate) cells, because down-regulation of IL-13R alpha(2) expression or the activator protein-1 signal generated by the receptor via in vivo administration of specific small interfering RNA or decoy oligonucleotides leads to loss of TGF-beta(1) production. Furthermore, acting on prior studies showing that IL-13R alpha(2) expression is induced (in part) by tumor necrosis factor-alpha (TNF-alpha),we show that receptor expression and TGF-alpha production is inhibited by administration of a TNF-alpha-neutralizing substance, TNF-alpha R-Fc(etanereept). Taking advantage of this latter fact, we then show in the CT-26 model that counter-immunosurveillance can he inhibited, anti-CT-26-specific CD8(+) cytolytic activity can be restored, and CT-26 metastatic tumor nodules can be greatly decreased by administration of TNF-alpha R-Fc. Corroborative data were obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity. C1 [Fichtner-Feigl, Stefan; Geissler, Edward K.; Schlitt, Hans-Juergen] Univ Regensburg, Dept Surg, D-93053 Regensburg, Germany. [Fichtner-Feigl, Stefan; Kitani, Atsushi; Young, Cheryl A.; Fuss, Ivan; Strober, Warren] NIAID, Host Def Lab, Mucosal Immun Sect, Bethesda, MD 20892 USA. [Terabe, Masaki; Berzofsky, Jay A.] NCI, NIH, Vaccine Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fichtner-Feigl, S (reprint author), Univ Regensburg, Dept Surg, Franz Josef Str Allee 11, D-93053 Regensburg, Germany. EM stefan.fichtner@klinik.uni-regensburg.de RI Geissler, Edward/R-4131-2016 FU Intramural NIH HHS [Z01 AI000432-23] NR 28 TC 40 Z9 41 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 MAY 1 PY 2008 VL 68 IS 9 BP 3467 EP 3475 DI 10.1158/0008-5472.CAN-07-5301 PG 9 WC Oncology SC Oncology GA 297FN UT WOS:000255602600048 PM 18451175 ER PT J AU Purow, BW Sundaresan, TK Burdick, MJ Kefas, BA Comeau, LD Hawkinson, MP Su, Q Kotliarov, Y Lee, J Zhang, W Fine, HA AF Purow, Benjamin W. Sundaresan, Tilak K. Burdick, Michael J. Kefas, Benjamin A. Comeau, Laurey D. Hawkinson, Michael P. Su, Qin Kotliarov, Yuri Lee, Jeongwu Zhang, Wei Fine, Howard A. TI Notch-1 regulates transcription of the epidermal growth factor receptor through p53 SO CARCINOGENESIS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BREAST-CANCER CELLS; TUMOR-SUPPRESSOR; UP-REGULATION; EGF-RECEPTOR; CYCLE ARREST; EXPRESSION; GENE; ACTIVATION; LIGANDS AB The Notch pathway plays a key role in the development and is increasingly recognized for its importance in cancer. We demonstrated previously the overexpression of Notch-1 and its ligands in gliomas and showed that their knockdown inhibits glioma cell proliferation and survival. To elucidate the mechanisms downstream of Notch-1 in glioma cells, we performed microarray profiling of glioma cells transfected with Notch-1 small interfering RNA. Notable among downregulated transcripts was the epidermal growth factor receptor (EGFR), known to be overexpressed or amplified in gliomas and prominent in other cancers as well. Further studies confirmed that Notch-1 inhibition decreased EGFR messenger RNA (mRNA) and EGFR protein in glioma and other cell lines. Transfection with Notch-1 increased EGFR expression. Additionally, we found a significant correlation in levels of EGFR and Notch-1 mRNA in primary high-grade human gliomas. Subsequent experiments showed that p53, an activator of the EGFR promoter, is regulated by Notch-1. Experiments with p53-positive and -null cell lines confirmed that p53 partially mediates the effects of Notch-1 on EGFR expression. These results show for the first time that Notch-1 upregulates EGFR expression and also demonstrate Notch-1 regulation of p53 in gliomas. These observations have significant implications for understanding the mechanisms of Notch in cancer and development. C1 [Purow, Benjamin W.; Sundaresan, Tilak K.] Univ Virginia, Div Neurooncol, Dept Neurol, Charlottesville, VA 22908 USA. [Kotliarov, Yuri; Lee, Jeongwu; Zhang, Wei] NINDS, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. [Sundaresan, Tilak K.; Fine, Howard A.] Robert Johnson Med Sch, Piscataway, NJ 08854 USA. [Burdick, Michael J.] Cleveland Clin, Dept Radiat Oncol, Cleveland, OH 44195 USA. [Su, Qin] NIAID, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Purow, BW (reprint author), Univ Virginia, Div Neurooncol, Dept Neurol, Charlottesville, VA 22908 USA. EM bwp5g@virginia.edu RI Kotliarov, Yuri/B-6938-2017 FU Howard Hughes Medical Institute; Intramural NIH HHS NR 42 TC 60 Z9 63 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2008 VL 29 IS 5 BP 918 EP 925 DI 10.1093/carcin/bgn079 PG 8 WC Oncology SC Oncology GA 325GI UT WOS:000257576600007 PM 18359760 ER PT J AU Chang, SC Rashid, A Gao, YT Andreotti, G Shen, MC Wang, BS Han, TQ Zhang, BH Sakoda, LC Leitzmann, MF Chen, BE Rosenberg, PS Chen, J Chanock, SJ Hsing, AW AF Chang, Shih-Chen Rashid, Asif Gao, Yu-Tang Andreotti, Gabriella Shen, Ming-Chang Wang, Bin-Sheng Han, Tian-Quan Zhang, Bai-He Sakoda, Lori C. Leitzmann, Michael F. Chen, Bingshu E. Rosenberg, Philip S. Chen, Jinbo Chanock, Stephen J. Hsing, Ann W. TI Polymorphism of genes related to insulin sensitivity and the risk of biliary tract cancer and biliary stone: a population-based case-control study in Shanghai, China SO CARCINOGENESIS LA English DT Article ID ACTIVATED RECEPTOR-GAMMA; GALLBLADDER-DISEASE; PRO12ALA POLYMORPHISM; OBESITY; ASSOCIATION; PREVALENCE; GALLSTONES; FREQUENCY; LIPIDS AB Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-gamma, PPAR-delta, RXR-alpha, RXR-beta and INS genes with biliary cancer and stones in a population-based case-control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-beta C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 0.99-2.84], with a more pronounced association among men (OR = 2.30; 95% CI = 1.14-4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (>= 23kg/m(2)) (OR = 1.80; 95% CI 5 1.09-2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones. C1 [Chang, Shih-Chen; Andreotti, Gabriella; Sakoda, Lori C.; Leitzmann, Michael F.; Chen, Bingshu E.; Rosenberg, Philip S.; Chanock, Stephen J.; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, DHHS, Bethesda, MD 20892 USA. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Shen, Ming-Chang] Shanghai Tumor Hosp, Shanghai, Peoples R China. [Wang, Bin-Sheng] Zhongshan Hosp, Shanghai, Peoples R China. [Han, Tian-Quan] Rui Jian Hosp, Shanghai, Peoples R China. [Zhang, Bai-He] Oriental Hepatobiliary Surg Hosp, Shanghai, Peoples R China. [Chen, Jinbo] Univ Penn, Dept Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Chanock, Stephen J.] Natl Canc Inst, Gaithersburg, MD 20877 USA. [Chanock, Stephen J.] NCI, Pediat Oncol Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, DHHS, Bethesda, MD 20892 USA. EM hsinga@mail.nih.gov FU Intramural NIH HHS NR 37 TC 17 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2008 VL 29 IS 5 BP 944 EP 948 DI 10.1093/carcin/bgn025 PG 5 WC Oncology SC Oncology GA 325GI UT WOS:000257576600011 PM 18375961 ER PT J AU Zahm, SH Morton, LM Bernstein, L Wang, SS Colt, JS Severson, RK Welch, R Hartge, P AF Zahm, Shelia Hoar Morton, Lindsay M. Bernstein, Leslie Wang, Sophia S. Colt, Joanne S. Severson, Richard K. Welch, Robert Hartge, Patricia TI Re: Hair dye use, genetic variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma, author response SO CARCINOGENESIS LA English DT Letter C1 [Zahm, Shelia Hoar; Morton, Lindsay M.; Wang, Sophia S.; Colt, Joanne S.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Bernstein, Leslie] City Hope Comprehens Canc Ctr, Beckman Res Inst, Duarte, CA 91010 USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI 48201 USA. [Severson, Richard K.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. [Welch, Robert] NCI, Core Genotyping Facil, Adv Technol Ctr, Natl Inst Hlth,Dept Hlth & Human Serv, Gaithersburg, MD 20877 USA. RP Zahm, SH (reprint author), NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM zahms@mail.nih.gov RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 FU Intramural NIH HHS [Z01 CP010170-07] NR 2 TC 1 Z9 1 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAY PY 2008 VL 29 IS 5 BP 1084 EP 1085 DI 10.1093/carcin/bgn023 PG 2 WC Oncology SC Oncology GA 325GI UT WOS:000257576600031 PM 18212328 ER PT J AU White, CJ Anderson, HV Brindis, RG Cates, CU Cohen, DJ Ho, K Hopkins, LN Jaff, MR Koroshetz, WJ Rosenfield, KA AF White, Christopher J. Anderson, H. Vernon Brindis, Ralph G. Cates, Christopher U. Cohen, David J. Ho, Kalon Hopkins, L. Nelson Jaff, Michael R. Koroshetz, Walter J. Rosenfield, Kenneth A. TI The carotid artery revascularization and endarterectomy (CARE) registry: Objectives, design, and implications SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE peripheral vascular disease; carotid stent; carotid surgery ID STENOSIS AB This is the first comprehensive national registry that will provide data characterizing contemporary results of carotid endarterectomy (CEA) and carotid artery stenting (CAS). Carotid endarterectomy (CEA) has become the standard revascularization therapy to prevent stroke in patients with carotid artery disease, while carotid artery stenting (CAS) offers a percutaneous alternative in selected patients. Given the rapid growth in the numbers of CAS procedures being performed, there is a critical need for a national program to assess quality outcomes. The Carotid Artery Revascularization and Endarterectomy (CARE) Registry was developed through a multispecialty collaboration resulting in a comprehensive data collection tool for carotid revascularization procedures. The intent of the CARE registry is to collect and analyze clinical data to measure clinical practice, patient outcomes, and enable quality improvement for carotid revascularization. Finally, the CARE Registry satisfies the Center for Medicare and Medicaid Services (CMS) data reporting criteria for reimbursement. (C) 2008 Wiley-Liss, Inc. C1 [White, Christopher J.] Alton Ochsner Med Fdn & Ochsner Clin, Dept Cardiol, New Orleans, LA 70121 USA. [Anderson, H. Vernon] Univ Texas Houston, Div Cardiol, Houston, TX USA. [Brindis, Ralph G.] No Calif Kaiser Permanente, Div Cardiol, Oakland, CA USA. [Cates, Christopher U.] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Cohen, David J.] St Lukes Hosp, Mid Amer Heart Inst, Sect Cardiovasc Res, Kansas City, MO 64111 USA. [Ho, Kalon] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Cardiovasc Inst, Boston, MA 02215 USA. [Hopkins, L. Nelson] SUNY Buffalo, Toshiba Stroke Res Ctr, Dept Neurosurg, Buffalo, NY 14260 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Dept Med, Sect Vasc Med, Div Cardiovasc Med, Boston, MA 02114 USA. [Koroshetz, Walter J.] NINDS, Bethesda, MD 20892 USA. [Rosenfield, Kenneth A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP White, CJ (reprint author), Alton Ochsner Med Fdn & Ochsner Clin, Dept Cardiovasc Dis, 1514 Jefferson Highway, New Orleans, LA 70121 USA. EM cwhite@ochsner.org RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 NR 12 TC 26 Z9 26 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAY 1 PY 2008 VL 71 IS 6 BP 721 EP 725 DI 10.1002/ccd.21502 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 291ZB UT WOS:000255235000001 PM 18412064 ER PT J AU Lederman, RJ AF Lederman, Robert J. TI Recanalization of chronic peripheral artery occlusions: Moving forward by looking sideways SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Editorial Material ID MAGNETIC-RESONANCE; EXPERIENCE; DISSECTION C1 NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Div Intramural Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ledermar@nhlbi.nih.gov OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL005062-05] NR 11 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAY 1 PY 2008 VL 71 IS 6 BP 734 EP 735 DI 10.1002/ccd.21594 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 291ZB UT WOS:000255235000004 PM 18412068 ER PT J AU Lemonnier, L Trebak, M Putney, JW AF Lemonnier, Loic Trebak, Mohamed Putney, James W., Jr. TI Complex regulation of the TRPC3, 6 and 7 channel subfamily by diacylglycerol and phosphatidylinositol-4,5-bisphosphate SO CELL CALCIUM LA English DT Article DE calcium channels; ion channels; TRP channels; TRPC7; phosphatidylinositol-4,5-bisphosphate; Diacylglycerols; patch-clamp ID CATION CHANNELS; TRANSIENT RECEPTOR; FUNCTIONAL-CHARACTERIZATION; PHYSIOLOGICAL RELEVANCE; SIGNALING MECHANISM; ION CHANNELS; ACTIVATION; INHIBITION; KINASE; 4,5-BISPHOSPHATE AB TRPC3, 6 and 7 channels constitute a subgroup of non-selective, calcium-permeable cation channels within the TRP superfamily that are activated by products of phospholipase C-mediated breakdown of phosphatidylinositol-4,5-bisphosphate (PIP(2)). A number of ion channels, including other members of the TRP superfamily, are regulated directly by PIP(2). However, there is little information on the regulation of the TRPC channel subfamily by PIP(2). Pretreatment of TRPC7-expressing cells with a drug that blocks the synthesis of polyphosphoinositides inhibited the ability of the synthetic diacylglycerol, oleyl-acetyl glycerol, to activate TRPC7. In excised patches, TRPC7 channels were robustly activated by application of PIP(2) or ATP, but not by inositol 1,4,5-trisphosphate. Similar results were obtained with TRPC6 and TRPC3, although the effects of PIP(2) were somewhat less and with TRPC3 there was no significant effect of ATP. In the cell-attached configuration, TRPC7 channels could be activated by the synthetic diacylglycerol analog, oleyl-acetyl glycerol. However, this lipid mediator did not activate TRPC7 channels in excised patches. In addition, channel activation by PIP(2) in excised patches was significantly greater than that observed with oleyl-acetyl glycerol in the cell-attached configuration. These findings reveal complex regulation of TRPC channels by lipid mediators. The results also reveal for the first time direct activation by PIP(2) of members of the TRPC ion channel subfamily. Published by Elsevier Ltd. C1 [Lemonnier, Loic; Trebak, Mohamed; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM loiclemonnier@voila.fr; trebakm@mail.amc.edu; putney@niehs.nih.gov RI Trebak, Mohamed/E-7405-2014 FU Intramural NIH HHS [Z01 ES090087-11, Z99 ES999999] NR 37 TC 64 Z9 70 U1 1 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD MAY PY 2008 VL 43 IS 5 BP 506 EP 514 DI 10.1016/j.ceca.2007.09.001 PG 9 WC Cell Biology SC Cell Biology GA 307NP UT WOS:000256325900008 PM 17942152 ER PT J AU Leung, K Kim, JO Ganesh, L Kabat, J Schwartz, O Nabel, GJ AF Leung, Kwanyee Kim, Jae-Ouk Ganesh, Lakshmanan Kabat, Juraj Schwartz, Owen Nabel, Gary J. TI HIV-1 assembly: Viral glycoproteins segregate quantally to lipid rafts that associate individually with HIV-1 capsids and virions SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMA-MEMBRANE; EBOLA-VIRUS; ENVELOPE GLYCOPROTEIN; GAG; PROTEINS; TRAFFICKING; IDENTIFICATION; NEUTRALIZATION; STOICHIOMETRY AB HIV-1 assembly depends on its structural protein, Gag, which after synthesis on ribosomes, traffics to the late endosome/plasma membrane, associates with HIV Env glycoprotein, and forms infectious virions. While Env and Gag migrate to lipid microdomains, their stoichiometry and specificity of interaction are unknown. Pseudotyped viral particles can be made with one viral core surrounded by heterologous envelope proteins. Taking advantage of this property, we analyzed the association of HIV Env and Ebola glycoprotein (GP), with HIV-1 Gag coexpressed in the same cell. Though both viral glycoproteins were expressed, each associated independently with Gag, giving rise to distinct virion populations, each with a single glycoprotein type. Confocal imaging demonstrated that Env and GP localized to distinct lipid raft microdomains within the same cell where they associated with different virions. Thus, a single Gag particle associates "quantally" with one lipid raft, containing homogeneous trimeric viral envelope proteins, to assemble functional virions. C1 [Leung, Kwanyee; Kim, Jae-Ouk; Ganesh, Lakshmanan; Nabel, Gary J.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Kabat, Juraj; Schwartz, Owen] NIAID, NIH, Biol Imaging Facil, Bethesda, MD 20892 USA. RP Nabel, GJ (reprint author), NIAID, NIH, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 35 TC 42 Z9 42 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD MAY PY 2008 VL 3 IS 5 BP 285 EP 292 DI 10.1016/j.chom.2008.04.004 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 302MO UT WOS:000255972600005 PM 18474355 ER PT J AU Salerno, VP Calliari, A Provance, DW Sotelo-Silveira, JR Sotelo, JR Mercer, JA AF Salerno, Veronica P. Calliari, Aldo Provance, D. William, Jr. Sotelo-Silveira, Jose R. Sotelo, Jose R. Mercer, John A. TI Myosin-Va mediates RNA distribution in primary fibroblasts from multiple organs SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE Myosin-Va; mRNA transport; beta-actin mRNA ID ACTIN MESSENGER-RNA; PERIAXOPLASMIC RIBOSOMAL PLAQUES; DENDRITIC SPINES; PURKINJE-CELLS; ENDOPLASMIC-RETICULUM; MELANOSOME TRANSPORT; MYELINATED AXONS; MUTANT MICE; LOCALIZATION; TRANSLATION AB Myosin-Va has been shown to have multiple functions in a variety of cell types, including a role in RNA transport in neurons. Using primary cultures of cells from organs of young dilute-lethal (Myo5a(d-l)/Myo5a(d-l)) null mutant mice and wild-type controls, we show that in some, but not all, tissues, RNA distribution is dramatically different in the homozygous null mutant cells. The dependence of RNA localization on myosin-Va correlates with the relative abundance of the brain-specific splicing pattern of the myosin-Va tail. We also show that myosin-Va is involved in RNA localization soon after synthesis, because the effects of its absence are diminished for RNAs that are more than 30 min old. Finally, we show that localization of P-actin mRNA is significantly changed by the absence of myosin-Va. These results suggest that myosin-Va is involved in a transient transport or tethering function in the perinuclear region. Cell Motil. C1 [Salerno, Veronica P.; Provance, D. William, Jr.; Mercer, John A.] McLaughlin Res Inst, Great Falls, MT 59405 USA. [Salerno, Veronica P.] Univ Fed Rio de Janeiro, EEFD, Dept Biociencias Atividade Fis, BR-21941 Rio De Janeiro, Brazil. [Calliari, Aldo; Sotelo-Silveira, Jose R.; Sotelo, Jose R.] Inst Invest Biol Clemente Estable, Dept Prot & Acidos Nucl, Montevideo, Uruguay. [Calliari, Aldo] Univ Republica, Fac Vet, Dept Biol Celular & Mol, Montevideo, Uruguay. [Sotelo-Silveira, Jose R.] NCI, SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21701 USA. RP Mercer, JA (reprint author), McLaughlin Res Inst, 1520 23rd St South, Great Falls, MT 59405 USA. EM jam@mri.montana.edu RI Salerno, Veronica/F-2678-2012; Provance Jr., David/D-5294-2013; OI Provance Jr., David/0000-0002-9824-0672; Mercer, John/0000-0003-0307-4438 FU FIC NIH HHS [R03 TW007220, R03 TW007220-01A2]; NIGMS NIH HHS [R01 GM066901, R01 GM066901-04] NR 44 TC 17 Z9 17 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD MAY PY 2008 VL 65 IS 5 BP 422 EP 433 DI 10.1002/cm.20272 PG 12 WC Cell Biology SC Cell Biology GA 300FC UT WOS:000255808700006 PM 18357619 ER PT J AU Kelly, K Yin, JJ AF Kelly, Kathleen Yin, Juan Juan TI Prostate cancer and metastasis initiating stem cells SO CELL RESEARCH LA English DT Review DE prostate cancer; metastasis; stem; progenitor; androgen; hedgehog ID EPITHELIAL-CELLS; PROXIMAL REGION; IN-VIVO; PROSPECTIVE IDENTIFICATION; BONE METASTASES; MURINE PROSTATE; RB DEFICIENCY; GROWTH; TISSUE; GENE AB Androgen refractory prostate cancer metastasis is a major clinical challenge. Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell. Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis. This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts. C1 [Kelly, Kathleen; Yin, Juan Juan] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kelly, K (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bldg 37,Room 1068, Bethesda, MD 20892 USA. EM kellyka@mail.nih.gov FU Intramural NIH HHS NR 90 TC 32 Z9 33 U1 1 U2 3 PU INST BIOCHEMISTRY & CELL BIOLOGY PI SHANGHAI PA SIBS, CAS, 319 YUEYANG ROAD, SHANGHAI, 200031, PEOPLES R CHINA SN 1001-0602 EI 1748-7838 J9 CELL RES JI Cell Res. PD MAY PY 2008 VL 18 IS 5 BP 528 EP 537 DI 10.1038/cr.2008.50 PG 10 WC Cell Biology SC Cell Biology GA 308RZ UT WOS:000256409000002 PM 18414448 ER PT J AU Farley, J Ozbun, LL Birrer, MJ AF Farley, John Ozbun, Laurent L. Birrer, Michael J. TI Genomic analyses of epithelial ovarian cancer SO CELL RESEARCH LA English DT Review DE gynecologic; malignancies; expression profiling; pathway analysis ID DISTAL FALLOPIAN-TUBE; GENE-EXPRESSION; CLEAR-CELL; SPONTANEOUS TRANSFORMATION; INCESSANT OVULATION; MUCINOUS TUMORS; CARCINOMAS; DETERMINANTS; PATHOGENESIS; ETIOLOGY AB Ovarian cancer is a major health problem for women in the United States. Despite evidence of considerable heterogeneity, most cases of ovarian cancer are treated in a similar fashion. The molecular basis for the clinicopathologic characteristics of these tumors remains poorly defined. Whole genome expression profiling is a genomic tool, which can identify dysregulated genes and uncover unique sub-classes of tumors. The application of this technology to ovarian cancer has provided a solid molecular basis for differences in histology and grade of ovarian tumors. Differentially expressed genes identified pathways implicated in cell proliferation, invasion, motility, chromosomal instability, and gene silencing and provided new insights into the origin and potential treatment of these cancers. The added knowledge provided by global gene expression profiling should allow for a more rational treatment of ovarian cancers. These techniques are leading to a paradigm shift from empirical treatment to an individually tailored approach. This review summarizes the new genomic data on epithelial ovarian cancers of different histology and grade and the impact it will have on our understanding and treatment of this disease. C1 [Ozbun, Laurent L.; Birrer, Michael J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Farley, John] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. RP Birrer, MJ (reprint author), NCI, Ctr Canc Res, 37 Convent Dr,Bldg 37,Room 1130, Bethesda, MD 20892 USA. EM birrerm@mail.nil.gov NR 59 TC 37 Z9 42 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1001-0602 J9 CELL RES JI Cell Res. PD MAY PY 2008 VL 18 IS 5 BP 538 EP 548 DI 10.1038/cr.2008.52 PG 11 WC Cell Biology SC Cell Biology GA 308RZ UT WOS:000256409000003 PM 18427574 ER PT J AU Stary, A Shafrir, Y Hering, S Wolschann, P Guy, HR AF Stary, Anna Shafrir, Yinon Hering, Steffen Wolschann, Peter Guy, H. Robert TI Structural model of the Ca(V)1.2 pore SO CHANNELS LA English DT Article DE homology model; Ca(V)1.2 pore structure; domain arrangement; MD simulation; open conformation ID GATED CA2+ CHANNEL; CALCIUM-CHANNEL; MOLECULAR DETERMINANTS; CRYSTAL-STRUCTURE; ION SELECTIVITY; INNER PORE; VOLTAGE; INACTIVATION; ARCHITECTURE; SIMULATIONS AB Understanding the structure and functional mechanisms of voltage - gated calcium channels remains a major task in membrane biophysics. In the absence of three dimensional structures, homology modeling techniques are the method of choice, to address questions concerning the structure of these channels. We have developed models of the open Ca(V)1.2 pore, based on the crystal structure of the mammalian voltage - gated potassium channel K(V)1.2 and a model of the bacterial sodium channel NaChBac. Our models are developed to be consistent with experimental data and modeling criteria. The models highlight major differences between voltage - gated potassium and calcium channels in the P segments, as well as the inner pore helices. Molecular dynamics simulations support the hypothesis of a clockwise domain arrangement and experimental observations of asymmetric calcium channel behavior. In the accompanying paper these models were used to study structural effects of a channelopathy mutation. C1 [Stary, Anna; Wolschann, Peter] Univ Vienna, Inst Theoret Chem, Vienna, Austria. [Stary, Anna; Hering, Steffen] Univ Vienna, Inst Pharmacol & Toxicol, Vienna, Austria. [Shafrir, Yinon; Guy, H. Robert] NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Stary, A (reprint author), Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, Gottingen, Germany. EM astary@gwdg.de RI Stary-Weinzinger, Anna/A-3629-2014 OI Stary-Weinzinger, Anna/0000-0002-9202-0484 FU FWF [15914, P19614-B11]; NIH, National Cancer Institute, Center for Cancer Research FX This work was supported by FWF grants 15914 and P19614-B11 (to Steffen Herring) and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research ( to H. Robert Guy). NR 32 TC 17 Z9 17 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6950 J9 CHANNELS JI Channels PD MAY-JUN PY 2008 VL 2 IS 3 BP 210 EP 215 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 344SW UT WOS:000258948600011 PM 18836302 ER PT J AU Stary, A Kudrnac, M Beyl, S Hohaus, A Timin, EN Wolschann, P Guy, HR Hering, S AF Stary, Anna Kudrnac, Michaela Beyl, Stanislav Hohaus, Annette Timin, Eugen N. Wolschann, Peter Guy, H. Robert Hering, Steffen TI Molecular dynamics and mutational analysis of a channelopathy mutation in the IIS6 helix of Ca(V)1.2 SO CHANNELS LA English DT Article DE calcium channel; mutagenesis; channelopathy; MD simulation; Ca(V)1.2; channel activation ID FAMILIAL HEMIPLEGIC MIGRAINE; LINKED RETINAL DISORDER; CA2+ CHANNELS; ACTIVATION; DETERMINANTS; CONFORMATION; RESIDUES; CACNA1F AB A channelopathy mutation in segment IIS6 of Ca(V)1.4 (I745T) has been shown to cause severe visual impairment by shifting the activation and inactivation curves to more hyperpolarized voltages and slowing activation and inactivation kinetics. A similar gating phenotype is caused by the corresponding mutation, I781T, in Ca(V)1.2 (midpoint of activation curve (V-0.5) shifted to - 37.7 +/- 1.2 mV). We show here that wild - type gating can partially be restored by a helix stabilizing rescue mutation N785A. V-0.5 of I781T/N785A (V0.5 = -21.5 +/- 0.6 mV) was shifted back towards wild - type (V0.5 = - 9.9 +/- 1.1 mV). Homology models developed in our group (see accompanying article for details) were used to perform Molecular Dynamics - simulations (MD - simulations) on wild - type and mutant channels. Systematic changes in segment IIIS6 (M1187 - F1194) and in helix IIS6 (N785 - L786) were studied. The simulated structural changes in S6 segments of I781T/N785A were less pronounced than in I781T. A delicate balance between helix flexibility and stability enabling the formation of hydrophobic seals at the inner channel mouth appears to be important for wild - type CaV1.2 gating. Our study illustrates that effects of mutations in the lower part of IIS6 may not be localized to the residue or even segment being mutated, but may affect conformations of interacting segments. C1 [Hering, Steffen] Univ Vienna, Dept Pharmacol & Toxicol, Inst Pharmacol & Toxicol, Vienna, Austria. [Stary, Anna; Wolschann, Peter] Univ Vienna, Inst Theoret Chem, Vienna, Austria. [Guy, H. Robert] NCI, Cell Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Hering, S (reprint author), Univ Vienna, Dept Pharmacol & Toxicol, Inst Pharmacol & Toxicol, Vienna, Austria. EM steffen.hering@univie.ac.at RI Stary-Weinzinger, Anna/A-3629-2014 OI Stary-Weinzinger, Anna/0000-0002-9202-0484 FU FWF [15914, P19614-B11]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX We thank Boris Zhorov for suggesting mutation N785A and Thomas Peterbauer for help with confocal microscopy, and Marion Maw for initiating this work. This project was supported by FWF grants 15914 and P19614-B11 (to Steffen Hering) and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to H. Robert Guy). NR 23 TC 7 Z9 7 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6950 J9 CHANNELS JI Channels PD MAY-JUN PY 2008 VL 2 IS 3 BP 216 EP 223 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 344SW UT WOS:000258948600012 PM 18836301 ER PT J AU Zhao, BZ He, YY Bilski, PJ Chignell, CF AF Zhao, Baozhong He, Yu-Ying Bilski, Piotr J. Chignell, Colin F. TI Pristine (C-60) and hydroxylated [C-60(OH)(24)] fullerene phototoxicity towards HaCaT keratinocytes: Type I vs type II mechanisms SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID WATER-SOLUBLE FULLERENE; SINGLET OXYGEN; GAMMA-CYCLODEXTRIN; MOLECULAR-OXYGEN; PHOTOPHYSICAL PROPERTIES; PROTEIN PEROXIDES; ELECTRON-TRANSFER; AQUEOUS-SOLUTION; CELLS; DERIVATIVES AB The increasing use of fullerene nanomaterials has prompted widespread concern over their biological effects. Herein, we have studied the phototoxicity of gamma-cyclodextrin bicapped pristine C-60 [(gamma-CyD)(2)/C-60] and its water-soluble derivative C-60(OH)(24) toward human keratinocytes. Our results demonstrated that irradiation of (gamma-CyD)(2)/C-60 or C-60(OH)(24) in D2O generated singlet oxygen with quantum yields of 0.76 and 0.08, respectively. Irradiation (> 400 nm) of C-60(OH)(24) generated superoxide as detected by the EPR spin trapping technique; superoxide generation was enhanced by addition of the electron donor nicotinamide adenine dinucleotide (reduced) (NADH). During the irradiation of (gamma-CyD)(2)/C-60, superoxide was generated only in the presence of NADH. Cell viability measurements demonstrated that (y-CyD)(2)/ C-60 was about 60 times more phototoxic to human keratinocytes than C-60(OH)(24). UVA irradiation of human keratinocytes in the presence of (gamma-CyD)(2)/C-60 resulted in a significant rise in intracellular protein-derived peroxides, suggesting a type II mechanism for phototoxicity. UVA irradiation of human keratinocytes in the presence of C-60(OH)(24) produced diffuse intracellular fluorescence when the hydrogen peroxide probe Peroxyfluor-1 was present, suggesting a type I mechanism. Our results clearly show that the phototoxicity induced by (gamma-CyD)(2)/C-60 is Mainly mediated by singlet oxygen with a minor contribution from superoxide, while C-60(OH)(24) phototoxicity is mainly due to superoxide. C1 [Zhao, Baozhong; He, Yu-Ying; Bilski, Piotr J.; Chignell, Colin F.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Zhao, BZ (reprint author), NIEHS, Lab Pharmacol & Chem, POB 12233, Res Triangle Pk, NC 27709 USA. EM zhaob2@niehs.nih.gov RI Zhao, Baozhong/B-5865-2011 FU Intramural NIH HHS [Z01 ES102225-01, Z99 ES999999] NR 52 TC 48 Z9 49 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2008 VL 21 IS 5 BP 1056 EP 1063 DI 10.1021/tx800056w PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 302XE UT WOS:000256002500013 PM 18422350 ER PT J AU Siraki, AG Deterding, LJ Bonini, MG Jiang, JJ Ehrenshaft, M Tomer, KB Mason, RP AF Siraki, Arno G. Deterding, Leesa J. Bonini, Marcelo G. Jiang, JinJie Ehrenshaft, Marilyn Tomer, Kenneth B. Mason, Ronald P. TI Procainamide, but not N-acetylprocainamide, induces protein free radical formation on myeloperoxidase: A potential mechanism of agranulocytosis SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID CUTANEOUS PHOTOSENSITIZING AGENTS; HORSERADISH-PEROXIDASE; HYDROGEN-PEROXIDE; AROMATIC-HYDROCARBONS; 4-AMINOBENZOIC ACID; LUPUS-ERYTHEMATOSUS; PHOTOLYSIS PRODUCTS; HUMAN-NEUTROPHILS; NITROXIDE METHOD; IN-VITRO AB Procainamide (PA) is a drug that is used to treat tachycardia in postoperative patients or for long-term maintenance of cardiac arrythmias. Unfortunately, its use has also been associated with agranulocytosis. Here, we have investigated the metabolism of PA by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that PA oxidation by MPO/H2O2 would produce a PA cation radical that, in the absence of a biochemical reductant, would lead to the free radical oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms by the reaction of DMPO with a protein free radical. We found that PA metabolism by MPO/H2O2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. N-acetyl-PA did not cause DMPO-MPO formation, indicating that the unsubstituted aromatic amine was more oxidizable. PA had a lower calculated ionization potential than N-acetyl-PA. The DMPO adducts of MPO metabolism, as analyzed by electron spin resonance spectroscopy, included a nitrogen-centered radical and a phenyl radical derived from PA, either of which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with PA/H2O2 and was found to contain DMPO using the anti-DMPO antibody. Mass spectrometry analysis confirmed the identity of the protein as human MPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by free radical metabolites of PA, which we characterized by spin trapping. We propose that drug-induced free radical formation on MPO may play a role in the origin of agranulocytosis. C1 [Siraki, Arno G.; Bonini, Marcelo G.; Jiang, JinJie; Ehrenshaft, Marilyn; Mason, Ronald P.] NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. [Deterding, Leesa J.; Tomer, Kenneth B.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Siraki, AG (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sirakia@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS [Z01 ES050139-13] NR 64 TC 13 Z9 13 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAY PY 2008 VL 21 IS 5 BP 1143 EP 1153 DI 10.1021/tx700415b PG 11 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 302XE UT WOS:000256002500022 PM 18489081 ER PT J AU Prisinzano, TE Rothman, RB AF Prisinzano, Thomas E. Rothman, Richard B. TI Salvinorin a analogs as probes in opiold pharmacology SO CHEMICAL REVIEWS LA English DT Review ID SAGE SALVIA-DIVINORUM; SITE-DIRECTED MUTAGENESIS; RECEPTOR-AGONIST; NEOCLERODANE DITERPENES; A ANALOGS; OPIATE RECEPTORS; BINDING POCKET; KAPPA-AGONISTS; SALVINICIN-B; WILD-TYPE C1 [Rothman, Richard B.] Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66049 USA. RP Rothman, RB (reprint author), Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov RI Prisinzano, Thomas/B-7877-2010 FU Intramural NIH HHS [Z01 DA000121-17] NR 109 TC 52 Z9 54 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0009-2665 J9 CHEM REV JI Chem. Rev. PD MAY PY 2008 VL 108 IS 5 BP 1732 EP 1743 DI 10.1021/cr0782269 PG 12 WC Chemistry, Multidisciplinary SC Chemistry GA 301BJ UT WOS:000255871100014 PM 18476672 ER PT J AU Kim, HY AF Kim, Hee-Yong TI Biochemical and biological functions of docosahexaenoic acid in the nervous system: modulation by ethanol SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Article DE docosahexaenoic acid; neuronal cells; survival; development; ethanol; n-3 fatty acid deficiency; phosphatidylserine; Akt; hippocampal neurons ID CHEMICAL CROSS-LINKING; C6 GLIOMA-CELLS; MOLECULAR-SPECIES COMPOSITION; POLYUNSATURATED FATTY-ACIDS; HAMSTER OVARY CELLS; RAT-BRAIN; PHOSPHATIDYLSERINE BIOSYNTHESIS; MASS-SPECTROMETRY; CONFORMATIONAL-CHANGES; PEROXISOMAL DISORDERS AB Docosahexaenoic acid (DHA, 22:6n-3), an n-3 fatty acid highly concentrated in the central nervous system, is essential for proper neuronal and retinal function. While a high level of DHA is generally maintained in neuronal membranes, inadequate supply of n-3 fatty acid or ethanol exposure leads to a significant loss of DHA in neuronal cells. The roles of DHA in neuronal signaling have been emerging. In this review, biological, biochemical and molecular mechanisms supporting the essential function of DHA in neuronal survival and development are described in relation to n-3 fatty acid depleting conditions. Published by Elsevier Ireland Ltd. C1 NIAAA, Mol Signalling Lab, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, NIH, 5625 Fishers Lane,Room 3N07,MSC9410, Bethesda, MD 20892 USA. EM hykim@mail.nih.gov FU Intramural NIH HHS [Z01 AA000284-18] NR 62 TC 15 Z9 18 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD MAY PY 2008 VL 153 IS 1 BP 34 EP 46 DI 10.1016/j.chemphyslip.2008.02.014 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 312FJ UT WOS:000256654200005 PM 18359292 ER PT J AU Gawrisch, K Soubias, O AF Gawrisch, Klaus Soubias, Olivier TI Structure and dynamics of polyunsaturated hydrocarbon chains in lipid bilayers - significance for GPCR function SO CHEMISTRY AND PHYSICS OF LIPIDS LA English DT Review DE docosahexaenoic acid; docosapentaenoic acid; phosphatidylcholine; phosphatidylethanolamine; phosphatidylserine; G-protein coupled membrane receptor; rhodopsin; nuclear magnetic resonance ID NOESY CROSS-RELAXATION; DOCOSAHEXAENOIC ACID; NEUTRON-DIFFRACTION; BIOLOGICAL-MEMBRANES; SPATIAL-DISTRIBUTION; PHYSICAL-PROPERTIES; DISK MEMBRANES; FATTY-ACIDS; X-RAY; NMR AB This review summarizes results of our recent solid-state NMR investigations on polyunsaturated 18:022:6n3-PC/PE/PS and 18:0-22:5n6-PC bilayers. Data on structure and dynamics of the polyunsaturated docosahexaenoyl (DHAn3,22:6n3) and docosapentaenoyl chains (DPAn6,22:5n6), investigated at physiological conditions,are reported. Lipid-protein interaction was studied on reconstituted bilayers containing the G-protein coupled membrane receptor (GPCR) rhodopsin as well as on rod outer segment (ROS) disk membranes prepared from bovine retinas. Results reveal surprisingly rapid conformational transitions of polyunsaturated chains and existence of weakly specific interactions of DHAn3 with spatially distinct sites on rhodopsin. Published by Elsevier Ireland Ltd. C1 [Gawrisch, Klaus; Soubias, Olivier] NIAAA, Sect NMR, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), NIAAA, Sect NMR, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM klausg@mail.nih.gov FU Intramural NIH HHS [Z01 AA000003-15, Z99 AA999999] NR 48 TC 33 Z9 35 U1 3 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-3084 J9 CHEM PHYS LIPIDS JI Chem. Phys. Lipids PD MAY PY 2008 VL 153 IS 1 BP 64 EP 75 DI 10.1016/j.chemphyslip.2008.02.016 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 312FJ UT WOS:000256654200008 PM 18396152 ER PT J AU Lee, KS Idle, JR AF Lee, Kyung S. Idle, Jeffrey R. TI Pinning down the polo-box domain SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID KINASE-1 AB Polo-like kinase 1 (Plk1) appears to be an attractive target for anticancer therapy. In this issue of Chemistry & Biology, Reindl et al. (2008) describe the identification of a small molecule called Poloxin that appears to interfere with the function of the polo-box domain (PBD) of Plk1. C1 [Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Charles Univ Prague, Inst Pharmacol, Fac Med 1, Prague, Czech Republic. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov OI Idle, Jeff/0000-0002-6143-1520 NR 9 TC 9 Z9 12 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD MAY PY 2008 VL 15 IS 5 BP 415 EP 416 DI 10.1016/j.chembiol.2008.04.009 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 305MT UT WOS:000256183200002 PM 18482691 ER PT J AU Fee, E AF Fee, Elizabeth TI Divorce between theory and practice: the system of public health training in the United States SO CIENCIA & SAUDE COLETIVA LA English DT Article DE Education; Public health; Practice; History; United States AB Many analysts have complained about the severe disconnect between public health as it is taught in schools of public health and public health as it is practiced in health departments. At least in the United States, few faculty members teaching in schools of public health have ever worked in public health departments. By the same token, few of those working in public health departments have degrees from schools of public health; most receive on-the-job training. This history traces the roots of this disconnect or "divorce between theory and practice." It finds that the 1930s were the prime years of community-based public health education, when the pressure of the Depression and the funding newly made available from the federal government by New Deal legislation encouraged practical training programs linked to local communities and health departments. The "divorce" began in the post-war period as an unintended consequence of the system for funding medical education and research at a time of general unpopularity of public health during the McCarthy era. Schools of public health were generally ignored in the 1950s and they began to adapt the strategy that continues today, of using research grants, primarily from the National Institutes of Health, to grow their faculty and facilities. C1 NIH, Natl Lib Med, Hist Med Div, Bethesda, MA USA. RP Fee, E (reprint author), NIH, Natl Lib Med, Hist Med Div, 8600 Rockville Pike Bldg 38,1E 21, Bethesda, MA USA. EM feee@mail.nlm.nih.gov NR 31 TC 4 Z9 5 U1 0 U2 4 PU ABRASCO PI RIO DE JANEIRO PA RUA HESPERIA, 16-PARTE MANGUINHOS, RIO DE JANEIRO, 21050-040, BRAZIL SN 1413-8123 J9 CIENC SAUDE COLETIVA JI Cienc. Saude Coletiva PD MAY-JUN PY 2008 VL 13 IS 3 BP 841 EP 851 DI 10.1590/S1413-81232008000300007 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 385MU UT WOS:000261819100007 PM 18813578 ER PT J AU Lee, JH Kim, JW Ko, NY Mun, SH Kim, DK Kim, JD Kim, HS Lee, KR Kim, YK Radinger, M Her, E Choi, WS AF Lee, J-H. Kim, J-W. Ko, N-Y. Mun, S-H. Kim, D-K. Kim, J-D. Kim, H-S. Lee, K-R. Kim, Y-K. Radinger, M. Her, E. Choi, W-S. TI Camellia japonica suppresses immunoglobulin E-mediated allergic response by the inhibition of Syk kinase activation in mast cells SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE allergy; Camellia japonica; mast cells; Src-family kinase; Syk kinase ID AFFINITY IGE RECEPTOR; ANTIALLERGIC ACTIVITY; 2 PARTS; DISEASES; ANAPHYLAXIS; IMMUNOLOGY; ABSORPTION; EXTRACT; EUGENOL; SEEDS AB Background Novel approaches are being explored to develop new therapies for various allergic diseases. Complementary and alternative medicines are considered to be promising avenues for the development of such new therapies. Objectives To investigate the effect of many Korean plants on the IgE-mediated allergic response in mast cells and in vivo, and its mechanism of action. Materials and methods The anti-allergic activity was tested by evaluating effects on degranulation of mast cells in culture and passive cutaneous anaphylaxis (PCA) in vivo. Its mechanism of action was investigated by immunoblotting analysis, immunoprecipitation, RT-PCR, and other molecular biological approaches in mast cells. Results We screened approximately 100 natural plant extracts collected in Korea for in vitro anti-allergic activity. The leaf extract of Camellia japonica (LECJ) exhibited the most potent effect on degranulation in antigen-stimulated rodent and human mast cells. LECJ reversibly inhibited degranulation in a dose-dependent manner, with IC50 values of similar to 50 mu g/mL for the mast cells, and it also suppressed the expression and secretion of TNF-alpha and IL-4 in rat basophilic leukaemia-2H3 mast cells. In agreement with its in vitro activity, LECJ significantly inhibited mast cell-mediated PCA in an animal model. LECJ inhibited activating phosphorylation of tyrosine Y371 on Syk kinase, indicating that LECJ inhibits the activity of Src-family kinases in mast cells. In the in vitro kinase assay, LECJ directly inhibited Lyn kinase, the major Src-family kinase in the cells. It also suppressed Akt and MAP kinases, which are critical for the production of various pro-inflammatory cytokines in mast cells. In high-performance liquid chromatography analysis, quercetin-3-beta-d-glucoside and eugenol were identified as the major active components. Conclusion The present results strongly suggest that the anti-allergic activity of LECJ is mediated through inhibiting degranulation and allergic cytokine secretion by inhibition of Src-family kinase in mast cells and it may be useful for the treatment of mast cell-related immediate and delayed allergic diseases. C1 [Lee, J-H.; Kim, J-W.; Ko, N-Y.; Mun, S-H.; Kim, D-K.; Kim, J-D.; Kim, H-S.; Her, E.; Choi, W-S.] Konkuk Univ, Coll Med, Dept Immunol, Dept Immunol & Physiol, Chungju 380701, South Korea. [Kim, H-S.] Pusan Univ, Coll Pharm, Pusan, South Korea. [Lee, K-R.] Sungkyunkwan Univ, Coll Pharm, Nat Prod Lab, Suwon, South Korea. [Kim, Y-K.] Kwan Dong Univ, Coll Med, Kangnung, South Korea. [Radinger, M.] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Choi, WS (reprint author), Konkuk Univ, Coll Med, Dept Immunol, Dept Immunol & Physiol, Chungju 380701, South Korea. EM erk.her@kku.ac.kr; wahnchoi@kku.ac.kr FU Intramural NIH HHS NR 41 TC 23 Z9 23 U1 1 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD MAY PY 2008 VL 38 IS 5 BP 794 EP 804 DI 10.1111/j.1365-2222.2008.02936.x PG 11 WC Allergy; Immunology SC Allergy; Immunology GA 289MY UT WOS:000255059800010 PM 18261158 ER PT J AU Gamiel, JL Tobian, AAR Laeyendecker, OB Reynolds, SJ Morrow, RA Serwadda, D Gray, RH Quinn, TC AF Gamiel, Jordyn L. Tobian, Aaron A. R. Laeyendecker, Oliver B. Reynolds, Steven J. Morrow, Rhoda Ashley Serwadda, David Gray, Ronald H. Quinn, Thomas C. TI Improved performance of enzyme-linked immunosorbent assays and the effect of human immunodeficiency virus coinfection on the serologic detection of herpes simplex virus type 2 in Rakai, Uganda SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID GENITAL ULCER DISEASE; ANTIBODIES; ACQUISITION; INFECTION; SERA; TRANSMISSION; IMMUNOASSAY; IMMUNOBLOT AB Ugandan subjects (820) were tested by Focus HerpeSelect enzyme-linked immunosorbent assay (ELISA), Kalon herpes simplex virus type 2 ELISA, and BioKit rapid test, and the results were compared to those of Western blotting. Higher-than-standard-index cutoff values gave optimal sensitivity and specificity. Kalon ELISA was the optimal assay when an index value of 1.5 was used (sensitivity, 91.7%; specificity, 92.4%). C1 [Gamiel, Jordyn L.; Laeyendecker, Oliver B.; Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Laeyendecker, Oliver B.; Reynolds, Steven J.; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [Morrow, Rhoda Ashley] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD 21205 USA. RP Quinn, TC (reprint author), Ross Bldg 1159,720 Rutland Ave, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU National Institute of Allergy and Infectious Diseases FX We are grateful to the study participants, whose commitment and cooperation made this study possible. We also appreciate help with statistical analysis from Melissa Riedesel and Thoai Ngo.; This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 17 TC 37 Z9 37 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD MAY PY 2008 VL 15 IS 5 BP 888 EP 890 DI 10.1128/CVI.00453-07 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 340TC UT WOS:000258666900020 PM 18321879 ER PT J AU Brennan, DJ Rexhepaj, E O'Brien, SL McSherry, E O'Connor, DP Fagan, A Culhane, AC Higgins, DG Jirstrom, K Millikan, RC Landberg, G Duffy, MJ Hewitt, SM Gallaghe, WM AF Brennan, Donal J. Rexhepaj, Elton O'Brien, Sallyann L. McSherry, Elaine O'Connor, Darran P. Fagan, Ailis Culhane, Aedin C. Higgins, Desmond G. Jirstrom, Karin Millikan, Robert C. Landberg, Goran Duffy, Michael J. Hewitt, Stephen M. Gallaghe, William M. TI Altered cytoplasmic-to-nuclear ratio of survivin is a prognostic indicator in breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 6th Meeting of the Society-of-Academic-and-Research-Surgery CY JAN 11-13, 2006 CL Royal Coll Surg Edinburgh, Edinburgh, SCOTLAND SP Soc Acad & Res Surg HO Royal Coll Surg Edinburgh ID CHROMOSOMAL PASSENGER COMPLEX; CELL-PROLIFERATION; MITOTIC SPINDLE; EXPRESSION; APOPTOSIS; PREDICTS; PROTEIN; NODE; P53; PHOSPHORYLATION AB Purpose: Survivin (BIRC5) is a promising tumor biomarker. Conflicting data exist on its prognostic effect in breast cancer. These data may at least be partly due to the manual interpretation of immunohistochemical staining, especially as survivin can be located in both the nucleus and cytoplasm. Quantitative determination of survivin expression using image analysis offers the opportunity to develop alternative scoring models for survivin immunohistochemistry. Here, we present such a model. Experimental Design: A breast cancer tissue microarray containing 102 tumors was stained with an anti-survivin antibody. Whole-slide scanning was used to capture high-resolution images. These images were analyzed using automated algorithms to quantify the staining. Results: Increased nuclear, but not cytoplasmic, survivin was associated with a reduced overall survival (OS; P = 0.038) and disease-specific survival (P = 0.0015). A high cytoplasmicto-nuclear ratio (CNR) of survivin was associated with improved OS (P = 0.005) and disease-specific survival (P = 0.05). Multivariate analysis revealed that the survivin CNR was an independent predictor of CIS (hazard ratio, 0.09; 95% confidence interval, 0.01-0.76; P = 0.027). A survivin CNR of >5 correlated positively with estrogen receptor (P = 0.019) and progesterone receptor (P = 0.033) levels, whereas it was negatively associated with Ki-67 expression (P = 0.04), p53 status (P = 0.005), and c-myc amplification (P = 0.016). Conclusion: Different prognostic information is supplied by nuclear and cytoplasmic survivin in breast cancer. Nuclear survivin is a poor prognostic marker in breast cancer. Moreover, CNR of survivin, as determined by image analysis, is an independent prognostic factor. C1 [Brennan, Donal J.; Rexhepaj, Elton; O'Brien, Sallyann L.; McSherry, Elaine; O'Connor, Darran P.; Gallaghe, William M.] Univ Coll Dublin, Sch Biomol & Biomed Sci, Conway Inst, Dublin 4, Ireland. [Fagan, Ailis; Higgins, Desmond G.; Duffy, Michael J.] Univ Coll Dublin, Sch Med & Med Sci, Dublin 4, Ireland. [Duffy, Michael J.] St Vincents Univ Hosp, Dept Pathol & Lab Med, Dublin 4, Ireland. [Culhane, Aedin C.; Jirstrom, Karin; Landberg, Goran] Harvard Univ, Sch Publ Hlth, Dept Biostat & Computat Biol, Dana Farber Canc Inst, Boston, MA 02115 USA. Lund Univ, Malmo Univ Hosp, Dept Lab Med, Ctr Mol Pathol, Malmo, Sweden. [Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Hewitt, Stephen M.] NCI, NIH, Ctr Canc Res, Tissue Array Res Program,Lab Pathol, Bethesda, MD 20892 USA. RP Gallaghe, WM (reprint author), Univ Coll Dublin, Sch Biomol & Biomed Sci, Conway Inst, Dublin 4, Ireland. EM william.gallagher@ucc.ie RI Higgins, des/J-6314-2012; OI Hewitt, Stephen/0000-0001-8283-1788; Higgins, Des/0000-0002-3952-3285; Gallagher, William/0000-0002-4307-5999 FU Intramural NIH HHS NR 37 TC 59 Z9 61 U1 2 U2 8 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 MAY 1 PY 2008 VL 14 IS 9 BP 2681 EP 2689 DI 10.1158/1078-0432.CCR-07-1760 PG 9 WC Oncology SC Oncology GA 297KT UT WOS:000255616300021 PM 18451232 ER PT J AU Portera, CC Walshe, JM Rosing, DR Denduluri, N Berman, AW Vatas, U Velarde, M Chow, CK Steinberg, SM Nguyen, D Yang, SX Swain, SM AF Portera, Chia C. Walshe, Janice M. Rosing, Douglas R. Denduluri, Neelima Berman, Arlene W. Vatas, Ujala Velarde, Margarita Chow, Catherine K. Steinberg, Seth M. Nguyen, Diana Yang, Sherry X. Swain, Sandra M. TI Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODIES; PHASE-II; DIMERIZATION INHIBITOR; DILATED CARDIOMYOPATHY; ADJUVANT CHEMOTHERAPY; NEUREGULIN RECEPTOR; TYROSINE KINASES; PROSTATE-CANCER; ERBB RECEPTORS; SINGLE-AGENT AB Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab inpatients with human epidermal growth factor receptor 2 (HER2) - positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2(+) metastatic breast cancer, <= 3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) >= 55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits. C1 [Swain, Sandra M.] Washington Hosp Ctr, Washington Inst Canc, Washington, DC 20001 USA. [Portera, Chia C.; Walshe, Janice M.; Denduluri, Neelima; Berman, Arlene W.; Vatas, Ujala; Velarde, Margarita] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Rosing, Douglas R.] NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. [Chow, Catherine K.] NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Ctr Canc Res, Biostat & Data Management Sect, Off Clin Director, Bethesda, MD 20892 USA. [Nguyen, Diana; Yang, Sherry X.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Swain, SM (reprint author), Washington Hosp Ctr, Washington Inst Canc, 110 Irving St NW, Washington, DC 20001 USA. EM Sandra.M.Swain@medstar.net FU Intramural NIH HHS [Z01 BC010435-07] NR 47 TC 86 Z9 88 U1 1 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 MAY 1 PY 2008 VL 14 IS 9 BP 2710 EP 2716 DI 10.1158/1078-0432.CCR-07-4636 PG 7 WC Oncology SC Oncology GA 297KT UT WOS:000255616300025 PM 18451236 ER PT J AU Liu, G Kolesar, J McNeel, DG Leith, C Schell, K Eickhoff, J Lee, F Traynor, A Marnocha, R Alberti, D Zwiebel, J Wilding, G AF Liu, Glenn Kolesar, Jill McNeel, Douglas G. Leith, Catherine Schell, Kathy Eickhoff, Jens Lee, Fred Traynor, Anne Marnocha, Rebecca Alberti, Dona Zwiebel, James Wilding, George TI A phase I pharmacokinetic and pharmacodynamic correlative study of the antisense Bcl-2 oligonucleotide G3139, in combination with carboplatin and paclitaxel, in patients with advanced solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUOUS INTRAVENOUS-INFUSION; METASTATIC COLORECTAL-CANCER; REFRACTORY PROSTATE-CANCER; CELL LUNG-CANCER; OBLIMERSEN SODIUM; APOPTOSIS; EXPRESSION; PROTEIN; TRIAL; TAXOL AB Purpose: This phase I trial assessed the safety and tolerability of G3139 when given in combination with carboplatin and paclitaxel chemotherapy. The effect of G3139 treatment on Bcl-2 expression in peripheral blood mononuclear cells (PBMC) and paired tumor biopsies was also determined. Experimental Design: Patients with advanced solid malignancies received various doses of G3139 (continuous i.v. infusion days 1-7), carboplatin (day 4), and paclitaxel (day 4), repeated in 3-week cycles, in a standard cohort-of-three dose-escalation schema. Changes in Bcl-2/Bax transcription/expression were assessed at baseline and day 4 (prechemotherapy) in both PBMCs and paired tumor biopsies. The pharmacokinetic interactions between G3139 and carboplatin/paclitaxel were measured. Results: Forty-two patients were evaluable for safety analysis. Primary toxicities were hematologic (myelosuppression and thrombocytopenia). Dose escalation was stopped with G3139 at 7 mg/kg/d, carboplatin at area under the curve of 6, and paclitaxel at 175 mg/m(2) due to significant neutropenia seen in cycle 1 and safety concerns in further escalating chemotherapy in this phase I population. With G3139 at 7 mg/kg/d, 13 patients underwent planned tumor biopsies, of which 12 matched pairs were obtained. Quantitative increases in intratumoral G3139 with decreases in intratumoral Bcl-2 gene expression were seen. This paralleled a decrease in Bcl-2 protein expression observed in PBMCs. Conclusions: Although the maximal tolerated dose was not reached, the observed toxicities were consistent with what one would expect from carboplatin and paclitaxel alone. In addition, we show that achievable intratumoral G3139 concentrations can result in Bcl-2 down-regulation in solid tumors and PBMCs. C1 [Liu, Glenn; Kolesar, Jill; McNeel, Douglas G.; Schell, Kathy; Traynor, Anne; Marnocha, Rebecca; Alberti, Dona; Wilding, George] Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, Madison, WI 53792 USA. [Leith, Catherine] Univ Wisconsin, Dept Pathol, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Eickhoff, Jens] Univ Wisconsin, Dept Biostat, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Lee, Fred] Univ Wisconsin, Dept Radiol, Sch Med & Publ Hlth, Madison, WI 53792 USA. [Zwiebel, James] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Liu, G (reprint author), Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, 600 Highland Ave,K6-534 CSC, Madison, WI 53792 USA. EM gxl@medicine.wisc.edu FU NCI NIH HHS [U01 CA062491-12, U01 CA062491]; NCRR NIH HHS [M01 RR003186-200429, M01 RR003186, M01 RR03186]; PHS HHS [22XS096] NR 38 TC 13 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 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAY 1 PY 2008 VL 14 IS 9 BP 2732 EP 2739 DI 10.1158/1078-0432.CCR-07-1490 PG 8 WC Oncology SC Oncology GA 297KT UT WOS:000255616300028 PM 18451239 ER PT J AU Pfeiffer, CM Osterloh, JD Kennedy-Stephenson, J Picciano, MF Yetley, EA Rader, JI Johnson, CL AF Pfeiffer, Christine M. Osterloh, John D. Kennedy-Stephenson, Jocelyn Picciano, Mary Frances Yetley, Elizabeth A. Rader, Jeanne I. Johnson, Clifford L. TI Trends in circulating concentrations of total homocysteine among US adolescents and adults: Findings from the 1991-1994 and 1999-2004 National Health and Nutrition Examination Surveys SO CLINICAL CHEMISTRY LA English DT Article ID PLASMA TOTAL HOMOCYSTEINE; FOLIC-ACID FORTIFICATION; GLOMERULAR-FILTRATION-RATE; EXAMINATION SURVEY NHANES; UNITED-STATES; RANDOMIZED-TRIALS; SERUM; DISEASE; FOLATE; METAANALYSIS AB BACKGROUND: The National Health and Nutrition Examination Survey (NHANES) has monitored total homocysteine (tHcy) concentrations in a nationally-representative sample of the US population since 1991. Until recently, however, data could not be compared across survey periods because of changes in analytical methods and specimen matrices. Such an analysis of these data could supplement current knowledge regarding whether the US folic acid fortification program has modified national plasma tHcy concentrations. METHODS: We examined tHcy data in the prefortification NHANES III survey (phase 11, 1991-1994) and in 3 postfortification survey periods (1999-2000, 20012002, and 2003-2004). We applied method adjustment equations to the survey data based on method comparison studies of separate samples. Persons with chronic kidney disease were excluded from the analyses. RESULTS: Mean plasma tHcy concentrations decreased by 8%, 9%, and 10% for adolescent, adult, and older men andby6%,3%, and 13% for women, respectively, from before to after fortification. Concentrations remained unchanged between the first and third postfortification survey periods. Prevalence estimates of increased plasma tHcy concentrations (> 13 mu mol/L) for older men and women decreased from prefortification (32% and 20%, respectively) to postfortification (14% and 5%, respectively) but remained unchanged thereafter (16% and 14%, respectively [males] and 5% and 9%, respectively [females]). CONCLUSIONS: After adjusting for method changes, we quantified a prefortification to postfortification decrease in circulating tHcy concentrations of about 10% in a national sample of the US population. This change is similar to effects seen in intervention trials with folic acid and in smaller observational studies. (c) 2008 American Association for Clinical Chemistry. C1 [Pfeiffer, Christine M.; Osterloh, John D.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30341 USA. [Kennedy-Stephenson, Jocelyn; Johnson, Clifford L.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Picciano, Mary Frances; Yetley, Elizabeth A.] NIH, Off Regulatory Supplements, Bethesda, MD 20892 USA. [Rader, Jeanne I.] Food & Drug Adm, Off Regulatory Sci, College Pk, MD USA. RP Pfeiffer, CM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, 4770 Buford Hwy,MS F55, Atlanta, GA 30341 USA. EM cpfeiffer@cdc.gov NR 39 TC 33 Z9 36 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD MAY PY 2008 VL 54 IS 5 BP 801 EP 813 DI 10.1373/clinchem.2007.100214 PG 13 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 293OM UT WOS:000255344600006 PM 18375482 ER PT J AU Kim, SY Lee, CH Midura, BV Yeung, C Mendoza, A Hong, SH Ren, L Wong, D Korz, W Merzouk, A Salari, H Zhang, H Hwang, ST Khanna, C Helman, LJ AF Kim, Su Young Lee, Chih Hung Midura, Brieanne V. Yeung, Choh Mendoza, Arnulfo Hong, Sung Hyeok Ren, Ling Wong, Donald Korz, Walter Merzouk, Ahmed Salari, Hassan Zhang, Hong Hwang, Sam T. Khanna, Chand Helman, Lee J. TI Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE chemokines; CXCR4 inhibition; melanoma; osteosarcoma; pulmonary metastasis ID B16 TUMOR-CELLS; CXCR4; OSTEOSARCOMA; EXPRESSION; RECEPTOR; CANCER; INVOLVEMENT; MELANOMA AB Metastasis continues to be the leading cause of mortality for patients with cancer. High expression of the chemokine receptor CXCR4 correlates with poor prognosis in many cancers, including osteosarcoma and melanoma. CXCL12, the ligand for CXCR4, is expressed at high levels in the lung and lymph node, which are the primary sites to which these tumors metastasize respectively. These findings suggest that therapy aimed at disruption of this specific receptor/ligand complex may lead to a decrease in metastases. CTCE-9908, a small peptide CXCR4 antagonist was utilized in two murine metastasis models to test this hypothesis. Treatment of osteosarcoma cells in vitro with CTCE-9908 led to the following changes: decreased adhesion, decreased migration, decreased invasion, and decreased growth rate. Following tail vein injection of osteosarcoma cells, mice that were treated with CTCE-9908 had a 50% reduction in the number of gross metastatic lung nodules and a marked decrease in micro-metastatic disease. Similar findings were observed following injection of melanoma cells and treatment with CTCE-9908. However, these results could only be consistently reproduced when the cells were pre-treated with the inhibitor. A novel ex vivo luciferase assay showed decreased numbers of cells in the lung immediately after injection into mice, when treated with CTCE-9908, suggesting the importance of interactions between the receptor and the ligand. Our findings show that inhibition of the CXCR4/CXCL12 pathway decreases metastatic disease in two murine tumor models and expands on previous reports to describe potential mechanisms of action. C1 [Kim, Su Young; Midura, Brieanne V.; Yeung, Choh; Mendoza, Arnulfo; Hong, Sung Hyeok; Ren, Ling; Khanna, Chand; Helman, Lee J.] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lee, Chih Hung] Kaohsiung Med Univ, Kaohsiung Med Univ Hosp, Dept Dermatol, Kaohsiung, Taiwan. [Wong, Donald; Korz, Walter; Merzouk, Ahmed; Salari, Hassan] Chemokine Therapeut Corp, Vancouver, BC, Canada. [Zhang, Hong; Hwang, Sam T.] NCI, Dermatol Branch, NIH, Bethesda, MD USA. RP Helman, LJ (reprint author), NCI, Pediat Oncol Branch, NIH, 10 Ctr Dr,Bldg 31,Room 3A11, Bethesda, MD 20892 USA. EM helmanl@mail.nih.gov RI Lee, Chih-Hung /B-4081-2010 FU Intramural NIH HHS [Z99 CA999999] NR 16 TC 133 Z9 138 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAY PY 2008 VL 25 IS 3 BP 201 EP 211 DI 10.1007/s10585-007-9133-3 PG 11 WC Oncology SC Oncology GA 290HB UT WOS:000255112800002 PM 18071913 ER PT J AU Engbring, JA Hossain, R VanOsdol, SJ Kaplan-Singer, B Wu, M Hibino, S Koblinski, JE AF Engbring, Jean A. Hossain, Rydhwana VanOsdol, Sherilyn J. Kaplan-Singer, Benjamin Wu, Michael Hibino, Suguru Koblinski, Jennifer E. TI The laminin alpha-1 chain derived peptide, AG73, increases fibronectin levels in breast and melanoma cancer cells SO CLINICAL & EXPERIMENTAL METASTASIS LA English DT Article DE B16F10 melanoma cells; MDA-MB-231 breast cancer cells; laminin-111; bone metastasis; AG73; fibronectin ID LAMININ ALPHA-1 CHAIN; AMINO-ACID-SEQUENCE; EXPERIMENTAL METASTASIS; IN-VITRO; G-DOMAIN; A CHAIN; BINDING; IDENTIFICATION; EXPRESSION; RKRLQVQLSIRT AB Laminin-111 promotes the malignant phenotype, and a 12-mer synthetic peptide (AG73, RKRLQVQLSIRT) from the carboxyl terminus of the alpha 1 chain increases B16F10 melanoma metastasis to the lung and liver. Using an antibody array, fibronectin was identified as an up-regulated protein in B16F10 cells after incubation with this peptide. The increased fibronectin is cell-associated with no increase in soluble fibronectin. The AG73 peptide increased the number and size of bone metastases with both B16F10 melanoma and MDA-231 breast carcinoma cells in an intracardiac injection model. Using siRNA transfection, we found that a reduction in fibronectin expression did not reduce bone metastasis in the presence of the metastasis-promoting peptide AG73. We conclude that the laminin peptide AG73 increases metastasis independently of fibronectin expression. C1 [Engbring, Jean A.; Hossain, Rydhwana; VanOsdol, Sherilyn J.; Kaplan-Singer, Benjamin; Wu, Michael; Hibino, Suguru; Koblinski, Jennifer E.] Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Koblinski, JE (reprint author), Northwestern Univ, Robert H Lurie Comprehens Canc Inst, Feinberg Sch Med, Dept Pathol,Breast Canc Res Program, 303 E Super St,Lurie 4-105, Chicago, IL 60611 USA. EM j-koblinski@northwestern.edu OI Wu, Michael C./0000-0002-3357-6570 NR 35 TC 5 Z9 5 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0262-0898 J9 CLIN EXP METASTAS JI Clin. Exp. Metastasis PD MAY PY 2008 VL 25 IS 3 BP 241 EP 252 DI 10.1007/s10585-007-9138-y PG 12 WC Oncology SC Oncology GA 290HB UT WOS:000255112800006 PM 18185912 ER PT J AU Howell, CD Dowling, TC Paul, M Wahed, AS Terrault, NA Taylor, M Jeffers, L Hoofnagle, JH AF Howell, Charles D. Dowling, Thomas C. Paul, Marika Wahed, Abdus S. Terrault, Norah A. Taylor, Milton Jeffers, Lennox Hoofnagle, Jay H. CA Virahep-C Study Grp TI Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID PEGYLATED INTERFERON-ALPHA-2B; RACIAL-DIFFERENCES; ANTIVIRAL THERAPY; RANDOMIZED-TRIAL; GENE-EXPRESSION; PLUS RIBAVIRIN; ALPHA-2A; PROPRANOLOL; KINETICS AB Background & Aims: The relationship between serum peginterferon pharmacokinetics and pharmacodynamics and the early virologic response (EVR) to peginterferon and ribavirin therapy was assessed in patients with chronic hepatitis C virus (HCV) genotype 1 infection. Methods: A total of 333 patients (160 African Americans [AA] and 173 Caucasian Americans [CA]) who received peginterferon alfa-2a (180 mu g/wk) without a dose modification during the initial 4 weeks of therapy were analyzed. Peginterferon and 2,5-oligoadenylate synthetase (2,5-OAS) serum levels were measured on days 0, 1, 2, 3, 7, 14, 28, 56, 84, and 168 of treatment. The EVR (>= 2-log(10) decline in HCV RNA levels by week 12 of therapy) was the primary virologic end point. Results: Peginterferon pharmacokinetics after the first dose were similar in AA and CA, but AA had greater peginterferon concentrations at days 1, 3, 14, and 28 (P < .05). AA had higher absolute serum 2,5-OAS levels on days 0, 1, 2, 3, 7, 14, 28, and 56 (P < .05), but the magnitude of 2,5-OAS induction during treatment were similar. AA patients showed a smaller decline in serum HCV RNA during the first 28 days of treatment (P < .001) and a lower EVR (65% vs 83%). AA and CA with EVR had significantly higher serum peginterferon concentrations and serum 2,5-OAS induction during the first 12 weeks than patients without an EVR. Conclusions: Peginterferon alfa-2a pharmacokinetic and pharmacodynamic variability is associated with EVR in both AA and CA with HCV infection, but do not explain the racial disparity in combination treatment efficacy. C1 [Howell, Charles D.; Virahep-C Study Grp] Univ Maryland, Baltimore Sch Med, Baltimore, MD 21201 USA. [Dowling, Thomas C.] Univ Maryland, Baltimore Sch Pharm, Baltimore, MD 21201 USA. [Paul, Marika; Wahed, Abdus S.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Terrault, Norah A.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. [Taylor, Milton] Indiana Univ, Dept Biol, Bloomington, IN USA. [Jeffers, Lennox] Univ Miami, Sch Med, Miami, FL USA. [Hoofnagle, Jay H.] NIH, Bethesda, MD 20892 USA. RP Howell, CD (reprint author), Univ Maryland, Baltimore Sch Med, 22 S Greene St,N3W50, Baltimore, MD 21201 USA. EM chowell@umaryland.edu RI Dowling, Thomas/D-2147-2013; OI Dowling, Thomas/0000-0003-3214-9283; Wahed, Abdus/0000-0001-6911-7221 FU NCRR NIH HHS [M01 RR000645, M01 RR000042, M01 RR000046, M01 RR000079, M01 RR00046, M01 RR016500, M01 RR016500-040018, M01 RR016500-056934, M01 RR16500, M02 RR000079, M01 RR016500-030018, M01 RR00645]; NIDDK NIH HHS [U01 DK60346, U01 DK60342, U01 DK60340, U01 DK60335, U01 DK60324, U01 DK060346, U01 DK060344, U01 DK060342, U01 DK060340, U01 DK060335-05, U01 DK060335-03, U01 DK060335-01, U01 DK060335, U01 DK060324, K24 DK072036-03, K24 DK072036-01, K24 DK072036, K24 DK072036-02, K24 DK072036-04, U01 DK060309, U01 DK060327, U01 DK060329, U01 DK060335-02, U01 DK060335-04, U01 DK060341, U01 DK060345, U01 DK060349, U01 DK060352, U01 DK60309, U01 DK60327, U01 DK60329, U01 DK60341, U01 DK60345, U01 DK60349, U01 DK60352, 1 K24 DK072036-01, U01 DK60344] NR 21 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD MAY PY 2008 VL 6 IS 5 BP 575 EP 583 DI 10.1016/j.cgh.2008.02.035 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 300ED UT WOS:000255806200019 PM 18407798 ER PT J AU Kuo, DZ Milstone, AM Omokaro, SO Friedman, AD Karanjawala, ZE Borowitz, M Joyner, ML Halsey, NA Sibinga, EM AF Kuo, Dennis Z. Milstone, Aaron M. Omokaro, Stephanie O. Friedman, Alan D. Karanjawala, Zarir E. Borowitz, Michael Joyner, Mary L. Halsey, Neal A. Sibinga, Erica M. TI Epstein-Barr virus-associated central nervous system lymphoproliferative disease in a patient with acquired immunodeficiency syndrome responsive to highly active antiretroviral therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID LYMPHOMA; AIDS; DISORDERS; SURVIVAL AB A 20-year-old man with acquired immunodeficiency syndrome (AIDS) and central nervous system (CNS) lymphoproliferative disease experienced improvement with highly active antiretroviral therapy (HAART) without radiation therapy. Our experience highlights the importance of biopsy in evaluating multifocal radiographic CNS lesions and the central role of HAART in treating AIDS-related CNS disease. C1 [Kuo, Dennis Z.; Joyner, Mary L.; Sibinga, Erica M.] Johns Hopkins Univ, Sch Med, Div Gen Pediat & Adolescent Med, Baltimore, MD 21287 USA. [Milstone, Aaron M.; Halsey, Neal A.] Johns Hopkins Univ, Div Pediat Infect Dis, Baltimore, MD USA. [Omokaro, Stephanie O.; Friedman, Alan D.] Johns Hopkins Univ, Div Pediat Oncol, Baltimore, MD USA. [Karanjawala, Zarir E.; Borowitz, Michael] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Halsey, Neal A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Omokaro, Stephanie O.] NCI, NIH, Bethesda, MD 20892 USA. RP Kuo, DZ (reprint author), Johns Hopkins Univ, Sch Med, Div Gen Pediat & Adolescent Med, 200 N Wolfe St, Baltimore, MD 21287 USA. EM dkuo5@jhmi.edu NR 8 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 1 PY 2008 VL 46 IS 9 BP 1476 EP 1478 DI 10.1086/587111 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 285NU UT WOS:000254784300028 PM 18419459 ER PT J AU Mannon, RB AF Mannon, Roslyn B. TI Leflunomide therapy in kidney transplantation: Ready for prime time? SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID BK REPLICATION; NEPHROPATHY; VIRUS C1 NIDDK, Transplantat Branch, NIH, Bethesda, MD 20892 USA. RP Mannon, RB (reprint author), NIDDK, Transplantat Branch, NIH, 10 Ctr Dr,MSC 1450,CRC 5-5750, Bethesda, MD 20892 USA. EM rozm@mail.nih.gov FU Intramural NIH HHS NR 13 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2008 VL 3 IS 3 BP 652 EP 653 DI 10.2215/CJN.01050308 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 294CS UT WOS:000255382300003 PM 18385395 ER PT J AU Cerda, J Lameire, N Eggers, P Pannu, N Uchino, S Wang, H Bagga, A Levin, A AF Cerda, Jorge Lameire, Norbert Eggers, Paul Pannu, Neesh Uchino, Sigehiko Wang, Haiyan Bagga, Arvind Levin, Adeera TI Epidemiology of acute kidney injury SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; HEMOLYTIC-UREMIC SYNDROME; SOUTH-AFRICA; DEVELOPING-COUNTRIES; IMPROVING OUTCOMES; CENTER EXPERIENCE; EASTERN INDIA; RISK-FACTORS; CHILDREN; MORTALITY AB Background and objectives: The worldwide incidence of acute kidney injury is poorly known because of underreporting, regional disparities, and differences in definition and case mix. New definitions call for revision of the problem with unified criteria. Design, setting, participants, & measurements: This article reports on the research recommendations of an international multidisciplinary committee, assembled to define a research agenda on acute kidney injury epidemiology using a modified three-step Delphi process. Results: Knowledge of incidence and risk factors is crucial because it drives local and international efforts on detection and treatment. Also, notable differences exist between developing and developed countries: Incidence seems higher in the former, but underreporting compounded by age and gender disparities makes available data unreliable. In developing countries, incidence varies seasonally; incidence peaks cause critical shortages in medical and nursing personnel. Finally, in developing countries, lack of systematic evaluation of the role of falciparum malaria, obstetric mechanisms, and hemolytic uremic syndrome on acute kidney injury hampers efforts to prevent acute kidney injury. Conclusions: The committee concluded that epiderniologic studies should include (1) prospective out- and inpatient studies that measure incidence of community and hospital acute kidney injury and post-acute kidney injury chronic kidney disease; (2) incidence measurements during seasonal peaks in developing and developed countries; and (3) whenever available, use of reliable existing administrative or institutional databases. Epidemiologic studies using standardized definitions in community and institutional settings in developing and underdeveloped countries are essential first steps to achieving early detection and intervention and improved patient outcomes. C1 [Cerda, Jorge] Albany Med Coll, Div Nephrol, Albany, NY 12209 USA. [Lameire, Norbert] Ghent Univ Hosp, Dept Internal Med, B-9000 Ghent, Belgium. [Eggers, Paul] NIDDK, NIH, Bethesda, MD USA. [Pannu, Neesh] Univ Alberta, Div Nephrol, Edmonton, AB, Canada. [Uchino, Sigehiko] Saitama Med Ctr, Dept Emergency & Crit Care Med, Saitama, Japan. [Wang, Haiyan] Beijing Univ, Hosp 1, Inst Nephrol, Beijing, Peoples R China. [Bagga, Arvind] All India Inst Med Sci, Div Pediat Nephrol, New Delhi, India. [Levin, Adeera] Univ British Columbia, Dept Nephrol, Vancouver, BC V5Z 1M9, Canada. RP Cerda, J (reprint author), Albany Med Coll, Div Nephrol, 62 Hackett Blvd, Albany, NY 12209 USA. EM cerdaj@mail.amc.edu NR 89 TC 89 Z9 102 U1 0 U2 9 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAY PY 2008 VL 3 IS 3 BP 881 EP 886 DI 10.2215/CJN.04961107 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 294CS UT WOS:000255382300035 PM 18216347 ER PT J AU Kieburtz, K Tilley, B Ravina, B Galpern, W Shannon, K Tanner, C Wooten, GF AF Kieburtz, Karl Tilley, Barbara Ravina, Bernard Galpern, Wendy Shannon, Kathleen Tanner, Caroline Wooten, G. Frederick CA NINDS NET-PD Investigators TI A pilot clinical trial of creatine and minocycline in early Parkinson disease: 18-month results SO CLINICAL NEUROPHARMACOLOGY LA English DT Review DE clinical trial; creatine; futility; minocycline; Parkinson disease ID NEUROPROTECTION; FUTILITY; BURDEN; MODEL AB Objective: To report an 18-month follow-up on creatine and minocycline futility study, the Neuroprotective Exploratory Trials in Parkinson Disease, Futility Study 1 (NET-PD FS-1). Background: The NET-PD FS-1 futility study on creatine and minocycline found neither agent futile in slowing down the progression of disability in Parkinson disease (PD) at 12 months using the prespecified futility threshold. An additional 6 months of follow-up aimed to assess safety and potential interactions of the study interventions with anti-parkinsonian therapy. Methods: Additional 6 months of follow-up in randomized, blinded phase H trial of creatine (dosage, 10 g/d) and minocycline (dosage, 200 mg/d) in subjects with early PD. Results: By 18 months, symptomatic treatment of PD symptoms was required in 61% of creatine, 62% of minocycline, and 60% of placebo-treated subjects. Study treatment was prematurely discontinued in 9%, 23%, and 6% of subjects in the creatine, minocycline, and placebo arms, respectively. Creatine and minocycline did not seem to adversely influence the response to symptomatic therapy nor increase adverse events. Conclusions: Data from this small, 18-month phase II trial of creatine and minocycline do not demonstrate safety concerns that would preclude a large, phase III efficacy trial, although the decreased tolerability of minocycline is a concern. C1 [Galpern, Wendy] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Kieburtz, Karl] Univ Rochester, Rochester, NY 14627 USA. [Tilley, Barbara] Med Univ S Carolina, Charleston, IL USA. [Shannon, Kathleen] Rush Univ, Med Ctr, Chicago, IL 60612 USA. [Tanner, Caroline] Parkinson Inst, Sunnyvale, CA USA. [Wooten, G. Frederick] Univ Virginia, Charlottesville, VA USA. RP Galpern, W (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Room 2225,6001 Execut Blvd, Bethesda, MD 20892 USA. EM galpernw@ninds.nih.gov OI Miyasaki, Janis/0000-0002-6372-6007 NR 20 TC 57 Z9 58 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-5664 J9 CLIN NEUROPHARMACOL JI Clin. Neuropharmacol. PD MAY-JUN PY 2008 VL 31 IS 3 BP 141 EP 150 DI 10.1097/WNF.0b013e3181342f32 PG 10 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 311CU UT WOS:000256578600003 ER PT J AU Elster, EA Leeser, DB Morrissette, C Pepek, JM Quiko, A Hale, DA Chamberlain, C Salaita, C Kirk, AD Mannon, RB AF Elster, Eric A. Leeser, David B. Morrissette, Craig Pepek, Joseph M. Quiko, Albin Hale, Douglas A. Chamberlain, Christine Salaita, Christine Kirk, Allan D. Mannon, Roslyn B. TI Obesity following kidney transplantation and steroid avoidance immunosuppression SO CLINICAL TRANSPLANTATION LA English DT Article DE end-stage renal disease; immunosuppression; kidney transplantation; obesity; steroid avoidance ID RENAL-TRANSPLANTATION; WEIGHT-GAIN; RISK-FACTOR; DISEASE; MONOTHERAPY; RECIPIENTS; INDUCTION; THERAPY AB Obesity is an important co-morbidity within end-stage renal disease (ESRD) and renal transplant populations. Previous studies have suggested that chronic corticosteroids result in increased body weight post-transplant. With the recent adoption of steroid-sparing immunosuppressive strategies, we evaluated the effect of these strategies on body mass index (BMI) after renal transplantation. We examined 95 renal transplant recipients enrolled in National Institutes of Health clinical transplant trials over the past three yr who received either lymphocyte depletion-based steroid sparing or traditional immunosuppressive therapy that included steroids for maintenance immunosuppression. Recipients were overweight prior to transplant and no significant differences existed in pre-transplant BMI among treatment groups. Regardless of therapy, BMI increased post-transplant in all recipients. The BMI increase consisted of an average weight gain of 5.01 +/- 7.12 kg (mean, SD) post-transplant. Additionally, in a number of recipients placed on maintenance steroids, subsequent withdrawal at a mean of 100 d post-transplant had no impact on weight gain. Thus, body weight and BMI increase following kidney transplantation, even in the absence of steroids. Thus, patients gain weight after renal transplantation regardless of the treatment strategy. Steroid avoidance alone does not reduce risk factors associated with obesity in our patient population. C1 [Elster, Eric A.; Leeser, David B.; Hale, Douglas A.; Chamberlain, Christine; Salaita, Christine; Kirk, Allan D.; Mannon, Roslyn B.] NIDDKD, Transplantat Branch, NIH, Bethesda, MD 20892 USA. [Elster, Eric A.; Pepek, Joseph M.] USN, Naval Med Res Ctr, Combat Casualty Care Directorate, Silver Spring, MD USA. [Elster, Eric A.; Leeser, David B.; Hale, Douglas A.; Kirk, Allan D.] USA, Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20310 USA. [Elster, Eric A.; Leeser, David B.; Quiko, Albin] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Elster, Eric A.] USN, Natl Naval Med Ctr, Dept Surg, Bethesda, MD 20084 USA. [Morrissette, Craig] USA, Walter Reed Army Inst Res, Silver Spring, MD USA. RP Elster, EA (reprint author), 503Robert Grant Ave, Silver Spring, MD USA. EM eric.elster@med.navy.mil RI Kirk, Allan/B-6905-2012 NR 16 TC 20 Z9 20 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0902-0063 J9 CLIN TRANSPLANT JI Clin. Transplant. PD MAY-JUN PY 2008 VL 22 IS 3 BP 354 EP 359 DI 10.1111/j.1399-0012.2008.00792.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 301OX UT WOS:000255906600012 PM 18279417 ER PT J AU Sherrill, JT AF Sherrill, Joel T. TI Commentary: Expanding the research agenda on interventions for child and adolescent anxiety disorders SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Editorial Material ID RANDOMIZED EFFECTIVENESS TRIAL; OBSESSIVE-COMPULSIVE DISORDER; COGNITIVE-BEHAVIORAL THERAPY; INTERNALIZING DISORDERS; ANXIOUS CHILDREN; CLINICAL-TRIAL; SOCIAL PHOBIA; PRIMARY-CARE; QUALITY AB The articles in this series describe complementary programs of research and innovative approaches to extend evidence-based interventions for youth with anxiety in several important directions: to extend the target age range [Pincus, D. B., Santucci, L. C., Ehrenreich, J. T., & Eyberg, S. M. (2008-this issue). Treating separation anxiety disorder in young children: Exploring the additive impact of exposure on. PUT treatment outcome. Cognitive and Behavioral Practice, 151; to extend interventions to more broadly defined target populations, including youth with co-occurring psychiatric symptoms [Weersing, V X, Gonzalez, A., Campo, J. V., & Lucas, A. N. (2008-this issue). Brief CBT for pediatric anxiety and depression: Piloting an integrated treatment approach. Cognitive and Behavioral Practice, 151 and somatic symptoms [Reigada, L. C., Fisher R H., Cutler C., & Masia Warner, C. (2008-this issue). An innovative treatment approach for children with anxiety disorders and medically unexplained somatic complaints. Cognitive and Behavioral Practice, 15]; to extend access in specific community-practice settings [Ginsburg, G. S., Becker K, Kingery, J., & Nichols, T. (2008-this issue). Transporting CBT for childhood anxiety disorders into inner city school-based mental health clinics. Cognitive and Behavioral Practice, 15; Reigada, L. C., Fisher, R H., Cutler, C., & Masia Warner C. (2008-this issue). An innovative treatment approach for children with anxiety disorders and medically unexplained somatic complaints. Cognitive and Behavioral Practice, 15; Weersing, V X, Gonzalez, A., Campo, J. V., & Lucas, A. N. (2008-this issue). Brief CBT for pediatric anxiety and depression: Piloting an integrated treatment approach. Cognitive and Behavioral Practice, 15]; and to extend access to these evidence-based approaches, in general [Khanna, M. S., & Kendall, P C. (2008-this issue). Computer assisted CBT for child anxiety: The Coping Cat CD. Cognitive and Behavioral Practice, 15]. This commentary addresses how, collectively, these programs of research illustrate promising approaches to intervention adaptation and testing. The discussion also explores potential directions that might facilitate future research, including potential directions for broadening the interventions research agenda to help ensure that high-quality, evidence-based interventions am ultimately available to children and adolescents with anxiety. C1 NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Sherrill, JT (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7145-9633, Bethesda, MD 20892 USA. EM jsherril@mail.nih.gov NR 32 TC 1 Z9 1 U1 2 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD MAY PY 2008 VL 15 IS 2 BP 166 EP 171 DI 10.1016/j.cbpra.2007.11.002 PG 6 WC Psychology, Clinical SC Psychology GA 322XC UT WOS:000257407600007 ER PT J AU Goldstein, RB Dawson, DA Stinson, FS Ruan, WJ Chou, SP Pickering, RP Grant, BF AF Goldstein, Rise B. Dawson, Deborah A. Stinson, Frederick S. Ruan, W. June Chou, S. Patricia Pickering, Roger P. Grant, Bridget F. TI Antisocial behavioral syndromes and body mass index among adults in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions SO COMPREHENSIVE PSYCHIATRY LA English DT Review ID DRUG-USE DISORDERS; INTERVIEW SCHEDULE AUDADIS; OPPOSITIONAL-DEFIANT DISORDER; GENERAL-POPULATION SAMPLE; CONDUCT DISORDER; PERSONALITY-DISORDER; ANXIETY DISORDERS; PSYCHIATRIC-DISORDERS; LIFE-COURSE; EXTERNALIZING PSYCHOPATHOLOGY AB Objective: To describe associations of antisocial behavioral syndromes, including DSM-IV antisocial personality disorder (ASPD) and conduct disorder without progression to ASPD ("CD only"), and syndromal antisocial behavior in adulthood without CID before age 15 (AABS, not a codable DSM-IV disorder), with body mass index (BMI) status in the general US adult population. Methods: This report is based on the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n=43 093; response rate, 81%). Respondents were classified according to whether they met criteria for ASPD, AABS, "CD only," or no antisocial syndrome, and on current BMI status based on self-reported height and weight. Associations of antisocial syndromes with BMI status were examined using multinomial logistic regression. Results: Among men, antisociality was not associated with BMI. Among women, ASPD was significantly associated with overweight and extreme obesity; AABS was associated with obesity and extreme obesity; and "CD only" was significantly associated with overweight, obesity, and extreme obesity. Conclusions: Assessment of antisocial features appears warranted in overweight, obese, and extremely obese women, and assessment of BMI status appears indicated in antisocial women. Prevention and treatment guidelines for overweight and obesity may need revision to address comorbid antisociality, and interventions targeting antisociality may need to include attention to weight concerns. Published by Elsevier Inc. C1 [Goldstein, Rise B.; Dawson, Deborah A.; Stinson, Frederick S.; Ruan, W. June; Chou, S. Patricia; Pickering, Roger P.; Grant, Bridget F.] NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU Intramural NIH HHS [Z99 AA999999] NR 129 TC 15 Z9 15 U1 7 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAY-JUN PY 2008 VL 49 IS 3 BP 225 EP 237 DI 10.1016/j.comppsych.2007.10.005 PG 13 WC Psychiatry SC Psychiatry GA 291BZ UT WOS:000255168600001 PM 18396181 ER PT J AU Marcus, SM Kerber, KB Rush, AJ Wisniewski, SR Nierenberg, A Balasubramani, GK Ritz, L Kornstein, S Young, EA Trivedi, MH AF Marcus, Sheila M. Kerber, Kevin B. Rush, A. John Wisniewski, Stephen R. Nierenberg, Andrew Balasubramani, G. K. Ritz, Louise Kornstein, Susan Young, Elizabeth A. Trivedi, Madhukar H. TI Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID STAR-ASTERISK-D; NATIONAL COMORBIDITY SURVEY; ILLNESS RATING-SCALE; REPORT QIDS-SR; PSYCHOMETRIC EVALUATION; PSYCHIATRIC-DISORDERS; GENDER-DIFFERENCES; CLINICAL-FEATURES; MAJOR DEPRESSION; QUICK INVENTORY AB Background: Although epidemiologic research consistently reports greater prevalence of major depressive disorder in women, small sample sizes in many studies do not allow for full elaboration of illness characteristics. This article examines sex differences in terms of illness attributes in a cohort of 2541 outpatients from across the United States who enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Methods: Confirmatory analyses were performed in 2541 outpatients comparing men and women with regard to sociodemographic features, comorbid Axis I and Axis III conditions, and illness characteristics. Results were compared with those of our previous report on the initial population of the first 1500 individuals enrolled in Sequenced Treatment Alternatives to Relieve Depression study. Results: In both samples, nearly two thirds of the sample (62.5%) were women. Women had greater symptom severity, but men had more episodes of major depression, despite no difference in the length of illness. No differences in age of onset emerged. As in the first cohort, women showed greater rates of an anxiety disorder, bulimia, and somatoform disorder, as well as more past suicide attempts, whereas men showed more alcohol and substance abuse. Women reported more appetite, weight, hypersomnia, interpersonal sensitivity, gastrointestinal and pain complaints, and less suicidal ideation. Irritability was equally common in men and women. Conclusion: This large analysis confirmed most of the clinical features and comorbidities found to be more prevalent in the first cohort of women. In addition, this analysis corroborated previous research suggesting higher rates of atypical and anxious depression in women but refuted the notion of an "irritable depression" found in men. The report confirmed the 1.7:1 ratio for depression seen across sexes in the National Comorbidity Survey. (c) 2008 Elsevier Inc. All rights reserved. C1 [Marcus, Sheila M.; Kerber, Kevin B.; Young, Elizabeth A.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48105 USA. [Rush, A. John; Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Wisniewski, Stephen R.; Balasubramani, G. K.] Univ Pittsburgh, Epidemiol Data Ctr, GSPH, Pittsburgh, PA USA. [Nierenberg, Andrew] Harvard Univ, Dept Psychiat, Boston, MA 02115 USA. [Ritz, Louise] NIMH, Rockville, MD 20857 USA. [Kornstein, Susan] Virginia Commonwealth Univ, Richmond, VA USA. [Young, Elizabeth A.] Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI USA. RP Marcus, SM (reprint author), Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48105 USA. EM smmarcus@umich.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Goundappa K, Balasubramani/0000-0001-7221-1825 FU NIMH NIH HHS [N01 MH 90003, N01 MH090003, N01MH90003] NR 37 TC 65 Z9 66 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAY-JUN PY 2008 VL 49 IS 3 BP 238 EP 246 DI 10.1016/j.comppsych.2007.06.012 PG 9 WC Psychiatry SC Psychiatry GA 291BZ UT WOS:000255168600002 PM 18396182 ER PT J AU Yu, BB Wang, ZQ AF Yu, Binbing Wang, Zhuoqiao TI Estimating relative risks for common outcome using PROC NLP SO COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE LA English DT Article DE prevalence ratio; PROC NLP; relative risk; risk difference ID PREVALENCE-ODDS-RATIO; BINOMIAL REGRESSION; COHORT AB In cross-sectional or cohort studies with binary outcomes, it is biologically interpretable and of interest to estimate the relative risk or prevalence ratio, especially when the response rates are not rare. Several methods have been used to estimate the relative risk, among which the log-binomial models yield the maximum likelihood estimate (MLE) of the parameters. Because of restrictions on the parameter space, the log-binomial models often run into convergence problems. Some remedies, e.g., the Poisson and Cox regressions, have been proposed. However, these methods may give out-of-bound predicted response probabilities. In this paper, a new computation method using the SAS Nonlinear Programming (NLP) procedure is proposed to find the MLEs. The proposed NLP method was compared to the COPY method, a modified method to fit the log-binomial model. Issues in the implementation are discussed. For illustration, both methods were applied to data on the prevalence of microalbuminuria. (micro-protein leakage into urine) for kidney disease patients from the Diabetes Control and Complications Trial. The sample SAS macro for calculating relative risk is provided in the appendix. Published by Elsevier Ireland Ltd. C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Wang, Zhuoqiao] Informat Management Serv Inc, Silver Spring, MD 20904 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 21 TC 11 Z9 16 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-2607 J9 COMPUT METH PROG BIO JI Comput. Meth. Programs Biomed. PD MAY PY 2008 VL 90 IS 2 BP 179 EP 186 DI 10.1016/j.cmpb.2007.12.010 PG 8 WC Computer Science, Interdisciplinary Applications; Computer Science, Theory & Methods; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 294CM UT WOS:000255381700009 PM 18291556 ER PT J AU Sotak, CH Sharer, K Koretsky, AP AF Sotak, Christopher H. Sharer, Kathryn Koretsky, Alan P. TI Manganese cell labeling of murine hepatocytes using manganese(III)-transferrin SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE manganese-enhanced MRI; manganese(III)-transferrin; relaxivity; isolated hepatocytes; mouse hepatocytes; iron(III)-transferrin; transferrin receptor; endocytosis ID RAT HEPATOCYTES; TRANSFERRIN-RECEPTOR; IRON UPTAKE; RELAXATION; TRANSPORT; PLASMA; BRAIN; LIVER; IONS; METABOLISM AB Manganese(III)-transferrin [Mn(III)-Tf] was investigated as a way to accomplish manganese-labeling of murine hepatocytes for MRI contrast. It is postulated that Mn(III)-Tf can exploit the same transferrin-receptor-dependent and -independent metabolic pathways used by hepatocytes to transport the iron analog Fe(III)-Tf. More specifically, it was investigated whether manganese delivered by transferrin could give MRI contrast in hepatocytes. Comparison of the T-1 and T-2 relaxation times of Mn(III)-Tf and Fe(III)-Tf over the same concentration range showed that the r(1) relaxivities of the two metalloproteins are the same in vitro, with little contribution from paramagnetic enhancement. The degree of manganese cell labeling following incubation for 2-7 h in 31.5 mu m Mn(III)-Tf was comparable to that of hepatocytes incubated in 500 mu m Mn2+ for 1 h. The intrinsic manganese tissue relaxivity between Mn(III)-Tf-labeled and Mn2+-labeled cells was found to be the same, consistent with Mn(III) being released from transferrin and reduced to Mn2+. For both treatment regimens, manganese uptake by hepatocytes appeared to saturate in the first 1-2 h of the incubation period and may explain why the efficiency of hepatocyte cell labeling by the two methods appeared to be comparable in spite of the similar to 16-fold difference in effective manganese concentration. Hepatocytes continuously released manganese, as detected by MRI, and this was the same for both Mn2+- and Mn(III)-Tf-labeled cells. Manganese release may be the result of normal hepatocyte function, much in the same way that hepatocytes excrete manganese into the bile in vivo. This approach exploits a biological process-namely receptor binding, endocytosis and endosomal acidification-to initiate the release of an MRI contrast agent, potentially conferring more specificity to the labeling process. The ubiquitous expression of transferrin receptors by eukaryotic cells should make Mn(III)-Tf particularly useful for manganese labeling of a wide variety of cells both in culture and in vivo. Published in 2008 by John Wiley & Sons, Ltd. C1 [Sotak, Christopher H.] Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. [Sotak, Christopher H.] Worcester Polytech Inst, Dept Chem & Biochem, Worcester, MA 01609 USA. [Sotak, Christopher H.] Univ Massachusetts, Sch Med, Dept Radiol, Worcester, MA 01655 USA. [Sharer, Kathryn; Koretsky, Alan P.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Sotak, CH (reprint author), Worcester Polytech Inst, Dept Biomed Engn, Worcester, MA 01609 USA. EM csotak@wpi.edu RI Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003047-01] NR 42 TC 11 Z9 12 U1 1 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD MAY-JUN PY 2008 VL 3 IS 3 BP 95 EP 105 DI 10.1002/cmmi.235 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 330ZR UT WOS:000257982000001 PM 18546093 ER PT J AU Donovan, EA Kummar, S AF Donovan, Erin A. Kummar, Shivaani TI Role of insulin-like growth factor-1R system in colorectal carcinogenesis SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE anti-IGF therapy; growth factors; acromegaly; epidemiologic studies in cancer ID FACTOR-I-RECEPTOR; IGF-BINDING PROTEIN-3; COLON-CARCINOMA CELLS; CANCER-RISK; TUMOR-GROWTH; FACTOR (IGF)-I; FACTOR BINDING-PROTEIN-3; MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; TYROSINE KINASE AB The insulin-like growth factor (IGF) system is comprised of receptors, ligands (IGF-I and IGF-II), and a family of binding proteins (IGFBPs). It plays an important role in growth and development and in the maintenance of normal homeostasis. We present a review of the current laboratory and epidemiologic evidence that suggests an important role of the IGF system in colorectal carcinogenesis. Due to the complexity of this system, we have focused the review on the role of the IGF-1 receptor and its ligands in colorectal carcinogenesis and the strategies to block this pathway as a potential anti-cancer therapy. Published by Elsevier Ireland Ltd. C1 [Donovan, Erin A.; Kummar, Shivaani] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. RP Kummar, S (reprint author), NCI, Ctr Canc Res, Med Oncol Branch, 9000 Rockville Pike,Bldg 10-12N226, Bethesda, MD 20892 USA. EM kummars@exchange.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 57 TC 46 Z9 48 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD MAY PY 2008 VL 66 IS 2 BP 91 EP 98 DI 10.1016/j.critrevonc.2007.09.003 PG 8 WC Oncology; Hematology SC Oncology; Hematology GA 297FL UT WOS:000255602400001 PM 17977741 ER PT J AU Ho, PWL Garner, CE Ho, JWM Leung, KC Chu, ACY Kwok, KHH Kung, MHW Burka, LT Ramsden, DB Ho, SL AF Ho, P. W. L. Garner, C. E. Ho, J. W. M. Leung, K. C. Chu, A. C. Y. Kwok, K. H. H. Kung, M. H. W. Burka, L. T. Ramsden, D. B. Ho, S. L. TI Estrogenic phenol and catechol metabolites of PCBs modulate catechol-O-methyltransferase expression via the estrogen receptor: Potential contribution to cancer risk SO CURRENT DRUG METABOLISM LA English DT Review DE COMT, carcinogenesis, xenobiotic catechols, PCB; estrogen ID BREAST-CANCER; POLYCHLORINATED-BIPHENYLS; INDUCED TUMORIGENESIS; MEDIATED METABOLISM; TUMOR INITIATION; DOWN-REGULATION; IN-VITRO; CATECHOLESTROGENS; ESTRADIOL; CARCINOGENESIS AB Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols. C1 [Ho, P. W. L.; Ho, J. W. M.; Leung, K. C.; Chu, A. C. Y.; Kwok, K. H. H.; Kung, M. H. W.; Ho, S. L.] Univ Hong Kong, Queen Mary Hosp, Univ Dept Med, Div Neurol, Hong Kong, Hong Kong, Peoples R China. [Ramsden, D. B.] Univ Birmingham, Div Med Sci, Dept Med, Birmingham B15 2TT, W Midlands, England. [Burka, L. T.] NIEHS, Div Intramural Res, Environm Toxicol Program, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Garner, C. E.] AstraZeneca, Drug Metab & Pharmacokinet, Canc & Infect Discovery Res, Waltham, MA 02451 USA. RP Ramsden, DB (reprint author), Univ Hong Kong, Queen Mary Hosp, Univ Dept Med, Div Neurol, Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. EM D.B.Ramsden@bham.ac.uk; slho@hkucc.hku.hk RI Ho, Shu Leong/C-4136-2009; Ho, Philip Wing-Lok/K-5814-2013 OI Ho, Philip Wing-Lok/0000-0001-7794-0146 NR 46 TC 16 Z9 17 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD MAY PY 2008 VL 9 IS 4 BP 304 EP 309 DI 10.2174/138920008784220600 PG 6 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 298IV UT WOS:000255682300006 PM 18473748 ER PT J AU Perruccio, EM Rowlette, LLS Comes, N Locatelli-Hoops, S Notari, L Becerra, SP Borras, T AF Perruccio, Elizabeth M. Rowlette, Laura Leigh S. Comes, Nuria Locatelli-Hoops, Silvia Notari, Luigi Becerra, S. Patricia Borras, Teresa TI Dexamethasone increases pigment epithelium-derived factor in perfused human eyes SO CURRENT EYE RESEARCH LA English DT Article DE DEX; human; PEDF; perfused anterior segment; trabecular meshwork ID HUMAN TRABECULAR MESHWORK; MATRIX METALLOPROTEINASES; INTRAOCULAR-PRESSURE; FACTOR PEDF; GLAUCOMA; EXPRESSION; CELLS; TIMPS AB Purpose: To investigate the effects of dexamethasone (DEX) on pigment epithelium-derived factor (PEDF) cDNA and secreted protein in human trabecular meshwork (TM). Methods: Anterior segment organ cultures were perfused with 0.1 mu M DEX (OD) and vehicle (OS). Primary human TM cells (HTM) were treated with DEX under similar conditions. PEDF mRNA and secreted PEDF protein were quantitated by RT-PCR and Western blot. Results: PEDF mRNA and secreted PEDF protein levels were significantly higher in DEX over vehicle-treated cultures. In contrast, DEX decreased the activity of a 92-kDa gelatinolytic zymogen in organ culture effluents. Conclusion: DEX action in the human TM might include a PEDF-mediating pathway. C1 [Comes, Nuria; Borras, Teresa] Univ N Carolina, Dept Ophthalmol, Chapel Hill, NC 27599 USA. [Perruccio, Elizabeth M.; Locatelli-Hoops, Silvia; Notari, Luigi; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Lab Retinal Cell & Mol Biol, NIH, Bethesda, MD USA. [Rowlette, Laura Leigh S.] Duke Univ, Med Ctr, Durham, NC USA. RP Borras, T (reprint author), Univ N Carolina, Dept Ophthalmol, 6109 Neurosci Res Bldg,CB 70411, Chapel Hill, NC 27599 USA. EM tborras@med.unc.edu FU Intramural NIH HHS [Z01 EY000306-13]; NEI NIH HHS [R01 EY011906, R01 EY013126, EY11906, EY13126] NR 19 TC 7 Z9 7 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD MAY-JUN PY 2008 VL 33 IS 5-6 BP 507 EP 515 DI 10.1080/02713680802110208 PG 9 WC Ophthalmology SC Ophthalmology GA 312LE UT WOS:000256672100013 PM 18568889 ER PT J AU Kreisl, TN AF Kreisl, Teri N. TI Neurologic complications of antitumor antibody therapies SO CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS LA English DT Review ID POSTERIOR LEUKOENCEPHALOPATHY SYNDROME; METASTATIC COLORECTAL-CANCER; PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; BEVACIZUMAB PLUS IRINOTECAN; B-CELL LYMPHOMA; MONOCLONAL-ANTIBODY; PHASE-II; MALIGNANT GLIOMA; CHEMOTHERAPY; RITUXIMAB AB Antibody-based therapy is being explored across a variety of disease types. Several successes in oncology have become part of standard care for diseases such as colorectal cancer and non-Hodgkin's lymphoma. Traditional chemotherapeutic agents have had significant dose-limiting neurologic toxicities associated with their use. Although there are rare incidences of significant neurologic complications of antibody cancer therapy, these treatments are generally very well tolerated. Because most antibody therapy is adjunctive to other treatments, attribution to the immunologic component is often difficult to discern. C1 NCI, Neuro Oncol Branch, Bethesda, MD 20892 USA. RP Kreisl, TN (reprint author), NCI, Neuro Oncol Branch, 9030 Old Georgetown Rd,Bloch Bldg 82,Room 243, Bethesda, MD 20892 USA. EM kreislt@mail.nih.gov NR 33 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1528-4042 J9 CURR NEUROL NEUROSCI JI Curr. Neurol. Neurosci. Rep. PD MAY PY 2008 VL 8 IS 3 BP 259 EP 263 DI 10.1007/s11910-008-0039-5 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 307LC UT WOS:000256319400010 PM 18541121 ER PT J AU Hall, KD Baracos, VE AF Hall, Kevin D. Baracos, Vickie E. TI Computational modeling of cancer cachexia SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Article DE body composition; cancer cachexia; energy metabolism; mathematical model; weight loss ID RESTING ENERGY-EXPENDITURE; WHOLE-BODY LIPOLYSIS; CELL LUNG-CANCER; WEIGHT-LOSS; PROTEIN-TURNOVER; CACHECTIC PATIENTS; PANCREATIC-CANCER; ORAL SUPPLEMENT; DIETARY-INTAKE; METABOLISM AB Purpose of review Measurements of whole-body energy expenditure, body composition, and in-vivo metabolic fluxes are required to quantitatively understand involuntary weight loss in cancer cachexia. Such studies are rare because cancer cachexia occurs near the end of life when invasive metabolic tests may be precluded. Thus, models of cancer-associated weight loss are an important tool for helping to understand this debilitating condition. Recent findings A computational model of human macronutrient metabolism was recently developed that simulates the normal metabolic adaptations to semi-starvation and re-feeding. Here, this model was used to integrate data on the metabolic changes in patients with cancer cachexia. The resulting computer simulations show how the known metabolic disturbances synergize with reduced energy intake to result in a progressive loss of body weight, fat mass, and fat-free mass. The model was also used to simulate the effects of nutritional support and investigate inhibition of lipolysis versus proteolysis as potential therapeutic approaches for cancer cachexia. Summary Computational modeling is a new tool that can integrate clinical data on the metabolic changes in cancer cachexia and provide a conceptual framework to help understand involuntary weight loss and predict the effects of potential therapies. C1 [Hall, Kevin D.] NIDDKD, Lab Biol Modelling, NIH, Bethesda, MD USA. [Baracos, Vickie E.] Univ Alberta, Dept Oncol, Edmonton, AB, Canada. RP Hall, KD (reprint author), NIDDK, NIH, 12A S Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010; OI Baracos, Vickie/0000-0002-9609-1001 FU Intramural NIH HHS [Z01 DK013036-01] NR 48 TC 11 Z9 11 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD MAY PY 2008 VL 11 IS 3 BP 214 EP 221 DI 10.1097/MCO.0b013e3282f9ae4d PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 306AK UT WOS:000256218800004 PM 18403915 ER PT J AU Young, NS Scheinberg, P Calado, RT AF Young, Neal S. Scheinberg, Phillip Calado, Rodrigo T. TI Aplastic anemia SO CURRENT OPINION IN HEMATOLOGY LA English DT Article DE antithymocyte globulin; aplastic anemia; bone marrow failure; cyclosporine; pancytopenia; stem cell transplantation ID COLONY-STIMULATING FACTOR; BONE-MARROW-TRANSPLANTATION; TELOMERASE REVERSE-TRANSCRIPTASE; STEM-CELL TRANSPLANTATION; TRISOMY-8 MYELODYSPLASTIC SYNDROME; ANTI-THYMOCYTE GLOBULIN; IMMUNOSUPPRESSIVE THERAPY; ANTITHYMOCYTE GLOBULIN; DYSKERATOSIS-CONGENITA; ANTILYMPHOCYTE GLOBULIN AB Purpose of review Most acquired aplastic anemia is the result of immune-mediated destruction of hematopoietic stem cells causing pancytopenia and an empty bone marrow, which can be successfully treated with either immunosuppressive therapy or hematopoietic stem-cell transplantation. Recent findings In aplastic anemia, oligoclonally expanded cytotoxic T cells induce apoptosis of hematopoietic progenitors. T-bet, a transcription factor that binds to the interferon-gamma promoter region, is upregulated in aplastic anemia T cells. Regulatory T cells are significantly reduced in patients' peripheral blood and in an aplastic anemia murine model, infusion of regulatory T cells ameliorates disease progression. In a minority of cases, loss-of-function mutations in telomerase complex genes may underlie disease development. Long-term survival, once strongly linked to response to immunosuppressive therapy, can now be achieved even among nonresponders due to significant advances in supportive care and better salvage treatments. Summary Evidence has accumulated in the recent years further corroborating an immune-mediated process underlying aplastic anemia pathogenesis. Hematopoietic stem-cell transplantation from a matched sibling donor is preferred for children and young adults with severe aplastic anemia, and immunosuppressive therapy is employed when hematopoietic stem-cell transplantation is not feasible due to age, lack of a histocompatible sibling, co-morbidities, or by patient choice. C1 [Young, Neal S.; Scheinberg, Phillip; Calado, Rodrigo T.] NHLBI, Hematol Branch, NIH, Bethesda, MD USA. RP Young, NS (reprint author), 10 Ctr Dr,Bldg 10-CRC,Rm 3E-5140, Bethesda, MD 20892 USA. EM youngns@mail.nih.gov RI Calado, Rodrigo/G-2619-2011; OI Scheinberg, Phillip/0000-0002-9047-4538 FU Intramural NIH HHS [Z01 HL002315-25, Z01 HL002315-26, ZIA HL002315-27, ZIA HL002315-28, ZIA HL002315-29, ZIA HL006089-01, ZIA HL006089-02] NR 89 TC 127 Z9 150 U1 2 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD MAY PY 2008 VL 15 IS 3 BP 162 EP 168 DI 10.1097/MOH.0b013e3282fa7470 PG 7 WC Hematology SC Hematology GA 296IU UT WOS:000255537500002 PM 18391779 ER PT J AU Pau, AK AF Pau, Alice K. TI Clinical management of drug interaction with antiretroviral agents SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE antiretrovirals; drug interactions; HIV; management; pharmacokinetics AB Purpose of review Combination antiretroviral therapy has improved the morbidity and mortality of HIV-infected patients worldwide. As patients live longer, management of HIV infection extends to treatment of a wide spectrum of co-morbid conditions. Pharmacokinetic interactions are common among antiretroviral drugs when they are used in combination and along with treatments for other conditions. This review discusses the clinical significance of drug interactions among antiretroviral drugs and other medications, resources to use in assessing drug interaction potential, and some key principles to follow when managing patients prescribed potentially interacting drugs. Recent findings Targeted pharmacokinetic drug interaction studies and extrapolations on the basis of potential mechanism of interactions provide an initial basis for recommendations regarding use of certain drug combinations. Some unexpected interactions have emerged in the literature through case reports in which untoward effects were observed. Summary Management of patients on multiple drug therapy can be a challenge. The key to safe and effective therapy relies on the clinician's vigilance in their ongoing assessment of interaction potential among drugs prescribed to each patient, the significance for such interactions, the need for modification to therapy, and close follow up to assess safety and toxicity. C1 NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Pau, AK (reprint author), NIAID, Div Clin Res, NIH, Bldg 10,Rm 11C103,10 Ctr Dr,MSC 1880, Bethesda, MD 20892 USA. EM apau@niaid.nih.gov NR 42 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2008 VL 3 IS 3 BP 319 EP 324 DI 10.1097/COH.0b013e3282f82c06 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NZ UT WOS:000208418400019 PM 19372985 ER PT J AU Hunt, PW Carrington, M AF Hunt, Peter W. Carrington, Mary TI Host genetic determinants of HIV pathogenesis: an immunologic perspective SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE CCR5; HIV pathogenesis; HLA; host genetic variation; KIR AB Purpose of review The purpose of this review is to highlight recent advances in our understanding of host genetic determinants of HIV pathogenesis and to provide a theoretical framework for interpreting these studies in the context of our evolving understanding of HIV immunopathogenesis. Recent findings The first genome-wide association analysis of host determinants of HIV pathogenesis and other recent studies evaluating the interaction between killer cell immunoglobulin-like receptors and human leukocyte antigen alleles have implicated both adaptive and innate immune responses in the control of HIV replication. Furthermore, genetic variation associated with the expression of CCR5 and its ligand have been strongly associated with both decreased susceptibility to HIV infection and delayed clinical progression, independent of their effects on viral replication, suggesting a potential role for CCR5 inhibitors as immune-based therapies in HIV disease. Summary Host factors associated with the control of HIV replication may help identify important targets for vaccine design, while those associated with delayed clinical progression provide targets for future immune-based therapies against HIV infection. C1 [Hunt, Peter W.] Univ Calif San Francisco, San Francisco Gen Hosp AIDS Div, San Francisco, CA 94143 USA. [Carrington, Mary] SAIC Frederick Inc, Canc & Inflammat Program, Natl Canc Inst, Frederick, MD USA. RP Hunt, PW (reprint author), SFGH Ward 84,Bldg 80,995 Potrero Ave, San Francisco, CA 94110 USA. EM phunt@php.ucsf.edu FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 58 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2008 VL 3 IS 3 BP 342 EP 348 DI 10.1097/COH.0b013e3282fbaa92 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NZ UT WOS:000208418400022 PM 19372988 ER PT J AU Brenchley, JM Douek, DC AF Brenchley, Jason M. Douek, Daniel C. TI The mucosal barrier and immune activation in HIV pathogenesis SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE gastrointestinal depletion; immune activation; microbial translocation; natural infection AB Purpose of review Significant gastrointestinal pathology occurs in progressive HIV and simian immunodeficiency virus (SIV) infections. This review will examine the relationship between the detrimental events to the gastrointestinal tract during the acute phase of infection and disease progression through the chronic phase and, ultimately, AIDS. Recent findings Gastrointestinal tract CD4 T cells are dramatically depleted in acutely HIV-infected humans and SIV-infected rhesus macaques, sooty mangabeys, and African green monkeys. In addition, HIV infection of humans and SIV-infection of rhesus macaques are characterized by enteropathy and increased intestinal permeability. While SIV-infected rhesus macaques and HIV-infected humans manifest chronic and systemic immune activation and microbial translocation, and progress to chronic infection and AIDS, however, SIV-infected sooty mangabeys and African green monkeys do not. Summary Recent studies have increased our understanding of the mechanisms that relate structural and immunological damage to the gastrointestinal tract during the acute phase of HIV/SIV infection to immune activation and disease progression in the chronic phase. C1 [Brenchley, Jason M.] NIAID, Viral Pathogenesis & Vaccine Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Viral Pathogenesis & Vaccine Sect, Mol Microbiol Lab, NIH, Bldg 4,Rm 301,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbrenchl@mail.nih.gov FU Intramural NIH HHS [Z01 AI001029-01, Z99 AI999999, ZIA AI001029-02] NR 59 TC 82 Z9 83 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2008 VL 3 IS 3 BP 356 EP 361 DI 10.1097/COH.0b013e3282f9ae9c PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NZ UT WOS:000208418400024 PM 19372990 ER PT J AU Grossman, Z Picker, LJ AF Grossman, Zvi Picker, Louis J. TI Pathogenic mechanisms in simian immunodeficiency virus infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE chronic immune activation; simian immunodeficiency virus pathogenesis; T cell dynamics AB Purpose of review Recent work in pathogenic simian immunodeficiency virus infection of Asian macaques and in natural, nonpathogenic simian immunodeficiency infections of African nonhuman primate species has demonstrated that persistent activation has profound effects on CD4(+) memory T cell proliferation, differentiation and survival. Disease progression in pathogenic infection has been closely linked to these dynamics, reflecting a complex interplay of virus-mediated killing, the effects of systemic activation and host regenerative mechanisms. We review these recent advances. Recent findings Massive depletion of CD4(+) effector-memory T cells invariably occurs during acute CCR5-tropic simian immunodeficiency virus infection, but is initially stabilized by new production of these cells from spared central memory precursors above the threshold required to maintain clinical immune competence. In pathogenic (but not natural, apathogenic) infections, a persistent state of immune activation, characterized by multiple, recurrent bursts of lymphocyte proliferation, differentiation, migration, death and functional modification of 'resting' cells, is associated with progressive depletion of central memory CD4(+) T cells, and ultimately, a collapse of effector site CD4(+) memory populations that is closely associated with overt immune deficiency. Summary The importance of maintaining the regenerative capacity of the central-memory compartment of CD4(+) T cells is increasingly evident. Defining the physiologic and molecular mechanisms responsible for instability of the CD4(+) central-memory T cell pool could enable new immunotherapeutic interventions. C1 [Picker, Louis J.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Dept Pathol, Beaverton, OR 97006 USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Dept Mol Microbiol & Immunol, Beaverton, OR 97006 USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Beaverton, OR 97006 USA. [Grossman, Zvi] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Grossman, Zvi] Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. RP Picker, LJ (reprint author), Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Dept Pathol, West Campus,505 NW 185th Ave, Beaverton, OR 97006 USA. EM pickerl@ohsu.edu FU NIH grants [RO1-AI054292, P51-RR00163]; Collaboration for AIDS Vaccine Discovery Program of the Bill and Melinda Gates Foundation; Intramural Research Program of the NIH FX This work was supported by NIH grants RO1-AI054292 and P51-RR00163, and the Collaboration for AIDS Vaccine Discovery Program of the Bill and Melinda Gates Foundation. This research was also supported in part by the Intramural Research Program of the NIH. NR 57 TC 14 Z9 15 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2008 VL 3 IS 3 BP 380 EP 386 DI 10.1097/COH.0b013e3282fbaae6 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NZ UT WOS:000208418400028 PM 19372994 ER PT J AU Mattapallil, JJ Roederer, M AF Mattapallil, Joseph J. Roederer, Mario TI Mucosa and vaccine-induced immune protection in nonhuman primates SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE acute infection; CD4 T-cells; HIV; mucosa; SIV; vaccine AB Purpose of review The purpose of this article is to review some of the recent progress in the development of HIV vaccines that induce immune responses in mucosal tissues that may correlate with protection of the mucosal CD4 T cell compartment. Recent findings Mucosal tissues are the primary sites for viral entry and the resident CD4 T cells serve as readily available target cells for active infection. Viral entry is associated with a massive destruction of these cells. The resident CD4 cells are memory T cells and hence play an important role in the generation of secondary immune responses. Protecting these CD4 T cells is critical for controlling viral infection and for preserving immune competence. Numerous mucosal vaccine regimens currently under development have been shown to induce both B and T cell responses in mucosal tissues. Though induction of neutralizing antibodies still remains an elusive goal, the demonstration that antibodies can have a protective role through alternative mechanisms offers hope that humoral responses can be harnessed to yield a protective response in mucosal tissues. Summary The mucosal immune system is highly compartmentalized and hence immunization regimens need to target mucosal tissues to be successful in inducing protective immune responses in mucosal tissues. C1 [Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Dept Def, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. [Roederer, Mario] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Mattapallil, JJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Dept Def, F Edward Hebert Sch Med, Room B4068,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM jmattapallil@usuhs.mil FU NIAID NIH HHS [K22 AI071812-01, K22 AI071812, K22 AI071812-02]; NIDCR NIH HHS [R21 DE018339-02, R21 DE018339, R21 DE018339-02S1, R21 DE018339-01] NR 48 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAY PY 2008 VL 3 IS 3 BP 387 EP 392 DI 10.1097/COH.0b013e3282f9ae66 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA V24NZ UT WOS:000208418400029 PM 19372995 ER PT J AU Turnmala, MK Hussain, A AF Turnmala, Mohan K. Hussain, Arif TI Recent developments in germ cell tumors of the testes SO CURRENT OPINION IN ONCOLOGY LA English DT Review DE chemotherapy; genetic studies; germ cell tumor; imaging; nonseminomatous germ cell tumor; seminoma; surgery; surveillance; toxicity; tumor marker ID HIGH-DOSE CHEMOTHERAPY; LYMPH-NODE DISSECTION; CLINICAL STAGE-I; TESTICULAR CANCER; RANDOMIZED-TRIAL; SALVAGE CHEMOTHERAPY; PHASE-II; RISK; TOMOGRAPHY; SURVIVORS AB Purpose of review An overview on several important developments in testicular germ cell tumors in the past year is provided. Recent findings Despite being highly treatable even in advanced stages, recent studies demonstrate that testicular germ cell tumor mortalities can vary significantly in different regions of the world, suggesting limited access to appropriate treatments in certain geographic regions. Several clinically relevant studies on the role of retroperitoneal lymph node dissection in early and advanced stages of disease, and chemotherapy, particularly high-dose chemotherapy in the first-line and salvage settings, were reported. Large databases on testicular cancer survivors were analyzed to further define potentially delayed toxicities of initial treatments for testicular germ cell tumors. Summary Significant challenges for poor-risk germ cell tumors remain. Treatment paradigms and follow-up strategies for the different stages of testicular germ cell tumors continue to be defined and refined, as research in these areas continues. C1 [Hussain, Arif] Univ Maryland, Greenebaum Canc Ctr, Dept Med Pathol & Biochem, Baltimore, MD 21201 USA. [Turnmala, Mohan K.] Univ Maryland, Dept Med, Baltimore, MD 21201 USA. [Turnmala, Mohan K.] NIA, NIH, Baltimore, MD 21224 USA. [Hussain, Arif] Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. RP Hussain, A (reprint author), Univ Maryland, Greenebaum Canc Ctr, Dept Med Pathol & Biochem, 22 S Greene St, Baltimore, MD 21201 USA. EM ahussain@som.umaryland.edu NR 35 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD MAY PY 2008 VL 20 IS 3 BP 287 EP 293 PG 7 WC Oncology SC Oncology GA 294WO UT WOS:000255437200008 ER PT J AU Wong, WT Chew, EY AF Wong, Wai T. Chew, Emily Y. TI Ocular von Hippel-Lindau disease: clinical update and emerging treatments SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE antiangiogenic therapy; genotype-phenotype correlations; von Hippel-Lindau disease ID TUMOR-SUPPRESSOR GENE; GENOTYPE-PHENOTYPE CORRELATIONS; RECEPTOR INHIBITOR SU5416; GERMLINE MUTATIONS; RETINAL HEMANGIOBLASTOMA; PHOTODYNAMIC THERAPY; VHL GENE; BEVACIZUMAB; ANGIOMATOSIS; CANCER AB Purpose of review von Hippel-Lindau disease is an inherited, multisystemic cancer syndrome often involving the retina. This review will provide an update for the clinical characterization and treatment of ocular von Hippel-Lindau disease. Recent findings A comprehensive and quantitative clinical characterization of ocular von Hippel-Lindau disease has been limited by small patient numbers and nonrepresentative sampling. Recently, a large population of patients with clinically and genetically defined von Hippel-Linclau disease was systemically characterized in a single center, enabling a quantitative evaluation of the ocular involvement of this syndrome. Correlations between the nature of von Hippel-Lindau gene mutations and the ocular phenotype were also examined, providing clues as to how disruptions in von Hippel-Lindau protein function may result in eye disease. This understanding may be relevant to the development of new therapies targeting the molecular biology of von Hippel-Lindau disease, some of which are presently being investigated. Summary Quantitative studies enable a full characterization of the impact of von Hippel-Lindau disease on eye health and visual function. Establishing correlations between the genotype of the von Hippel-Lindau mutation and the phenotype of eye disease may inform us as to how ocular von Hippel-Linclau disease arises, and help guide molecular interventions in ocular von Hippel-Lindau disease. C1 [Wong, Wai T.] NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Wong, WT (reprint author), 7 Mem Dr,Bldg 7,Room 217, Bethesda, MD 20892 USA. EM wongw@alum.mit.edu RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [ZIE EY000487-01, Z99 EY999999] NR 37 TC 20 Z9 24 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD MAY PY 2008 VL 19 IS 3 BP 213 EP 217 DI 10.1097/ICU.0b013e3282fb7c04 PG 5 WC Ophthalmology SC Ophthalmology GA 296MG UT WOS:000255548100008 PM 18408496 ER PT J AU Yeh, S Colyer, MH Weichel, ED AF Yeh, Steven Colyer, Marcus H. Weichel, Eric D. TI Current trends in the management of intraocular foreign bodies SO CURRENT OPINION IN OPHTHALMOLOGY LA English DT Article DE delayed foreign body removal; intraocular foreign body (IOFB) open globe injury; pars plana vitrectomy; posttraumatic endophthalmitis ID PENETRATING OCULAR TRAUMA; PARS-PLANA VITRECTOMY; POSTERIOR SEGMENT; PROGNOSTIC-FACTORS; LENS IMPLANTATION; BODY REMOVAL; SURGICAL-MANAGEMENT; IRAQI FREEDOM; EYE INJURY; ENDOPHTHALMITIS AB Purpose of review The aim of this article is to present the recent literature on the preoperative assessment, intraoperative management and postoperative care of patients with intraocular foreign bodies and present a management algorithm. Recent findings The preoperative assessment includes an evaluation of concomitant, potentially life-threatening conditions, as well as a relevant history and ophthalmic examination. Neuroimaging, preferably with noncontrast helical computed tomography, provides excellent information about intraocular foreign body size, shape and location. The preoperative assessment provides valuable information for prognosis, counseling, and intraoperative guidance. The decision of delayed versus immediate intraocular foreign body removal must be guided by the patient's medical status, availability of adequate operating facilities and staff, and the presence of clinical endophthalmitis. The administration of perioperative systemic and topical third or fourth-generation fluoroquinolones may play a role in decreasing the incidence of postoperative endophthalmitis. Intravitreal antibiotics warrant consideration in patients with a Gram stain positive for organisms, in cases suspicious for endophthalmitis, and in high-risk settings. Both the material and size of the foreign body are considerations in the choice of instrument and extraction site used (sclerotomy versus scleral tunnel) at time of pars plana vitrectomy and intraocular foreign body removal. Postoperatively, patients should be monitored closely for the development of endophthalmitis, retinal detachment and proliferative vitreoretinopathy. Summary This review summarizes the recent literature on the assessment of intraocular foreign bodies and techniques for their removal. An algorithm provides guidelines for their perioperative and operative management. C1 [Colyer, Marcus H.; Weichel, Eric D.] Walter Reed Army Med Ctr, Ophthalmol Serv, Dept Surg, Washington, DC 20307 USA. [Yeh, Steven; Weichel, Eric D.] NEI, NIH, Washington, DC USA. RP Weichel, ED (reprint author), Walter Reed Army Med Ctr, Ophthalmol Serv, Dept Surg, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM weichele@nei.nih.gov NR 61 TC 41 Z9 45 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8738 J9 CURR OPIN OPHTHALMOL JI Curr. Opin. Ophthalmol. PD MAY PY 2008 VL 19 IS 3 BP 225 EP 233 DI 10.1097/ICU.0b013e3282fa75f1 PG 9 WC Ophthalmology SC Ophthalmology GA 296MG UT WOS:000255548100010 PM 18408498 ER PT J AU Ferre, S Quiroz, C Woods, AS Cunha, R Popoli, P Ciruela, F Lluis, C Franco, R Azdad, K Schiffmann, SN AF Ferre, S. Quiroz, C. Woods, A. S. Cunha, R. Popoli, P. Ciruela, F. Lluis, C. Franco, R. Azdad, K. Schiffmann, S. N. TI An update on adenosine A(2A)-dopamine D(2) receptor interactions: Implications for the function of G protein-coupled receptors SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE adenosine A(2A) receptor; dopamine D(2) receptor; G protein-coupled receptors; receptor heteromers; striatum; basal ganglia disorders; drug addiction ID ADENOSINE A(2A) RECEPTORS; DOPAMINE D-2 RECEPTORS; CENTRAL-NERVOUS-SYSTEM; RAT GLOBUS-PALLIDUS; ADENYLYL-CYCLASE; 6-HYDROXYDOPAMINE-LESIONED RATS; BINDING CHARACTERISTICS; HETEROMERIC COMPLEXES; SYNAPTIC-TRANSMISSION; PARKINSONS-DISEASE AB Adenosine A(2A)-dopamine D(2) receptor interactions play a very important role in striatal function. A(2A)-D(2) receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. Thus, there is evidence for the coexistence of two reciprocal antagonistic interactions between A(2A) and D(2) receptors in the same neurons, the GABAergic enkephalinergic neurons. An antagonistic A(2A)-D(2) intramembrane receptor interaction, which depends on A(2A)-D(2) receptor heteromerization and G(q/11)-PLC signaling, modulates neuronal excitability and neurotransmitter release. On the other hand, an antagonistic A(2A)-D(2) receptor interaction at the adenylyl-cyclase level, which depends on G(s/olf)- and G(i/o)-type V adenylyl-cyclase signaling, modulates protein phosphorylation and gene expression. Finally, under conditions of upregulation of an activator of G protein signaling (AGS3), such as during chronic treatment with addictive drugs, a synergistic A(2A)-D(2) receptor interaction can also be demonstrated. AGS3 facilitates a synergistic interaction between G(s/olf) - and G(i/o)-coupled receptors on the activation of types II/IV adenylyl cyclase, leading to a paradoxical increase in protein phosphorylation and gene expression upon co-activation of A(2A) and D(2) receptors. The analysis of A(2)-D(2) receptor interactions will have implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction. C1 [Ferre, S.; Quiroz, C.; Woods, A. S.] NIDA, IRP, NIH, DHHS, Baltimore, MD 21224 USA. [Cunha, R.] Univ Coimbra, Ctr Neurosci Coimbra, Fac Med, Inst Biochem, P-3004504 Coimbra, Portugal. [Popoli, P.] Ist Super Sanita, I-00161 Rome, Italy. [Ciruela, F.] Univ Barcelona, Fac Med, Unitat Farmacol, Dept Patol & Terapeut Expt, Barcelona 08907, Spain. [Lluis, C.; Franco, R.] Univ Barcelona, Inst Invest Biomed August Pi I Sunyer, CIBERNED, E-08028 Barcelona, Spain. [Azdad, K.; Schiffmann, S. N.] Univ Libre Bruxelles, B-1070 Brussels, Belgium. RP Ferre, S (reprint author), NIDA, IRP, NIH, DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; OI Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Cunha, Rodrigo/0000-0003-2550-6422 FU Intramural NIH HHS [Z01 DA000493-02] NR 77 TC 127 Z9 129 U1 1 U2 13 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAY PY 2008 VL 14 IS 15 BP 1468 EP 1474 DI 10.2174/138161208784480108 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 311RX UT WOS:000256618400002 PM 18537670 ER PT J AU Cunha, RA Ferre, S Vaugeois, JM Chen, JF AF Cunha, Rodrigo A. Ferre, Sergi Vaugeois, Jean-Marie Chen, Jiang-Fan TI Potential therapeutic interest of adenosine A(2A) receptors in psychiatric disorders SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE adenosine; A(2A) receptor; caffeine; mood disorders; psychiatric diseases; anxiety; depression; schizophrenia; attention deficit hyperactivity disorder; ADHD ID DEFICIT HYPERACTIVITY DISORDER; METHYL-D-ASPARTATE; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SPONTANEOUSLY HYPERTENSIVE-RAT; CENTRAL-NERVOUS-SYSTEM; MAGNETIC-RESONANCE-SPECTROSCOPY; PITUITARY-ADRENOCORTICAL AXIS; MAJOR DEPRESSIVE DISORDER; MINIMAL BRAIN-DYSFUNCTION; SUBSTANCE USE DISORDERS AB The interest on targeting adenosine A(2A) receptors in the realm of psychiatric diseases first arose based on their tight physical and functional interaction with dopamine D-2 receptors. However, the role of central A(2A) receptors is now viewed as much broader than just controlling D-2 receptor function. Thus, there is currently a major interest in the ability of A(2A) receptors to control synaptic plasticity at glutamatergic synapses. This is due to a combined ability of A(2A) receptors to facilitate the release of glutamate and the activation of NMDA receptors. Therefore, A(2A) receptors are now conceived as a normalizing device promoting adequate adaptive responses in neuronal circuits, a role similar to that fulfilled, in essence, by dopamine. This makes A(2A) receptors particularly attractive targets to manage psychiatric disorders since adenosine may act as go-between glutamate and dopamine, two of the key players in mood processing. Furthermore, A(2A) receptors also control glia function and brain metabolic adaptation, two other emerging mechanisms to understand abnormal processing of mood, and A(2A) receptors are important players in controlling the demise of neurodegeneration, considered an amplificatory loop in psychiatric disorders. Current data only provide an indirect confirmation of this putative role of A(2A) receptors, based on the effects of caffeine (an antagonist of both A(1) and A(2A) receptors) in psychiatric disorders. However, the introduction of A(2A) receptors antagonists in clinics as anti-parkinsonian agents is hoped to bolster our knowledge on the role of A(2A) receptors in mood disorders in the near future. C1 [Cunha, Rodrigo A.] Univ Coimbra, Ctr Neurosci Coimbra, Inst Biochem, Fac Med, P-3000 Coimbra, Portugal. [Ferre, Sergi] NIDA, IRP, NIH, DHHS, Baltimore, MD USA. [Vaugeois, Jean-Marie] Univ Rouen, Neuropsychopharmacol Depress Unit, CNRS, FRE IFRMP 2735,Inst Biomed Res, F-76821 Mont St Aignan, France. [Chen, Jiang-Fan] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. RP Cunha, RA (reprint author), Univ Coimbra, Ctr Neurosci Coimbra, Inst Biochem, Fac Med, P-3000 Coimbra, Portugal. EM cunharod@gmail.com RI Ferre, Sergi/K-6115-2014; Cunha, Rodrigo/E-7475-2015 OI Ferre, Sergi/0000-0002-1747-1779; Cunha, Rodrigo/0000-0003-2550-6422 FU Intramural NIH HHS [Z01 DA000493-02] NR 272 TC 106 Z9 110 U1 1 U2 15 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAY PY 2008 VL 14 IS 15 BP 1512 EP 1524 DI 10.2174/138161208784480090 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 311RX UT WOS:000256618400006 PM 18537674 ER PT J AU Fessler, MB AF Fessler, Michael B. TI Liver X receptor: Crosstalk node for the signaling of lipid metabolism, carbohydrate metabolism, and innate immunity SO CURRENT SIGNAL TRANSDUCTION THERAPY LA English DT Review ID PANCREATIC BETA-CELLS; INDUCED INSULIN-RESISTANCE; CASSETTE TRANSPORTER A1; PROSTATE-CANCER CELLS; NECROSIS-FACTOR-ALPHA; HUMAN ABCG1 GENE; LDLR-KO MICE; LXR-ALPHA; CHOLESTEROL EFFLUX; OXYSTEROL RECEPTOR AB Liver X Receptor-alpha (LXR alpha also known as NR1H3) and LXR beta (NR1H2) are members of the nuclear receptor superfamily of ligand-activated transcription factors, a superfamily which includes the more widely known glucocorticoid receptor, estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptors. The LXRs are activated by physiologic sterol ligands (e. g., oxysterols) and by synthetic agonists. In recent years, our understanding of the importance of LXRs has expanded across several fields of (patho-) physiology. Perhaps best known from a sizeable literature as homeostatic 'cholesterol sensors' that drive transcriptional programs promoting cellular cholesterol efflux, 'reverse cholesterol transport,' and bile acid synthesis, more recent roles for LXRs in glucose homeostasis, atherosclerosis, and innate immunity have also been identified. These discoveries complement an emerging literature that continues to draw surprisingly intimate connections between host metabolism and host defense. The present review will discuss the roles of LXR in the signaling of metabolism and innate immunity, and the potential for synthetic LXR agonists as novel therapeutics in dyslipidemia, atherosclerosis, disordered glucose metabolism, and inflammation. C1 NIEHS, Biol Res Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Fessler, MB (reprint author), NIEHS, Biol Res Lab, NIH, 111 TW Alexander Dr,POB 12233,Maildrop D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU Intramural NIH HHS [Z01 ES102005-02] NR 113 TC 3 Z9 3 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-3624 J9 CURR SIGNAL TRANSD T JI Curr. Signal Transduct. Ther. PD MAY PY 2008 VL 3 IS 2 BP 75 EP 81 DI 10.2174/157436208784223170 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 305JS UT WOS:000256175100001 PM 24563635 ER PT J AU Roederer, M AF Roederer, Mario TI How many events is enough? Are you positive? SO CYTOMETRY PART A LA English DT Editorial Material ID T-CELLS C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM roederer@nih.gov NR 3 TC 34 Z9 34 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2008 VL 73A IS 5 BP 384 EP 385 DI 10.1002/cyto.a.20549 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 293TW UT WOS:000255359100004 PM 18307257 ER PT J AU McLaughlin, BE Baumgarth, N Bigos, M Roederer, M De Rosa, SC Altman, JD Nixon, DF Ottinger, J Oxford, C Evans, TG Asmuth, DM AF McLaughlin, Bridget E. Baumgarth, Nicole Bigos, Martin Roederer, Mario De Rosa, Stephen C. Altman, John D. Nixon, Douglas F. Ottinger, Janet Oxford, Carol Evans, Thomas G. Asmuth, David M. TI Nine-color flow cytometry for accurate measurement of T cell subsets and cytokine responses. Part I: Panel design by an empiric approach SO CYTOMETRY PART A LA English DT Article DE polychromatic flow cytometry; T cell immunophenotyping; fluorochrome conjugated antibody; compensation ID VACCINATION; ASSAY AB Polychromatic flow cytometry offers the unprecedented ability to investigate multiple antigens per cell. Unfortunately, unwanted spectral overlaps and compensation problems increase when more than four colors are used, but these problems can be minimized if staining combinations are chosen carefully. We used an empiric approach to design, test and identify six-color T cell immunophenotyping reagent panels that can be expanded to include three or more functional or other markers in the FITC, PE, and APC channels without significant spectral limitations. Thirty different six-color T cell surface antigen reagent panels were constructed to identify major T cell subsets and maturational subtypes as defined by CCR7 and CD45RA expression, while excluding monocytes, B and non-viable cells. Staining performance of each panel was compared on cryopreserved cells from a single healthy donor recorded on a multiparameter cell sorter. Ten of the thirty reagent panels offered reliable resolution of T cell major and maturational surface markers. Of these, two panels were selected that showed the least spectral overlap and resulting background increase in the FITC, PE, and APC channels. These channels were left unoccupied for inclusion of additional phenotypic or functional markers, such as cytokines. Careful reagent titration and testing of multiple candidate panels are necessary to ensure quality results in multiparametric measurements. (C) 2008 International Society for Advancement of Cytometry. C1 [McLaughlin, Bridget E.; Asmuth, David M.] Univ Calif Davis, Div Infect Dis, Davis, CA 95616 USA. [Baumgarth, Nicole] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Bigos, Martin] Gladstone Inst Virol & Immunol, San Francisco, CA USA. [Roederer, Mario] NIAID, NIH, Bethesda, MD 20892 USA. [De Rosa, Stephen C.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Altman, John D.] Emory Univ, Emory Vaccine Ctr Yerkes, Atlanta, GA 30322 USA. [Ottinger, Janet] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [Ottinger, Janet] Duke Univ, Med Ctr, Duke Ctr AIDS Res, Durham, NC USA. [Oxford, Carol] Univ Calif Davis, Med Pathol & Lab Med, Davis, CA 95616 USA. [Evans, Thomas G.] Novartis Inst Biol Res, Cambridge, MA USA. RP Asmuth, DM (reprint author), Univ Calif Davis, Div Infect Dis, Davis, CA 95616 USA. OI Nixon, Douglas/0000-0002-2801-1786 FU NCRR NIH HHS [C06RR-12088-01]; NIAID NIH HHS [AI051999, R01 AI051999-03] NR 22 TC 41 Z9 43 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2008 VL 73A IS 5 BP 400 EP 410 DI 10.1002/cyto.a.20555 PG 11 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 293TW UT WOS:000255359100008 PM 18383316 ER PT J AU McLaughlin, BE Baumgarth, N Bigos, M Roederer, M De Rosa, SC Altman, JD Nixon, DE Ottinger, J Li, J Beckett, L Shacklett, BL Evans, TG Asmuth, DM AF McLaughlin, Bridget E. Baumgarth, Nicole Bigos, Martin Roederer, Mario De Rosa, Stephen C. Altman, John D. Nixon, Douglas E. Ottinger, Janet Li, Judy Beckett, Laurel Shacklett, Barbara L. Evans, Thomas G. Asmuth, David M. TI Nine-color flow cytometry for accurate measurement of T cell subsets and cytokine responses. Part II: Panel performance across different instrument platforms SO CYTOMETRY PART A LA English DT Article DE polychromatic flow cytometry; multicolor flow cytometry; high-resolution immunophenotyping; fluorochrome conjugated antibody; compensation ID VACCINATION; COMPENSATION; ANTIGEN AB Cellular immune responses elicited by vaccination are complex and require polychromatic analysis to accurately characterize the phenotype and function of rare, responding cells. Technical challenges and a lack of instrument standardization between research sites have limited the application of polychromatic cytometry in multicenter clinical trials. Two previously developed six-color T cell subset immunophenotyping reagent panels deliberately designed to accommodate three additional low frequency functional measurements were compared for their reproducibility of staining across three different flow cytometers. We repeatedly measured similar T cell subset frequencies between the two reagent panels and across the three different cytometers. Spectral overlap reduced sensitivity in two of the three open measurement channels (PE [IL-2] and APC [IFN gamma]) for one reagent combination, particularly in subsets with low cytokine expression. There was no significant interassay variation for measurements across instrument platforms. Careful panel design will identify reagent combinations that minimize spectral spillover into channels reserved for cytokine measurement and comparable results can be achieved using different cytometers, however, it is important to establish standardized quality control procedures for each instrument to minimize variation between cytometers. (C) 2008 International Society for Advancement of Cytometry. C1 [McLaughlin, Bridget E.; Baumgarth, Nicole; Asmuth, David M.] Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. [Bigos, Martin] J David Gladstone Inst Virol & Immunol, San Francisco, CA USA. [Roederer, Mario] NIAID, NIH, Bethesda, MD 20892 USA. [De Rosa, Stephen C.] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. [Altman, John D.] Emory Univ, Emory Vaccine Ctr Yerkes, Atlanta, GA 30322 USA. [Nixon, Douglas E.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [Ottinger, Janet] Duke Univ, Med Ctr, Duke Ctr AIDS Res, Durham, NC USA. [Li, Judy; Beckett, Laurel] Univ Calif Davis, Div Biostat, Davis, CA 95616 USA. [Evans, Thomas G.] Novartis Inst Biol Res, Cambridge, MA USA. RP Asmuth, DM (reprint author), Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. RI Shacklett, Barbara/A-7288-2009; OI Shacklett, Barbara/0000-0002-7067-732X; Beckett, Laurel/0000-0002-2418-9843; Nixon, Douglas/0000-0002-2801-1786 FU NCRR NIH HHS [C06RR-12088-01]; NIAID NIH HHS [R01 AI051999-03, AI051999] NR 22 TC 20 Z9 21 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2008 VL 73A IS 5 BP 411 EP 420 DI 10.1002/cyto.a.20556 PG 10 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 293TW UT WOS:000255359100009 PM 18383309 ER PT J AU Rogers, WT Moser, AR Holyst, HA Bantly, A Mohler, ER Scangas, G Moore, JS AF Rogers, Wade T. Moser, Allan R. Holyst, Herbert A. Bantly, Andrew Mohler, Emile R., III Scangas, George Moore, Jonni S. TI Cytometric Fingerprinting: Quantitative characterization of multivariate distributions SO CYTOMETRY PART A LA English DT Article DE flow cytometry; cytomics; bioinformatics; computational biology; machine learning; empirical modeling ID T-CELL RESPONSES; ENDOTHELIAL PROGENITOR CELLS; DISTRIBUTION DIFFERENCES/; STATISTICAL VARIABLES; PRINCIPAL COMPONENTS; CLUSTER-ANALYSIS; FLOW; IMMUNIZATION; COMPLEX; QUALITY AB Recent technological advances in flow cytometry instrumentation provide the basis for high-dimensionality and high-throughput biological experimentation in a heterogeneous cellular context. Concomitant advances in scalable computational algorithms are necessary to better utilize the information that is contained in these high-complexity experiments. The development of such tools has the potential to expand the utility of flow cytometric analysis from a predominantly hypothesis-driven mode to one of discovery, or hypothesis-generating research. A new method of analysis of flow cytometric data called Cytometric Fingerprinting (CF) has been developed. CF captures the set of multivariate probability distribution functions corresponding to list-mode data and then "flattens" them into a computationally efficient fingerprint representation that facilitates quantitative comparisons of samples. An experimental and synthetic data were generated to act as reference sets for evaluating CF. Without the introduction of prior knowledge, CF was able to "discover" the location and concentration of spiked cells in ungated analyses over a concentration range covering four orders of magnitude, to a lower limit on the order of 10 spiked events in a background of 100,000 events. We describe a new method for quantitative analysis of list-mode cytometric data. CF includes a novel algorithm for space subdivision that improves estimation of the probability density function by dividing space into nonrectangular polytopes. Additionally it renders a multidimensional distribution in the form of a one-dimensional multi resolution hierarchical fingerprint that creates a computationally efficient representation of high dimensionality distribution functions. CF supports both the generation and testing of hypotheses, eliminates sources of operator bias, and provides an increased level of automation of data analysis. (C)) 2008 international Society for Advancement of Cytometry. C1 [Rogers, Wade T.; Moser, Allan R.; Holyst, Herbert A.] Cira Discovery Sci Inc, Philadelphia, PA USA. [Rogers, Wade T.; Moser, Allan R.] Hutzen Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI USA. [Rogers, Wade T.; Holyst, Herbert A.; Bantly, Andrew; Scangas, George; Moore, Jonni S.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Rogers, Wade T.; Holyst, Herbert A.; Bantly, Andrew; Scangas, George; Moore, Jonni S.] Univ Penn, Sch Med, Flow Cytometry & Cell Sorting Resource Lab, Philadelphia, PA 19104 USA. [Mohler, Emile R., III] Univ Penn, Sch Med, Vasc Med Sect,Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. RP Rogers, WT (reprint author), Cira Discovery Sci Inc, Philadelphia, PA USA. EM rogersw@mail.med.upenn.edu NR 26 TC 22 Z9 23 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2008 VL 73A IS 5 BP 430 EP 441 DI 10.1002/cyto.a.20545 PG 12 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 293TW UT WOS:000255359100011 PM 18383310 ER PT J AU Gudla, PR Nandy, K Collins, J Meaburn, KJ Misteli, T Lockett, SJ AF Gudla, Prabhakar R. Nandy, K. Collins, J. Meaburn, K. J. Misteli, T. Lockett, S. J. TI A high-throughput system for segmenting nuclei using multiscale techniques SO CYTOMETRY PART A LA English DT Article; Proceedings Paper CT Conference on Imaging, Manipulation, and Analysis of Biomolecules, Cells and Tissues V CY JAN, 2007 CL San Jose, CA SP SPIE DE high-throughput segmentation; multiscale edge representation; nonuniform illumination; multiscale thresholding; watershed; region merging; cluster analysis ID 3-DIMENSIONAL IMAGE SEGMENTATION; CELL-NUCLEI; TISSUE-SECTIONS; CHROMOSOME DYNAMICS; ALGORITHM; TRACKING; CLASSIFICATION; ORGANIZATION; WATERSHEDS; MICROSCOPY AB Automatic segmentation of cell nuclei is critical in several high-throughput cytometry applications whereas manual segmentation is laborious and irreproducible. One such emerging application is measuring the spatial organization (radial and relative distances) of fluorescence in situ hybridization (FISH) DNA sequences, where recent investigations strongly suggest a correlation between nonrandom arrangement of genes to carcinogenesis. Current automatic segmentation methods have varying performance in the presence of nonuniform illumination and clustering, and boundary accuracy is seldom assessed, which makes them suboptimal for this application. The authors propose a modular and model-based algorithm for extracting individual nuclei. It uses multiscale edge reconstruction for contrast stretching and edge enhancement as well as a multiscale entropy-based thresholding for handling nonuniform intensity variations. Nuclei are initially oversegmented and then merged based on area followed by automatic multistage classification into single nuclei and clustered nuclei. Estimation of input parameters and training of the classifiers is automatic. The algorithm was tested on 4,181 lymphoblast nuclei with varying degree of background nonuniformity and clustering. It extracted 3,515 individual nuclei and identified single nuclei and individual nuclei in clusters with 99.8 +/- 0.3% and 95.5 +/- 5.1% accuracy, respectively. Segmented boundaries of the individual nuclei were accurate when compared with manual segmentation with an average RMS deviation of 0.26 mu m (similar to 2 pixels). The proposed segmentation method is efficient, robust, and accurate for segmenting individual nuclei from fluorescence images containing clustered and isolated nuclei. The algorithm allows complete automation and facilitates reproducible and unbiased spatial analysis of DNA sequences. Published 2008 Wiley-Liss, Inc. C1 [Gudla, Prabhakar R.; Nandy, K.; Collins, J.; Lockett, S. J.] SAIC Frederick Inc, NCI Frederick, Image Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. [Meaburn, K. J.; Misteli, T.] NCI, Lab Receptor Biol & Gene Express, Cell Biol & Genomes Grp, Bethesda, MD 20892 USA. RP Gudla, PR (reprint author), SAIC Frederick Inc, NCI Frederick, Image Anal Lab, Adv Technol Program, Bldg 538,Room 104, Frederick, MD 21702 USA. EM reddyg@ncifcrf.gov RI Nandy, Kaustav/B-1549-2012; OI Meaburn, Karen/0000-0002-1327-5957 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 65 TC 49 Z9 49 U1 1 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2008 VL 73A IS 5 BP 451 EP 466 DI 10.1002/cyto.a.20550 PG 16 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 293TW UT WOS:000255359100013 PM 18338778 ER PT J AU Joesting, MS Cheever, TR Volzing, KG Yamaguchi, TP Wolf, V Naf, D Rubin, JS Marker, PC AF Joesting, Margaret S. Cheever, Thomas R. Volzing, Katherine G. Yamaguchi, Terry P. Wolf, Vladimir Naf, Dieter Rubin, Jeffrey S. Marker, Paul C. TI Secreted frizzled related protein 1 is a paracrine modulator of epithelial branching morphogenesis, proliferation, and secretory gene expression in the prostate SO DEVELOPMENTAL BIOLOGY LA English DT Article DE prostate development; SFRP1; non-canonical Wnt signaling; branching morphogenesis; JNK; knockout mice; transgenic mice ID UROGENITAL SINUS; CELL-DIFFERENTIATION; TISSUE RECOMBINANTS; ANDROGEN RECEPTOR; MOUSE PROSTATE; SFRP1; CANCER; MICE; GLAND; LUNG AB Previous in vitro studies identified secreted frizzled related protein 1 (SFRPl) as a candidate pro-proliferative signal during prostatic development and cancer progression. This study determined the in vivo roles of SFRPl in the prostate using expression studies in mice and by creating loss- and gain-of-function mouse genetic models. Expression studies using an SFRPl(lacz) knock-in allele showed that SFRPl is expressed in the developing mesenchyme/stroma of the prostate. Nevertheless, Sfrpl null prostates exhibited multiple prostatic developmental defects in the epithelium including reduced branching morphogenesis, delayed proliferation, and increased expression of genes encoding prostate-specific secretory proteins. Interestingly, over-expression of SFRPl in the adult prostates of transgenic mice yielded opposite effects including prolonged epithelial proliferation and decreased expression of genes encoding secretory proteins. These data demonstrated a previously unrecognized role for SFRPl as a stromal-to-epithelial paracrine modulator of epithelial growth, branching morphogenesis, and epithelial gene expression. To clarify the mechanism of SFRPl action in the prostate, the response of WNT signaling pathways to SFRPl was examined. Forced expression of SFRPl in prostatic epithelial cells did not alter canonical WNT/beta-catenin signaling or the activation of CamKII. However, forced expression of SFRPl led to sustained activation of JNK, and inhibition of JNK activity blocked the SFRPl-induced proliferation of prostatic epithelial cells, suggesting that SFRPl acts through the non-canonical WNT/JNK pathway in the prostate. (C) 2008 Elsevier Inc. All rights reserved. C1 [Marker, Paul C.] Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, Madison, WI 53705 USA. [Naf, Dieter] Natl Canc Inst, Lab Anim Sci Program, Frederick, MD 20878 USA. [Wolf, Vladimir; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Joesting, Margaret S.; Cheever, Thomas R.; Volzing, Katherine G.; Marker, Paul C.] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. RP Marker, PC (reprint author), Univ Wisconsin, Sch Pharm, Div Pharmaceut Sci, 777 Highland Ave, Madison, WI 53705 USA. EM marker@wisc.edu FU Intramural NIH HHS; NIA NIH HHS [AG024278, R01 AG024278, R01 AG024278-01A2, R01 AG024278-02, R01 AG024278-03]; NIDDK NIH HHS [DK069662, R01 DK091193, R21 DK069662, R21 DK069662-01, R21 DK069662-02] NR 48 TC 25 Z9 25 U1 0 U2 4 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 MAY 1 PY 2008 VL 317 IS 1 BP 161 EP 173 DI 10.1016/j.ydbio.2008.02.021 PG 13 WC Developmental Biology SC Developmental Biology GA 297PP UT WOS:000255628900014 PM 18371946 ER PT J AU Fulco, M Cen, Y Zhao, P Hoffman, EP McBurney, MW Sauve, AA Sartorelli, V AF Fulco, Marcella Cen, Yana Zhao, Po Hoffman, Eric P. McBurney, Michael W. Sauve, Anthony A. Sartorelli, Vittorio TI Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt SO DEVELOPMENTAL CELL LA English DT Article ID PANCREATIC BETA-CELLS; LIFE-SPAN EXTENSION; CALORIE RESTRICTION; PROTEIN-KINASE; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; SACCHAROMYCES-CEREVISIAE; INSULIN-SECRETION; MUSCLE DIFFERENTIATION; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTORS AB It is intuitive to speculate that nutrient availability may influence differentiation of mammalian cells. Nonetheless, a comprehensive complement of the molecular determinants involved in this process has not been elucidated yet. Here, we have investigated how nutrients (glucose) affect skeletal myogenesis. Glucose restriction (GR) impaired differentiation of skeletal myoblasts and was associated with activation of the AMP-activated protein kinase (AMPK). Activated AMPK was required to promote GR-induced transcription of the NAD(+) biosynthetic enzyme Nampt. Indeed, GR augmented the Nampt activity, which consequently modified the intracellular [NAD+]:[NADH] ratio and nicotinamide levels, and mediated inhibition of skeletal myogenesis. Skeletal myoblasts derived from SIRT1(-/-) heterozygous mice were resistant to the effects of either GR or AMPK activation. These experiments reveal that AMPK, Nampt, and SIRT1 are the molecular components of a functional signaling pathway that allows skeletal muscle cells to sense and react to nutrient availability. C1 [Fulco, Marcella; Sartorelli, Vittorio] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. [Cen, Yana; Sauve, Anthony A.] Cornell Univ, Weill Med Coll, Dept Pharmacol, New York, NY 10021 USA. [Zhao, Po; Hoffman, Eric P.] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [McBurney, Michael W.] Ottawa Hlth Res Ctr Inst, Ottawa, ON K1H 8L6, Canada. RP Sartorelli, V (reprint author), NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov RI Cen, Yana/F-4731-2014 OI Cen, Yana/0000-0001-6436-5744 FU Intramural NIH HHS [Z01 AR041126-08] NR 78 TC 369 Z9 389 U1 5 U2 32 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2008 VL 14 IS 5 BP 661 EP 673 DI 10.1016/j.devcel.2008.02.004 PG 13 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 301LX UT WOS:000255898800008 PM 18477450 ER PT J AU Mak, KK Bi, YM Wan, C Chuang, PT Clemens, T Young, M Yang, YZ AF Mak, Kinglun Kingston Bi, Yanming Wan, Chao Chuang, Pao-Tien Clemens, Thomas Young, Marian Yang, Yingzi TI Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression SO DEVELOPMENTAL CELL LA English DT Article ID HORMONE-RELATED PROTEIN; GROWTH-FACTOR-BETA; PARATHYROID-HORMONE; INDIAN HEDGEHOG; OSTEOCLAST DIFFERENTIATION; MESSENGER-RNA; KINASE-A; CELLS; OSTEOPROTEGERIN; ACTIVATION AB Hedgehog (Hh) signaling is required for osteoblast differentiation from mesenchymal progenitors during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. We found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. Upregulating Hh signaling selectively in mature osteoblasts led to increased bone formation and excessive bone resorption. As a consequence, these mutant mice showed severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts resulted in increased bone mass and protection from bone loss in older mice. Cellular and molecular studies showed that Hh signaling indirectly induced osteoclast differentiation by upregulating osteoblast expression of PTHrP, which promoted RANKL expression via PKA and its target transcription factor CREB. Our results demonstrate that Hh signaling in mature osteoblasts regulates both bone formation and resorption and that inhibition of Hh signaling reduces bone loss in aged mice. C1 [Mak, Kinglun Kingston; Yang, Yingzi] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Bi, Yanming; Young, Marian] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. [Wan, Chao; Clemens, Thomas] Univ Alabama, Dept Pathol, Div Mol & Cellular Pathol, Birmingham, AL 35294 USA. [Chuang, Pao-Tien] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Yang, YZ (reprint author), NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL66600, HL67822]; NIAMS NIH HHS [R01 AR049410] NR 66 TC 87 Z9 93 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2008 VL 14 IS 5 BP 674 EP 688 DI 10.1016/j.devcel.2008.02.003 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 301LX UT WOS:000255898800009 PM 18477451 ER PT J AU Kuo, CK Petersen, BC Tuan, RS AF Kuo, Catherine K. Petersen, Bryan C. Tuan, Rocky S. TI Spatiotemporal protein distribution of TGF-beta, their receptors, and extracellular matrix molecules during embryonic tendon development SO DEVELOPMENTAL DYNAMICS LA English DT Article DE tendon; tendon development; chick; TGF-beta; collagen type III; decorin; fibronectin ID GROWTH-FACTOR-BETA; FIBRILLOGENESIS IN-SITU; COLLAGEN FIBRILLOGENESIS; III COLLAGEN; NEUTRALIZING ANTIBODY; PATTERN-FORMATION; PATELLAR TENDON; ACHILLES-TENDON; FIBRIL SEGMENTS; FLEXOR TENDON AB Tendon is one of the least understood tissues of the musculoskeletal system in terms of development and morphogenesis. Collagen fibrillogenesis has been the most studied aspect of tendon development, focusing largely on the role of matrix molecules such as collagen type III and decorin. While involvement of matrix molecules in collagen fibrillogenesis during chick tendon development is well understood, the role of growth factors has yet to be elucidated. This work examines the expression patterns of transforming growth factor (TGF) -beta 1, -beta 2, and -beta 3, and their receptors with respect to expression patterns of collagen type III, decorin, and fibronectin. We focus on the intermediate stages of tendon development in the chick embryo, a period during which the tendon micro- and macro-architecture are being established. Our findings demonstrate for the first time that TGF-beta 1, -beta 2, and -beta 3 have distinct spatiotemporal developmental protein localization patterns in the developing tendon and strongly suggest that these isoforms have independent roles in tendon development. C1 [Kuo, Catherine K.; Petersen, Bryan C.; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1523,50 South Dr,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural NIH HHS [Z01 AR041131-07]; NIAMS NIH HHS [Z01 AR041131] NR 64 TC 30 Z9 34 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAY PY 2008 VL 237 IS 5 BP 1477 EP 1489 DI 10.1002/dvdy.21547 PG 13 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 300RM UT WOS:000255842900023 PM 18425852 ER PT J AU Ernst, M Mueller, SC AF Ernst, Monique Mueller, Sven C. TI The adolescent brain: Insights from functional neuroimaging research SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Review DE functional neuroimaging; adolescence; brain maturation ID EMOTIONAL FACIAL EXPRESSIONS; VISUOSPATIAL WORKING-MEMORY; DIFFUSION-WEIGHTED MR; MAGNETIC-RESONANCE; COGNITIVE-DEVELOPMENT; WHITE-MATTER; DEVELOPMENTAL-CHANGES; NUCLEUS-ACCUMBENS; DECISION-MAKING; FEARFUL FACES AB With the development of functional neuroimaging tools, the past two decades have witnessed an explosion of work examining functional brain maps, mostly in the adult brain. Against this backdrop of work in adults, developmental research begins to gather a substantial body of knowledge about brain maturation. The purpose of this review is to present some of these findings from the perspective of functional neuroimaging. First, a brief survey of available neuroimaging techniques (i.e., fMRI, MRS, MEG, PET, SPECT, and infrared techniques) is provided. Next, the key cognitive,emotional, and social changes taking place during adolescence are outlined. The third section gives examples of how these behavioral changes can be understood from a neuroscience perspective. The conclusion places this functional neuroimaging research in relation to clinical and molecular work, and shows how answers will ultimately come from the combined efforts of these disciplines. (c) 2008 Wiley Periodicals, Inc. C1 [Ernst, Monique; Mueller, Sven C.] NIMH, NIH, Emot Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, NIH, Emot Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 120 TC 34 Z9 34 U1 6 U2 20 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAY PY 2008 VL 68 IS 6 BP 729 EP 743 DI 10.1002/dneu.20615 PG 15 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 297HH UT WOS:000255607200004 PM 18383544 ER PT J AU O'Donovan, MJ Bonnot, A Mentis, GZ Arai, Y Chub, N Shneider, NA Wenner, P AF O'Donovan, Michael J. Bonnot, Agnes Mentis, George Z. Arai, Yoshi Chub, Nikolai Shneider, Neil A. Wenner, Peter TI Imaging the spatiotemporal organization of neural activity in the developing spinal cord SO DEVELOPMENTAL NEUROBIOLOGY LA English DT Article DE development; spinal cord; imaging; chick; mouse ID SPONTANEOUS RHYTHMIC ACTIVITY; SPONTANEOUS NETWORK ACTIVITY; 2ND-HARMONIC GENERATION MICROSCOPY; ACTIVITY-DEPENDENT DEPRESSION; CALCIUM-SENSITIVE DYES; MOTOR AXON COLLATERALS; IN-VIVO; CHICK-EMBRYO; RECURRENT INHIBITION; NEONATAL MOUSE AB In this review, we discuss the use of imaging to visualize the spatiotemporal organization of network activity in the developing spinal cord of the chick embryo and the neonatal mouse. We describe several different methods for loading ion-and voltage-sensitive dyes into spinal neurons and consider the advantages and limitations of each one. We review work in the chick embryo, suggesting that motoneurons play a critical role in the initiation of each cycle of spontaneous network activity and describe how imaging has been used to identify a class of spinal interneuron that appears to be the avian homolog of mammalian Renshaw cells or la-inhibitory interneurons. Imaging of locomotor-like activity in the neonatal mouse revealed a wave-like activation of motoneurons during each cycle of discharge. We discuss the significance of this finding and its implications for understanding how locomotor-like activity is coordinated across different segments of the cord. In the last part of the review, we discuss some of the exciting new prospects for the future. (c) 2008 Wiley Periodicals, Inc. C1 [O'Donovan, Michael J.; Mentis, George Z.; Chub, Nikolai; Shneider, Neil A.] NINDS, NIH, Sect Dev Neurobiol, Bethesda, MD 20892 USA. [Bonnot, Agnes] Univ PM Curie, CNRS, UMR 7102, NDSM, Paris, France. [Arai, Yoshi] Saiseikai Kawaguchi Gen Hosp, Dept Orthoped, Kawaguchi, Saitama 3328558, Japan. [Wenner, Peter] Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA. RP O'Donovan, MJ (reprint author), NINDS, NIH, Sect Dev Neurobiol, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov RI o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Shneider, Neil/0000-0002-3223-7366; Wenner, Peter/0000-0002-7072-2194 NR 100 TC 27 Z9 27 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1932-8451 J9 DEV NEUROBIOL JI Dev. Neurobiol. PD MAY PY 2008 VL 68 IS 6 BP 788 EP 803 DI 10.1002/dneu.20620 PG 16 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 297HH UT WOS:000255607200009 PM 18383543 ER PT J AU Berch, DB AF Berch, Daniel B. TI Working memory and mathematical cognitive development: Limitations of limited-capacity resource models SO DEVELOPMENTAL NEUROPSYCHOLOGY LA English DT Article ID GENERAL FLUID INTELLIGENCE; SHORT-TERM-MEMORY; INDIVIDUAL-DIFFERENCES; LEARNING-DISABILITIES; PHONOLOGICAL STORAGE; EXECUTIVE ATTENTION; COMPONENTS; CONSTRUCT; CHILDREN; PERFORMANCE C1 [Berch, Daniel B.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Berch, DB (reprint author), Univ Virginia, Curry Sch Educ, 405 Emmet St S,POB 400260, Charlottesville, VA 22904 USA. EM dberch@virginia.edu NR 84 TC 14 Z9 14 U1 1 U2 7 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 8756-5641 EI 1532-6942 J9 DEV NEUROPSYCHOL JI Dev. Neuropsychol. PD MAY-JUN PY 2008 VL 33 IS 3 BP 427 EP 446 DI 10.1080/87565640801982494 PG 20 WC Psychology, Developmental; Psychology; Psychology, Experimental SC Psychology GA 302GQ UT WOS:000255957200012 PM 18473207 ER PT J AU Dettmer, AM Ruggiero, AM Novak, MA Meyer, JS Suomi, SJ AF Dettmer, Amanda M. Ruggiero, Angela M. Novak, Melinda A. Meyer, Jerrold S. Suomi, Stephen J. TI Surrogate mobility and orientation affect the early neurobehavioral development of infant rhesus macaques (Macaca mulatta) SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE rhesus macaque; surrogate; development; behavior ID MATERNAL MOBILITY; MONKEYS; MOTHERS AB A biological mother's movement appears necessary for optimal development in infant monkeys. However, nursery-reared monkeys are typically provided with inanimate surrogate mothers that move very little. The purpose of this study was to evaluate the effects of a novel, highly mobile surrogate mother on motor development, exploration, and reactions to novelty. Six infant rhesus macaques (Macaca mulatta) were reared on mobile hanging surrogates (MS) and compared to six infants reared on standard stationary rocking surrogates (RS) and to 9-15 infants reared with their biological mothers (MR) for early developmental outcome. We predicted that MS infants would develop more similarly to MR infants than RS infants. In neonatal assessments conducted at Day 30, both MS and MR infants showed more highly developed motor activity than RS infants on measures of grasping (p=.009), coordination (p=.038), spontaneous crawl (p=.009), and balance (p =.003). At 2-3 months of age, both MS and MR infants displayed higher levels of exploration in the home cage than RS infants (p= .016). In a novel situation in which only MS and RS infants were tested, MS infants spent less time near their surrogates in the first five minutes of the test session than RS infants (p =. 05), indicating a higher level of comfort. Collectively, these results suggest that when nursery-rearing of infant monkeys is necessary, a mobile hanging surrogate may encourage more normative development of gross motor skills and exploratory behavior and may serve as a useful alternative to stationary or rocking surrogates. (C) 2008 Wiley Periodicals, Inc. C1 [Dettmer, Amanda M.; Novak, Melinda A.; Meyer, Jerrold S.] Univ Massachusetts, Neurosci & Behav Program, Amherst, MA 01003 USA. [Novak, Melinda A.; Meyer, Jerrold S.] Univ Massachusetts, Dept Psychol, Amherst, MA 01003 USA. [Ruggiero, Angela M.; Suomi, Stephen J.] NIH, Comparat Ethol Lab, Poolesville, MD 20837 USA. RP Dettmer, AM (reprint author), Univ Massachusetts, Neurosci & Behav Program, Tobin Hall,135 Hicks Way, Amherst, MA 01003 USA. EM adettmer@nsm.umass.edu OI Meyer, Jerrold/0000-0002-8382-7075 FU Intramural NIH HHS [Z01 HD001106-24, NIH0012212671]; NCRR NIH HHS [R24 RR011122, RR11122, R24 RR011122-12, R24 RR011122-03]; NIH HHS [R24 OD011180]; NINDS NIH HHS [T32 NS007490, T32 NS007490-06, T32 NS007490-09, T32NS007490] NR 11 TC 7 Z9 7 U1 2 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD MAY PY 2008 VL 50 IS 4 BP 418 EP 422 DI 10.1002/dev.20296 PG 5 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 298DJ UT WOS:000255666300011 PM 19810188 ER PT J AU Bornstein, MH Putnick, DL Heslington, M Gini, M Suwalsky, JTD Venuti, P de Falco, S Giusti, Z de Galperin, CZ AF Bornstein, Marc H. Putnick, Diane L. Heslington, Marianne Gini, Motti Suwalsky, Joan T. D. Venuti, Paola de Falco, Simona Giusti, Zeno de Galperin, Celia Zingman TI Mother-child emotional availability in ecological perspective: Three countries, two regions, two genders SO DEVELOPMENTAL PSYCHOLOGY LA English DT Review DE emotional availability; culture; infancy; parenting ID INFANT ATTACHMENT; SEX-DIFFERENCES; MATERNAL SENSITIVITY; PERSONALITY-TRAITS; FOLLOW-UP; PSYCHOLOGY; CULTURES; CONTEXT; REPRESENTATIONS; AMERICAN AB This study used a cross-national framework to examine country, region, and gender differences in emotional availability (EA), a prominent index of mutual socioemotional adaptation in the parent-child dyad. Altogether 220 Argentine, Italian, and U.S. mothers and their daughters and sons from both rural and metropolitan areas took part in home observations when the children were 20 months old. In terms of country, Italian mothers were more sensitive and optimally structuring, and Italian children were more responsive and involving, than Argentine and U.S. dyads. In terms of region, rural mothers were more intrusive than metropolitan mothers, and boys from metropolitan areas were more responsive than boys from rural areas. In terms of gender, mothers of girls were more sensitive and optimally structuring than mothers of boys, and daughters were more responsive and involving than sons. Understanding how country, region, and gender influence EA exposes forces that shape child development, parent-infant interaction, and family systems. C1 [Bornstein, Marc H.; Putnick, Diane L.; Heslington, Marianne; Gini, Motti; Suwalsky, Joan T. D.; Venuti, Paola; de Falco, Simona; Giusti, Zeno; de Galperin, Celia Zingman] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Dept Hlth & Human Serv, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov RI Putnick, Diane/B-1707-2009; OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS NR 190 TC 36 Z9 36 U1 9 U2 20 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD MAY PY 2008 VL 44 IS 3 BP 666 EP 680 DI 10.1037/0012-1649.44.3.666 PG 15 WC Psychology, Developmental SC Psychology GA 300RL UT WOS:000255842800004 PM 18473635 ER PT J AU Bornstein, MH Tamis-LeMonda, CS Hahn, CS Haynes, OM AF Bornstein, Marc H. Tamis-LeMonda, Catherine S. Hahn, Chun-Shin Haynes, O. Maurice TI Maternal responsiveness to young children at three ages: Longitudinal analysis of a multidimensional, modular, and specific parenting construct SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE parenting; responsiveness; longitudinal; infancy; modularity ID LANGUAGE; SENSITIVITY; COMPETENCE; METAANALYSIS; 2-YEAR-OLDS; ATTACHMENT; PATTERNS; DEFIANCE; BEHAVIOR; INFANTS AB Responsiveness defines the prompt, contingent, and appropriate reactions parents display to their children in the context of everyday exchanges. Maternal responsiveness occupies a theoretically central position in developmental science and possesses meaningful predictive validity over diverse domains of children's development, yet basic psychometric features of maternal responsiveness are still poorly understood. In this prospective longitudinal study, the authors examined structure, individual variation, and continuity of multiple dimensions of responsiveness in 40 mothers to their infants' activities at 10, 14, and 21 months during natural home-based play interactions. Both age-general and age-specific patterns emerged in maternal responding. The study's developmental results support the multidimensionality, modularity, and specificity of this central parenting construct. C1 [Bornstein, Marc H.; Hahn, Chun-Shin; Haynes, O. Maurice] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Tamis-LeMonda, Catherine S.] NYU, Dept Appl Psychol, New York, NY 10003 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS NR 42 TC 100 Z9 103 U1 4 U2 23 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD MAY PY 2008 VL 44 IS 3 BP 867 EP 874 DI 10.1037/0012-1649.44.3.867 PG 8 WC Psychology, Developmental SC Psychology GA 300RL UT WOS:000255842800019 PM 18473650 ER PT J AU Freathy, RM Timpson, NJ Lawlor, DA Pouta, A Ben-Shlomo, Y Ruokonen, A Ebrahim, S Shields, B Zeggini, E Weedon, MN Lindgren, CM Lango, H Melzer, D Ferrucci, L Paolisso, G Neville, MJ Karpe, F Palmer, CNA Morris, AD Elliott, P Jarvelin, MR Smith, GD McCarthy, MI Hattersley, AT Frayling, TM AF Freathy, Rachel M. Timpson, Nicholas J. Lawlor, Debbie A. Pouta, Anneli Ben-Shlomo, Yoav Ruokonen, Aimo Ebrahim, Shah Shields, Beverley Zeggini, Eleftheria Weedon, Michael N. Lindgren, Cecilia M. Lango, Hana Melzer, David Ferrucci, Luigi Paolisso, Giuseppe Neville, Matthew J. Karpe, Fredrik Palmer, Colin N. A. Morris, Andrew D. Elliott, Paul Jarvelin, Marjo-Riitta Smith, George Davey McCarthy, Mark I. Hattersley, Andrew T. Frayling, Timothy M. TI Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI SO DIABETES LA English DT Article ID GENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; ADULT OBESITY; VARIANTS; RISK; EPIDEMIOLOGY; CHILDHOOD; DISEASE; POLYMORPHISMS; INDIVIDUALS AB OBJECTIVE-Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits. RESEARCH DESIGN AND METHODS-We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations. RESULTS-Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% Cl 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.0481]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)). CONCLUSIONS-FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of > 12,000 individuals were needed to detect associations at P < 0. 05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions. C1 [Freathy, Rachel M.; Shields, Beverley; Weedon, Michael N.; Lango, Hana; Melzer, David; Hattersley, Andrew T.; Frayling, Timothy M.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Timpson, Nicholas J.; Zeggini, Eleftheria; Lindgren, Cecilia M.; McCarthy, Mark I.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Timpson, Nicholas J.; Lawlor, Debbie A.] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England. [Lawlor, Debbie A.; Ben-Shlomo, Yoav; Smith, George Davey] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Pouta, Anneli; Ruokonen, Aimo; Jarvelin, Marjo-Riitta] Natl Publ Hlth Inst, Oulu, Finland. [Pouta, Anneli; Ruokonen, Aimo; Jarvelin, Marjo-Riitta] Oulu Univ, Oulu, Finland. [Ebrahim, Shah] London Sch Hyg & Trop Med, London WC1, England. [Lindgren, Cecilia M.; Neville, Matthew J.; Karpe, Fredrik; McCarthy, Mark I.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Ferrucci, Luigi] NIA, NIH, Bethesda, MD 20892 USA. [Paolisso, Giuseppe] Univ Naples 2, Naples, Italy. [Palmer, Colin N. A.; Morris, Andrew D.] Univ Dundee, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. RP Frayling, TM (reprint author), Peninsula Med Sch, Inst Biomed & Clin Sci, Magdalen Rd, Exeter EX1 2LU, Devon, England. EM tim.frayling@pms.ac.uk RI Palmer, Colin/C-7053-2008; Morris, Andrew/C-2837-2009; Lango Allen, Hana/G-9026-2012; Study, GoDARTS/K-9448-2016; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; OI Palmer, Colin/0000-0002-6415-6560; Lango Allen, Hana/0000-0002-7803-8688; Davey Smith, George/0000-0002-1407-8314; Zeggini, Eleftheria/0000-0003-4238-659X; Paolisso, Giuseppe/0000-0002-2137-455X; Monsalve, Beatriz Elena/0000-0002-5994-866X; Freathy, Rachel/0000-0003-4152-2238; Melzer, David/0000-0002-0170-3838; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Karpe, Fredrik/0000-0002-2751-1770; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262 FU British Heart Foundation; Department of Health; Intramural NIH HHS [Z99 AG999999]; Medical Research Council [G0500539, G0600705, G9815508]; Wellcome Trust [069224, 072960, 079557, 090532, GR069224, GR072960] NR 35 TC 185 Z9 196 U1 0 U2 16 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD MAY PY 2008 VL 57 IS 5 BP 1419 EP 1426 DI 10.2337/db07-1466 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 297PN UT WOS:000255628700035 PM 18346983 ER PT J AU Semple, RK Cochran, EK Soos, MA Burling, KA Savage, DB Gorden, P O'Rahilly, S AF Semple, Robert K. Cochran, Elaine K. Soos, Maria A. Burling, Keith A. Savage, David B. Gorden, Phillip O'Rahilly, Stephen TI Plasma adiponectin as a marker of insulin receptor dysfunction - Clinical utility in severe insulin resistance SO DIABETES CARE LA English DT Article ID SERUM AB OBJECTIVE - Severe insulin resistance is associated with high morbidity. Identification of severely insulin-resistant patients who have genetic or acquired insulin receptor dysfunction may aid therapeutic decision making; however, onerous diagnostic tests allied to a low frequency of insulin receptor dysfunction often preclude formal diagnosis. Our previous observation of paradoxical hyperadiponectinemia in insulin receptoropathy provides a possible basis for a simpler and cheaper screening test. RESEARCH DESIGN AND METHODS - Receiver operating characteristics analysis was used to determine diagnostic thresholds for insulin receptoropathy in severe insulin resistance for adiponectin and for the insulin-regulated hepatic proteins sex hormone-binding globulin (SHBG) and IGF binding protein-1. (IGFBP-1). RESULTS - Adiponectin >7 mg/l in severe insulin resistance had a 97% positive predictive value for insulin receptoropathy and <5 mg/l a 97% negative predictive value. IGFBP-1 and SHBG had lesser, though still significant, utility. CONCLUSIONS - Use of these markers is likely to have significant value in accelerating the diagnosis of insulin receptoropathies. C1 [Semple, Robert K.; Soos, Maria A.; Burling, Keith A.; Savage, David B.; O'Rahilly, Stephen] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 2QQ, England. [Cochran, Elaine K.; Gorden, Phillip] Natl Inst Diabet, Clin Endocrinol Branch, Bethesda, MD USA. RP Semple, RK (reprint author), Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Cambridge CB2 2QQ, England. EM rks16@cam.ac.uk RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Semple, Robert/0000-0001-6539-3069 FU Wellcome Trust [080952/Z/06/Z, 078986/Z/06/Z] NR 8 TC 43 Z9 47 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2008 VL 31 IS 5 BP 977 EP 979 DI 10.2337/dc07-2194 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 303CE UT WOS:000256016300030 PM 18299442 ER PT J AU Metter, EJ Windham, BG Maggio, M Simonsick, EM Ling, SM Egan, JM Ferrucci, L AF Metter, E. Jeffrey Windham, B. Gwen Maggio, Marcello Simonsick, Eleanor M. Ling, Shari M. Egan, Josephine M. Ferrucci, Luigi TI Glucose and insulin measurements from the oral glucose tolerance test and mortality prediction SO DIABETES CARE LA English DT Article ID RISK; SENSITIVITY; CRITERIA; DISEASE; ARTERY; HEART; MEN; AGE AB OBJECTIVE - To verify what information from oral glucose tolerance tests (OGTTs) independently predicts mortality. RESEARCH DESIGN AND METHODS - A total of 1,401 initially nondiabetic participants from the Baltimore Longitudinal Study of Aging aged 17-95 years underwent. one or more CGTTs (median 2, range 1-8), with insulin and glucose measurements taken every 20 min over the course of 2 h included in this study. Proportional hazards using the longitudinally collected data and Bayesian model averaging were used to examine the association of OGTT measurements individually and grouped with mortality, adjusting for covariates. RESULTS - Participants were followed for a median 20.3 years (range 0.5-40). The first-hour OGTT glucose and insulin levels increased only modestly with age, whereas levels during the second hour increased 4% per decade. Individually, 100- and 120-min glucose measures and fasting and 100-min insulin levels were all independent predictors of mortality. When all measures were considered together, only higher 120-min glucose was a significant independent risk factor for mortality. CONCLUSION - The steeper rise with age of the OGTT 2-h glucose values and the prognostic primacy of the 120-min glucose value for mortality is consistent with previous reports and suggests the value of using the OGTT in clinical practice. C1 [Metter, E. Jeffrey; Windham, B. Gwen; Simonsick, Eleanor M.; Ling, Shari M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Maggio, Marcello] Univ Parma, Sect Geriatr, Dept Internal med & Biomed Sci, I-43100 Parma, Italy. [Egan, Josephine M.] NIA, Clin Invest Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Metter, EJ (reprint author), NIA, Harbor Hosp 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM metterj@mail.nih.gov FU Intramural NIH HHS [Z01 AG000015-49, Z01 AG000640-15] NR 22 TC 17 Z9 17 U1 4 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2008 VL 31 IS 5 BP 1026 EP 1030 DI 10.2337/dc07-2102 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 303CE UT WOS:000256016300039 PM 18268070 ER PT J AU Dawson, DA Li, TK Grant, BF AF Dawson, Deborah A. Li, Ting-Kai Grant, Bridget F. TI A prospective study of risk drinking: At risk for what? SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE risk drinking; prospective risk ID ALCOHOL-RELATED PROBLEMS; DSM-IV ALCOHOL; NATIONAL EPIDEMIOLOGIC SURVEY; USE DISORDER CRITERIA; BINGE-DRINKING; FOLLOW-UP; ALL-CAUSE; CARDIOVASCULAR MORTALITY; GENERAL-POPULATION; ANXIETY DISORDERS AB Data from two waves of a nationally representative U.S. population sample were used to link frequency of risk drinking in the year preceding the Wave I interview with the incidence or occurrence of various adverse outcomes in the approximately 3-year-period between the two interviews (n = 22,122 Wave I drinkers who were reinterviewed at Wave 2). Risk drinking was defined as consuming the equivalent of 5+ standard drinks in a day for men and the equivalent of 4+ standard drinks in a day for women. Controls included sociodemographic and health characteristics, mean quantity of drinks consumed on risk drinking days and average volume of intake on non-risk drinking days. The odds of nonhierarchical alcohol abuse and dependence, initiation of smoking and incidence of nicotine dependence were increased at all frequencies of risk drinking and showed a fairly continuous increase in magnitude with increasing frequency, reaching OR of 3.03-7.23 for daily/near daily risk drinking. The incidence of liver disease was strongly increased among weekly or more frequent risk drinkers (OR= 2.78-4.76). The odds of social harm and drug use were increased among daily/near daily risk drinkers (OR= 1.61-2.54), and the likelihood of drivers license revocation showed near- significant increases at all frequencies of risk drinking. Frequency of risk drinking interacted with volume of intake on non-risk drinking days in predicting alcohol abuse and illicit drug use and with duration of drinking in predicting alcohol dependence. Risk drinking poses a threat of many types of harm, both directly and indirectly through its association with smoking initiation and nicotine dependence. These findings have illustrative value for prevention programs, and they indicate that frequent risk drinking is a strong marker for alcoholism. Published by Elsevier Ireland Ltd. C1 [Dawson, Deborah A.; Grant, Bridget F.] NIAAA, LEB, Div Clin & Biol Res, NIH, Bethesda, MD 20892 USA. [Li, Ting-Kai] NIAAA, NIH, Off Director, Bethesda, MD USA. RP Dawson, DA (reprint author), NIAAA, LEB, Div Clin & Biol Res, NIH, Room 3071,5635 Fishers Lane,MCS9304, Bethesda, MD 20892 USA. EM ddawson@mail.nih.gov FU Intramural NIH HHS [Z01 AA000449-04] NR 63 TC 85 Z9 86 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 MAY 1 PY 2008 VL 95 IS 1-2 BP 62 EP 72 DI 10.1016/j.drugalcdep.2007.12.007 PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 290WG UT WOS:000255152900008 PM 18243584 ER PT J AU Bjork, JM Momenan, R Smith, AR Hommer, DW AF Bjork, James M. Momenan, Reza Smith, Ashley R. Hommer, Daniel W. TI Reduced posterior mesofrontal cortex activation by risky rewards in substance-dependent patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE risk-taking; decision-making; reward; anterior cingulate; posterior mesofrontal cortex; substance dependence; alcohol; cocaine; striatum ID ANTERIOR CINGULATE CORTEX; SPATIAL WORKING-MEMORY; MEDIAL FRONTAL-CORTEX; ALCOHOL-USE DISORDERS; DECISION-MAKING; PREFRONTAL CORTEX; RESPONSE-INHIBITION; ADOLESCENT ALCOHOL; CONDUCT DISORDER; DRUG-ABUSERS AB Substance-dependent individuals show disadvantageous decision-making, as well as alterated frontocortical recruitment when performing experimental tasks. We investigated whether substance-dependent patients (SDP) would show blunted recruitment of posterior mesofrontal cortex (PMC) by a conflict between concurrently increasing reward and risk of penalty in a monetary game of "chicken." SDP and controls performed: motor control (no reward) trials, guaranteed reward trials in which reward was not at risk, and risky trials where subjects were required to terminate their reward accrual before a secret varying time limit or else "bust" and forfeit that trial's winnings (low penalty) or the current trial's winnings plus an equal amount of previous winnings (high penalty). Reward accrual duration at risk of "busting" correlated negatively with trait neuroticism. The contrast between winning guaranteed reward versus non-reward activated the caudate head bilaterally in SDP but not controls. Accumulation of money at risk of low- or high-penalty (contrasted with accumulating guaranteed money) activated the PMC in both groups, but with a greater magnitude and more anterior extent in controls. Pre-decision signal increase in a PMC volume of interest negatively correlated with risk-taking in low-penalty trials, and was blunted in SDP relative to controls under both penalty conditions after controlling for individual differences in actual risk-taking and the higher neuroticism of SDP These data suggest that SDP are characterized by a combination of: (a) striatal hypersensitivity to reward, and (b) under-recruitment of the specialized conflict-monitoring circuitry of the PMC when reward entails potential penalties. Published by Elsevier Ireland Ltd. C1 [Bjork, James M.; Momenan, Reza; Smith, Ashley R.; Hommer, Daniel W.] NIAAA, NIH, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIAAA, NIH, Lab Clin & Translat Studies, 10 Ctr Dr,CRC Room 1-5330, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU Intramural NIH HHS [Z99 DA999999] NR 61 TC 26 Z9 26 U1 4 U2 5 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 MAY 1 PY 2008 VL 95 IS 1-2 BP 115 EP 128 DI 10.1016/j.drugalcdep.2007.12.014 PG 14 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 290WG UT WOS:000255152900014 PM 18295984 ER PT J AU Levin, KH Copersino, ML Epstein, D Boyd, SJ Gorelick, DA AF Levin, Kenneth H. Copersino, Marc L. Epstein, David Boyd, Susan J. Gorelick, David A. TI Longitudinal ECG changes in cocaine users during extended abstinence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE cocaine; ECG; withdrawal; QTc; longitudinal; abstinence ID SHORT-TERM ABSTINENCE; MOOD AB Background: Cocaine lengthens electrocardiographic QTc, QRS and PR intervals through blockade of sodium and potassium channels, but changes during withdrawal have not been well studied. Methods: We recorded weekly electrocardiograms (ECGs) from 25 physically healthy cocaine users (84.0% men, mean [S.D.] age 34.7 [4.1] years, 9.0 [5.2] years of cocaine use, 9.4 [3.5] days of use in the 2 weeks prior to admission) over 3 months of monitored abstinence on a closed ward. Subjects had minimal current use of other drugs. Baseline ECGs were recorded 20.5 h [16.6] after last cocaine use. Results: Baseline QTc interval correlated positively with total amount of cocaine used and amount used per day in the 2 weeks prior to ward admission. There was a significant 10.5 ms [12.9] shortening of QTc interval during the first week of withdrawal, with no further significant changes thereafter. There were no significant changes in PR or QRS intervals. Conclusions: These findings suggest that cocaine-associated QTc prolongation returns toward normal during the first week of cocaine abstinence. Published by Elsevier Ireland Ltd. C1 [Levin, Kenneth H.; Copersino, Marc L.; Epstein, David; Boyd, Susan J.; Gorelick, David A.] NIDA, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Gorelick, DA (reprint author), NIDA, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM dgorelic@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000241-15] NR 9 TC 13 Z9 13 U1 0 U2 1 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 MAY 1 PY 2008 VL 95 IS 1-2 BP 160 EP 163 DI 10.1016/j.drugalcdep.2007.12.001 PG 4 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 290WG UT WOS:000255152900020 PM 18242882 ER PT J AU Adamson, CS Freed, EO AF Adamson, Catherine S. Freed, Eric O. TI Recent progress in antiretrovirals - lessons from resistance SO DRUG DISCOVERY TODAY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 INTEGRASE INHIBITORS; TREATMENT-EXPERIENCED PATIENTS; SYNCYTIUM-INDUCING PHENOTYPE; MOLECULE CCR5 INHIBITOR; ENTRY INHIBITORS; TREATMENT-NAIVE; BETULINIC ACID; STRAND TRANSFER; HELICAL DOMAIN AB Recent failures in efforts to develop an effective vaccine against HIV-1 infection have emphasized the importance of antiretroviral therapy in treating HIV-1-infected patients. Thus far, inhibitors of two viral enzymes, reverse transcriptase and protease, have had a profoundly positive impact on the survival of HIV-1-infected patients. However, new inhibitors that act at diverse steps in the viral replication cycle are urgently needed because of the development of resistance to currently available antiretrovirals. This review summarizes recent progress in antiretroviral drug discovery and development by specifically focusing on novel inhibitors of three phases of replication: viral entry, integration of the viral DNA into the host cell genome and virus particle maturation. C1 [Adamson, Catherine S.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural NIH HHS [Z01 BC010775-01, Z01 BC010778-01] NR 94 TC 33 Z9 34 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAY PY 2008 VL 13 IS 9-10 BP 424 EP 432 DI 10.1016/j.drudis.2008.02.003 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 313NF UT WOS:000256746600008 PM 18468560 ER PT J AU Mayilyan, KR Weinberger, DR Sim, RB AF Mayilyan, Karine R. Weinberger, Daniel R. Sim, Robert B. TI The complement system in schizophrenia SO DRUG NEWS & PERSPECTIVES LA English DT Article ID MANNAN-BINDING LECTIN; ACUTE-PHASE PROTEINS; CENTRAL-NERVOUS-SYSTEM; MBL-MASP COMPLEXES; ALZHEIMERS-DISEASE; MAJOR DEPRESSION; APOPTOTIC CELLS; GENE-EXPRESSION; BRAIN-TISSUE; HUMAN SERUM AB Several lines of evidence suggest that immunological factors contribute to schizophrenia. Since 1989, the role of complement, a major effector of innate immunity and an adjuvant of adaptive immunity, has been explored in schizophrenia. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by two or more groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity in patients versus controls. More then one report indicated a significant high frequency of FB*F allotype and low prevalence of the FS phenotype of complement factor B in schizophrenia. From the data reported, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergo dynamic changes, depending on the illness course and the state of neuro-immune crosstalk. Recent findings, implicating complement in neurogenesis, synapse remodeling and pruning during brain development, suggest a reexamination of the potential role of complement in neurodevelopmental processes contributing to schizophrenia susceptibility. It is plausible that the multicomponent complement system has more than one dimensional association with schizophrenia susceptibility, pathopsychology and illness course, understanding of which will bring a new perspective for possible immunomodulation and immunocorrection of the disease. (C) 2008 Prous Science, S.A.U. or its licensors. All rights reserved. C1 [Mayilyan, Karine R.; Weinberger, Daniel R.] NIMH, NIH, IRP, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Sim, Robert B.] Univ Oxford, Dept Biochem, MRC Immunochem Unit, Oxford, England. RP Mayilyan, KR (reprint author), NIMH, NIH, IRP, Genes Cognit & Psychosis Program, 10 Ctr Dr,Rm 4S-235, Bethesda, MD 20892 USA. EM mayilyank@mail.nih.gov RI Sim, Robert/A-1354-2008 OI Sim, Robert/0000-0002-2855-7455 FU Intramural NIH HHS [Z01 MH002904-01] NR 99 TC 38 Z9 38 U1 3 U2 6 PU PROUS SCIENCE, SA-THOMSON REUTERS PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0214-0934 J9 DRUG NEWS PERSPECT JI Drug News Perspect. PD MAY PY 2008 VL 21 IS 4 BP 200 EP 210 DI 10.1358/dnp.2008.21.4.1213349 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 316HG UT WOS:000256939600002 PM 18560619 ER PT J AU Bebenek, K Garcia-Diaz, M Foley, MC Pedersen, LC Schlick, T Kunkel, TA AF Bebenek, Katarzyna Garcia-Diaz, Miguel Foley, Meredith C. Pedersen, Lars C. Schlick, Tamar Kunkel, Thomas A. TI Substrate-induced DNA strand misalignment during catalytic cycling by DNA polymerase lambda SO EMBO REPORTS LA English DT Article DE DNA polymerase; DNA strand slippage; single nucleotide deletions; indels ID FRAMESHIFT MUTATIONS; MOLECULAR-DYNAMICS; ERROR-PRONE; REPLICATION; MECHANISM; BETA; MUTAGENESIS; PROGRAM AB The simple deletion of nucleotides is common in many organisms. It can be advantageous when it activates genes beneficial to microbial survival in adverse environments, and deleterious when it mutates genes relevant to survival, cancer or degenerative diseases. The classical idea is that simple deletions arise by strand slippage. A prime opportunity for slippage occurs during DNA synthesis, but it remains unclear how slippage is controlled during a polymerization cycle. Here, we report crystal structures and molecular dynamics simulations of mutant derivatives of DNA polymerase lambda bound to a primer-template during strand slippage. Relative to the primer strand, the template strand is in multiple conformations, indicating intermediates on the pathway to deletion mutagenesis. Consistent with these intermediates, the mutant polymerases generate single-base deletions at high rates. The results indicate that dNTP-induced template strand repositioning during conformational rearrangements in the catalytic cycle is crucial to controlling the rate of strand slippage. C1 [Bebenek, Katarzyna; Garcia-Diaz, Miguel; Pedersen, Lars C.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Bebenek, Katarzyna; Garcia-Diaz, Miguel; Pedersen, Lars C.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Foley, Meredith C.; Schlick, Tamar] NYU, Dept Chem, Courant Inst Math Sci, New York, NY 10012 USA. RP Kunkel, TA (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [R01 ES012692] NR 32 TC 26 Z9 26 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X J9 EMBO REP JI EMBO Rep. PD MAY PY 2008 VL 9 IS 5 BP 459 EP 464 DI 10.1038/embor.2008.33 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 295VP UT WOS:000255502300015 PM 18369368 ER PT J AU Chen, JH Varma, A Diaz, MR Litvintseva, AP Wollenberg, KK Kwon-Chung, KJ AF Chen, Jianghan Varma, Ashok Diaz, Mara R. Litvintseva, Anastasia P. Wollenberg, Kurt K. Kwon-Chung, Kyung J. TI Cryptococcus neoformans strains and infection in apparently immunocompetent patients, China SO EMERGING INFECTIOUS DISEASES LA English DT Article ID VAR. NEOFORMANS; SEROTYPE-A; POPULATION; EPIDEMIOLOGY; MENINGITIS; AFRICA; GRUBII; RISK; AIDS AB To determine the population structure of the cryptococcosis agents in China, we analyzed the genotype of 120 Cryptococcus neoformans and 9 Cryptococcus grattii strains isolated from 1980 through 2006 from cryptococcosis patients residing in 16 provinces of mainland China. A total of 71% (91/129) of the clinical strains isolated from 1985 through 2006 were from patients without any apparent risk factors. Only 8.5% (11/129) were from AIDS patients; the remaining 20.5% (27/129) were from patients with underlying diseases other than HIV infection. One hundred twenty of the 129 isolates were C. neoformans serotype A, mating type MAT alpha strains that exhibited an identical M13-based VNI subtype, which was distinguishable from the reference VNI molecular type. The 9 remaining isolates were serotype B, MATa strains of C. gattii and portrayed a typical VGI molecular type. Data analyzed from multilocus sequences showed no variation and that these Chinese C. neoformans isolates belong to a cluster that has phylogenetically diverged from the VNI reference strain. Our finding that most cryptococcosis patients in China had no apparent risk factor is in stark contrast with reports from other countries. C1 [Varma, Ashok; Wollenberg, Kurt K.; Kwon-Chung, Kyung J.] NIAID, Lab Clin Infect Dis, Mol Microbiol Sect, NIH, Bethesda, MD 20892 USA. [Diaz, Mara R.] Univ Miami, Miami, FL 33152 USA. [Litvintseva, Anastasia P.] Duke Univ, Ctr Med, Durham, NC USA. [Chen, Jianghan] Shanghai Changzheng Hosp, Shanghai, Peoples R China. RP Kwon-Chung, KJ (reprint author), NIAID, Lab Clin Infect Dis, Mol Microbiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI25783, AI44975, P01 AI044975, R01 AI025783] NR 38 TC 98 Z9 114 U1 0 U2 8 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAY PY 2008 VL 14 IS 5 BP 755 EP 762 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 295XS UT WOS:000255508300009 PM 18439357 ER PT J AU Festuccia, WT Oztezcan, S Laplante, M Berthiaume, M Michel, C Dohgu, S Denis, RG Brito, MN Brito, NA Miller, DS Banks, WA Bartness, TJ Richard, D Deshaies, Y AF Festuccia, William T. Oztezcan, Serdar Laplante, Mathieu Berthiaume, Magalie Michel, Chantal Dohgu, Shinya Denis, Raphael G. Brito, Marcia N. Brito, Nilton A. Miller, David S. Banks, William A. Bartness, Timothy J. Richard, Denis Deshaies, Yves TI Peroxisome proliferator-activated receptor-gamma-mediated positive energy balance in the rat is associated with reduced sympathetic drive to adipose tissues and thyroid status SO ENDOCRINOLOGY LA English DT Article ID BLOOD-BRAIN-BARRIER; PPAR-GAMMA; NOREPINEPHRINE TURNOVER; IODOTHYRONINE DEIODINASE; ADAPTIVE THERMOGENESIS; INSULIN SENSITIVITY; AGONISM INCREASES; SYRIAN-HAMSTERS; NEUROPEPTIDE-Y; ZUCKER RATS AB Peroxisome proliferator-activated receptor-gamma (PPAR gamma) activation up-regulates thermogenesis-related genes in rodent white and brown adipose tissues (WAT and BAT) without increasing whole-body energy expenditure. We tested here whether such dissociation is the result of a negative modulation of sympathetic activity to WAT and BAT and thyroid axis components by PPAR gamma activation. Administration of the PPAR gamma agonist rosiglitazone (15 mg/kg center dot d) for 7 d to male Sprague Dawley rats increased food intake (10%), feed efficiency (31%), weight gain (45%), spontaneous motor activity (60%), and BAT and WAT mass and reduced whole-body oxygen consumption. Consistent with an anabolic setting, rosiglitazone markedly reduced sympathetic activity to BAT and WAT(> 50%) and thyroid status as evidenced by reduced levels of plasma thyroid hormones (T-4 and T-3) and mRNA levels of BAT and liver T-3-generating enzymes iodothyronine type 2 (-40%) and type 1 (-32%) deiodinases, respectively. Rosiglitazone also decreased mRNA levels of the thyroid hormone receptor (THR) isoforms alpha 1 (-34%) and beta (-66%) in BAT and isoforms alpha 1 (-20%) and alpha 2 (-47%) in retroperitoneal WAT. These metabolic effects were associated with a reduction in mRNAlevels of the pro-energy expenditure peptides CRH and CART in specific hypothalamic nuclei. A direct central action of rosiglitazone is, however, unlikely based on its low brain uptake and lack of metabolic effects of intracerebroventricular administration. In conclusion, a reduction in BAT sympathetic activity and thyroid status appears to, at least partly, explain the PPAR gamma-induced reduction in energy expenditure and the fact that up-regulation of thermogenic gene expression does not translate into functional stimulation of whole-body thermogenesis in vivo. C1 [Festuccia, William T.; Laplante, Mathieu; Berthiaume, Magalie; Michel, Chantal; Denis, Raphael G.; Richard, Denis; Deshaies, Yves] Univ Laval, Laval Hosp, Res Ctr, Fac Med,Laval Hosp DYouville, Ste Foy, PQ G1V 4G5, Canada. [Oztezcan, Serdar] Istanbul Univ, Istanbul Fac Med, Dept Biochem, TR-34452 Istanbul, Turkey. [Oztezcan, Serdar; Dohgu, Shinya; Banks, William A.] Vet Affairs Med Ctr, Educ & Clin Ctr, St Louis, MO 63106 USA. [Banks, William A.] St Louis Univ, Sch Med, Div Geriatr, Dept Internal Med, St Louis, MO 63104 USA. [Miller, David S.] NIEHS, Lab Pharmacol & Chem, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [Brito, Marcia N.; Brito, Nilton A.; Bartness, Timothy J.] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. RP Deshaies, Y (reprint author), Univ Laval, Laval Hosp, Res Ctr, Fac Med,Laval Hosp DYouville, Y3110,2725 Chemin, Ste Foy, PQ G1V 4G5, Canada. EM yves.deshaies@phs.ulaval.ca RI Festuccia, William/I-5138-2012; Deshaies, Yves/E-9858-2013; Brito, Nilton/F-1731-2015; Festuccia, William/C-7618-2012 OI Festuccia, William/0000-0003-4769-0806; Deshaies, Yves/0000-0002-6242-4592; Festuccia, William/0000-0003-4769-0806 NR 54 TC 73 Z9 75 U1 0 U2 4 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2008 VL 149 IS 5 BP 2121 EP 2130 DI 10.1210/en.2007-1553 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 291LX UT WOS:000255200000011 PM 18218698 ER PT J AU Yao, M Schulkin, J Denver, RJ AF Yao, Meng Schulkin, Jay Denver, Robert J. TI Evolutionarily conserved glucocorticoid regulation of corticotropin-releasing factor expression SO ENDOCRINOLOGY LA English DT Article ID HORMONE GENE-EXPRESSION; CENTRAL-NERVOUS-SYSTEM; PITUITARY CELL-LINE; CRH MESSENGER-RNA; PARAVENTRICULAR NUCLEUS; XENOPUS-LAEVIS; RESPONSE ELEMENT; PHARMACOLOGICAL ADRENALECTOMY; RECEPTOR IMMUNOREACTIVITY; SUPRAOPTIC NUCLEI AB Glucocorticoids (GCs) exert feedback regulation on corticotropin-releasing factor (CRF) neurons in mammals. The nature of GC actions is cell-type specific, being either inhibitory (e. g. paraventricular nucleus) or stimulatory (e. g. amygdala and bed nucleus of the stria terminalis). Nothing is known about differential regulation of CRF gene expression by GCs in nonmammalian vertebrates. We studied the actions of GCs on CRF expression in discrete brain regions of the frog Xenopus laevis. Treatment with corticosterone (CORT) decreased, whereas the corticosteroid synthesis inhibitor metyrapone increased CRF expression in the anterior preoptic area (homolog of the mammalian paraventricular nucleus), as measured by CRF primary transcript, mRNA, and CRF immunoreactivity (ir) (by immunocytochemistry). By contrast to the preoptic area, CORT increased CRF-ir in the medial amygdala and bed nucleus of the stria terminalis, whereas metyrapone decreased CRF-ir in the medial amygdala. CRF-ir and glucocorticoid receptor-ir were colocalized in cells in the frog brain. In transient transfection assays in PC-12 cells, GCs decreased forskolin-induced activation of the frog CRF promoters. Treatment with CORT also reduced CRF promoter activity in transfected tadpole brain in vivo. Frog glucocorticoid receptor bound with high-affinity in vitro to regions in the proximal promoters of frog CRF genes that are homologous with the human CRF gene. Our findings suggest that the neural cell-type specificity and molecular mechanisms of GC-dependent regulation of CRF are phylogenetically ancient, and that the limbic pathways mediating behavioral and physiological responses to stressors were likely present in the earliest land-dwelling vertebrates. C1 [Yao, Meng; Denver, Robert J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Denver, Robert J.] Univ Michigan, Dept Ecol & Evolut Biol, Ann Arbor, MI 48109 USA. [Schulkin, Jay] George Washington Univ, Dept Physiol, Washington, DC 20052 USA. [Schulkin, Jay] George Washington Univ, Dept Biophys, Washington, DC 20052 USA. [Schulkin, Jay] George Washington Univ, Dept Neurosci, Washington, DC 20052 USA. [Schulkin, Jay] NIMH, Mol Neuroimaging Sect, Bethesda, MD 20814 USA. RP Denver, RJ (reprint author), Univ Michigan, Dept Mol Cellular & Dev Biol, 830 N Univ Ave, Ann Arbor, MI 48109 USA. EM rdenver@umich.edu RI Yao, Meng/G-7219-2011; OI Yao, Meng/0000-0002-8906-1461 NR 75 TC 20 Z9 21 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2008 VL 149 IS 5 BP 2352 EP 2360 DI 10.1210/en.2007-1551 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 291LX UT WOS:000255200000035 PM 18202128 ER PT J AU Xie, T Chen, M Gavrilova, O Lai, EW Liu, J Weinstein, LS AF Xie, Tao Chen, Min Gavrilova, Oksana Lai, Edwin W. Liu, Jie Weinstein, Lee S. TI Severe obesity and insulin resistance due to deletion of the maternal G(s)alpha allele is reversed by paternal deletion of the G(s)alpha imprint control region SO ENDOCRINOLOGY LA English DT Article ID PROTEIN-ALPHA-SUBUNIT; ADIPOSE-TISSUE; PSEUDOHYPOPARATHYROIDISM TYPE-1A; KNOCKOUT MICE; GNAS GENE; METABOLISM; IDENTIFICATION; SENSITIVITY; GLUCOSE; ENERGY AB The G protein alpha-subunit G(s)alpha mediates receptor-stimulated cAMP production and is imprinted with reduced expression from the paternal allele in specific tissues. Disruption of the G(s)alpha maternal (but not paternal) allele leads to severe obesity, hypertriglyceridemia, and insulin resistance in mice and obesity in patients with Albright hereditary osteodystrophy. Paternal deletion of a G(s)alpha imprint control region (1A) leads to loss of tissue-specific G(s)alpha imprinting. To determine whether the metabolic abnormalities resulting from disruption of the G(s)alpha maternal allele could be reversed by loss of paternal G(s)alpha imprinting, females with a heterozygous G(s)alpha exon 1 deletion were mated to males with heterozygous deletion of the imprint control region (1A) to generate mice with maternal G(s)alpha deletion (E1(m-)), paternal 1A deletion (1A(p-)), double mutants (E1(m-): 1A(p-)), and wild type. E1(m-) mice developed obesity, glucose intolerance, insulin resistance, and hypertriglyceridemia, which were all normalized by the paternal 1A deletion in E1(m-): 1A(p-) mice. Obesity in E1(m-) was associated with reduced energy expenditure and sympathetic nerve activity, and these were also normalized in E1(m-): 1A(p-) mice. 1A(p-) mice had reduced body weight associated with proportional decreases in fat and lean mass as well as increased activity levels. The metabolic phenotype resulting from maternal G(s)alpha deletion is rescued by a genetic lesion that leads to loss of tissue-specific G(s)alpha imprinting, consistent with this phenotype being a direct consequence of G(s)alpha imprinting in one or more specific tissues. C1 [Xie, Tao; Chen, Min; Liu, Jie; Weinstein, Lee S.] NIH, Metab Dis Branch, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. [Gavrilova, Oksana] NIH, Mouse Metab Core Lab, Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA. [Lai, Edwin W.] NIH, Reproduct & Adult Endocrinol Program, NICHHD, Bethesda, MD 20892 USA. RP Weinstein, LS (reprint author), NIH, Metab Dis Branch, Natl Inst Diabet & Digest & Kidney Dis, Bldg 10,Room 8C101, Bethesda, MD 20892 USA. EM leew@amb.niddk.nih.gov FU Intramural NIH HHS NR 34 TC 29 Z9 29 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2008 VL 149 IS 5 BP 2443 EP 2450 DI 10.1210/en.2007-1458 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 291LX UT WOS:000255200000044 PM 18202131 ER PT J AU Lee, S Lynn, EG Kim, JA Quon, MJ AF Lee, Sihoon Lynn, Edward G. Kim, Jeong-A Quon, Michael J. TI Protein kinase C-zeta phosphorylates insulin receptor substrate-1, -3, and -4 but not -2: Isoform specific determinants of specificity in insulin signaling SO ENDOCRINOLOGY LA English DT Article ID RAT ADIPOSE-CELLS; MULTIPLE SERINE KINASES; PHOSPHATIDYLINOSITOL 3-KINASE; GLUCOSE-HOMEOSTASIS; SH2 DOMAINS; TYROSINE PHOSPHORYLATION; STIMULATE TRANSLOCATION; FULL ACTIVATION; IRS PROTEINS; PKC-ZETA AB Protein kinase C-zeta, a downstream effector of phosphatidylinositol 3-kinase (PI3K), phosphorylates insulin receptor substrate (IRS)-1 on serine residues impairing activation of PI3K in response to insulin. Because IRS-1 is upstream from PI3K, this represents a negative feedback mechanism that may contribute to signal specificity in insulin action. To determine whether similar feedback pathways exist for other IRS isoforms, we evaluated IRS-2, -3, and -4 as substrates for PKC-zeta. In an in vitro kinase assay, purified recombinant PKC-zeta phosphorylated IRS-1, -3 and -4 but not IRS-2. Similar results were obtained with an immune-complex kinase assay demonstrating that wild-type, but not kinase-deficient mutant PKC-zeta, phosphorylated IRS-1, -3, and -4 but not IRS-2. We evaluated functional consequences of serine phosphorylation of IRS isoforms by PKC-zeta in NIH-3T3(IR) cells cotransfected with epitope-tagged IRS proteins and either PKC-zeta or empty vector control. Insulin-stimulated IRS tyrosine phosphorylation was impaired by overepxression of PKC-zeta for IRS-1, -3, and -4 but not IRS-2. Significant insulin-stimulated increases in PI3K activity was coimmunoprecipitated with all IRS isoforms. In cells overexpressing PKC-zeta there was marked inhibition of insulin-stimulated PI3K activity associated with IRS-1, -3 and -4 but not IRS-2. That is, PI3K activity associated with IRS-2 in response to insulin was similar in control cells and cells overexpressing PKC-zeta. We conclude that IRS-3 and -4 are novel substrates for PKC-zeta that may participate in a negative feedback pathway for insulin signaling similar to IRS-1. The inability of PKC-zeta to phosphorylate IRS-2 may help determine specific functional roles for IRS-2. C1 [Lee, Sihoon; Lynn, Edward G.; Kim, Jeong-A; Quon, Michael J.] NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, 9 Mem Dr,Bldg 9,Room 1N-105 MSC 0920, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Lynn, Edward/0000-0002-8011-5558 FU Intramural NIH HHS NR 47 TC 21 Z9 21 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2008 VL 149 IS 5 BP 2451 EP 2458 DI 10.1210/en.2007-1595 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 291LX UT WOS:000255200000045 PM 18202124 ER PT J AU Engel-Cox, JA Van Houten, B Phelps, J Rose, SW AF Engel-Cox, Jill A. Van Houten, Bennett Phelps, Jerry Rose, Shyanika W. TI Conceptual model of comprehensive research metrics for improved human health and environment SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE conceptual model development; environmental health research; metrics development; performance measurement; research impact evaluation ID PARTICULATE AIR-POLLUTION; EPIDEMIOLOGIC EVIDENCE; MORTALITY; CHILDREN AB OBJECTIVE: Federal, state, and private research agencies and organizations have faced increasing administrative and public demand for performance measurement. Historically, performance measurement predominantly consisted of near-term outputs measured through bibliometrics. The recent focus is on accountability for investment based on long-term outcomes. Developing measurable outcome-based metrics for research programs has been particularly challenging, because of difficulty linking research results to spatially and temporally distant outcomes. Our objective in this review is to build a logic model and associated metrics through which to measure the contribution of environmental health research programs to improvements in human health, the environment, and the economy. DATA SOURCES: We used expert input and literature research on research impact assessment. DATA EXTRACTION: With these sources, we developed a logic model that defines the components and linkages between extramural environmental health research grant programs and the outputs and outcomes related to health and social welfare, environmental quality and sustainability, economics, and quality of life. DATA SYNTHESIS: The logic model focuses on the environmental health research portfolio of the National Institute of Environmental Health Sciences (NIEHS) Division of Extramural Research and Training. The model delineates pathways for contributions by five types of institutional partners in the research process: NIEHS, other government (federal, state, and local) agencies, grantee institutions, business and industry, and community partners. CONCLUSIONS: The model is being applied to specific NIEHS research applications and the broader research community. We briefly discuss two examples and discuss the strengths and limits of outcome-based evaluation of research programs. C1 [Van Houten, Bennett; Phelps, Jerry] Natl Inst Environm Hlth Sci, NIH, Dept Hlth & Human Serv, Div Extramural Res & Training, Res Triangle Pk, NC USA. [Engel-Cox, Jill A.] Battelle Mem Inst, Arlington, VA 22201 USA. [Rose, Shyanika W.] Battelle Mem Inst, Durham, NC USA. RP Engel-Cox, JA (reprint author), Battelle Mem Inst, 2101 Wilson Blvd,Suite 800, Arlington, VA 22201 USA. EM engelcoxj@battelle.org NR 38 TC 12 Z9 12 U1 1 U2 15 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2008 VL 116 IS 5 BP 583 EP 592 DI 10.1289/ehp.10925 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 296JF UT WOS:000255538600022 PM 18470312 ER PT J AU Gao, X Hu, X Qian, L Yang, S Zhang, W Zhang, D Wu, X Fraser, A Wilson, B Flood, PM Block, M Hong, JS AF Gao, Xi Hu, Xiaoming Qian, Li Yang, Sufen Zhang, Wei Zhang, Dan Wu, Xuefei Fraser, Alison Wilson, Belinda Flood, Patrick M. Block, Michelle Hong, Jau-Shyong TI Formyl-methionyl-leucyl-phenylaianine-induced dopaminergic neurotoxicity via microglial activation: A mediator between peripheral infection and neurodegeneration? SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE fMLP; inflammation; microglia; NADPH oxidase; neurotoxicity ID NECROSIS-FACTOR-ALPHA; PARKINSONS-DISEASE; NADPH-OXIDASE; OXIDATIVE STRESS; INFLAMMATORY DAMAGE; ALZHEIMERS-DISEASE; PEPTIDE RECEPTOR-2; HUMAN-NEUTROPHILS; NEURONS; FMLP AB BACKGROUND: Parkinson disease (PD), a chronic neurodegenerative disease, has been proposed to be a multifactorial disorder resulting from a combination of environmental mechanisms (chemical, infectious, and traumatic), aging, and genetic deficits. Microglial activation is important in the pathogenesis of PD. OBJECTIVES: We investigated dopaminergic (DA) neurotoxicity and the underlying mechanisms of formyl-methionyl-leucyl-phenylaianine (fMLP), a bacteria-derived peptide, in relation to PD. METHODS: We measured DA neurotoxicity using a DA uptake assay and immunocytochemical staining (ICC) in primary mesencephalic cultures from rodents. Microglial activation was observed via ICC, flow cytometry, and superoxide measurement. RESULTS: fMLP can cause selective DA neuronal loss at concentrations as low as 10(-13) M. Further, fMLP (10(-13) M) led to a significant reduction in DA uptake capacity in neuron/glia (N/G) cultures, but not in microglia-depleted cultures, indicating an indispensable role of microglia in fMLP-induced neurotoxicity. Using ICC of a specific microoial marker, OX42, we observed morphologic changes in activated microglia after fMLP treatment. Microglial activation after fMLP treatment was confirmed by flow cytometry analysis of major histocompatibility antigen class 11 expression on a microglia HAPI cell line. Mechanistic studies revealed that fMLP (10(-13) M)-induced increase in the production of extracellular superoxide from microglia is critical in mediating fMLP-elicited neurotoxicity. Pharmacologic inhibition of NADPH oxidase (PHOX) with diphenylene-iodonium or apocynin abolished the DA neurotoxicity of fMLP. N/G cultures from PHOX-deficient (gp91(PHOX-/-)) mice were also insensitive to fMLP-induced DA neurotoxicity. CONCLUSION: fMLP (10(-13) M) induces DA neurotoxicity through activation of microglial PHOX and subsequent production of superoxide, suggesting a role of fMLP in the central nervous system inflammatory process. C1 [Gao, Xi; Hu, Xiaoming; Yang, Sufen; Zhang, Wei; Zhang, Dan; Wu, Xuefei; Fraser, Alison; Wilson, Belinda; Block, Michelle] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Neuropharmacol Sect, Lab Pharmacol & Chem,Dept Hlth & Human Serv, Res Triangle Pk, NC USA. [Qian, Li; Flood, Patrick M.] Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC USA. RP Hong, JS (reprint author), Natl Inst Environm Hlth Sci, Natl Inst Hlth, Neuropharmacol Sect, Lab Pharmacol & Chem,Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC USA. EM hong3@nichs.nih.gov FU Intramural NIH HHS NR 44 TC 21 Z9 21 U1 2 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2008 VL 116 IS 5 BP 593 EP 598 DI 10.1289/ehp.11031 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 296JF UT WOS:000255538600023 PM 18470306 ER PT J AU MacLehose, RF Savitz, DA Herring, AH Hartmann, KE Singer, PC Weinberg, HS AF MacLehose, Richard F. Savitz, David A. Herring, Amy H. Hartmann, Katherine E. Singer, Philip C. Weinberg, Howard S. TI Drinking water disinfection by-products and time to pregnancy SO EPIDEMIOLOGY LA English DT Article ID SPONTANEOUS-ABORTION; TRIHALOMETHANE LEVELS; CHLOROFORM; EXPOSURE; BROMODICHLOROMETHANE; CANCER; CALIFORNIA; TOXICITY; RATS; TAP AB Background: Laboratory evidence suggests tap water disinfection by-products (DBPs) could have an effect very early in pregnancy, typically before clinical detectability. Undetected early losses would be expected to increase the reported number of cycles to clinical pregnancy. Methods: We investigated the association between specific DBPs (trihalomethanes, haloacetic acids, brominated-trihalomethanes, brominated-haloacetic acids, total organic halides, and bromodichloromethane) and time to pregnancy among women who enrolled in a study of drinking water and reproductive outcomes. We quantified exposure to DBPs through concentrations in tap water, quantity ingested through drinking, quantity inhaled or absorbed while showering or bathing, and total integrated exposure. The effect of DBPs on time to pregnancy was estimated using a discrete time hazard model. Results: Overall, we found no evidence of an increased time to pregnancy among women who were exposed to higher levels of DBPs. A modestly decreased time to pregnancy (ie, increased fecundability) was seen among those exposed to the highest level of ingested DBPs, but not for tap water concentration, the amount absorbed while showering or bathing, or the integrated exposure. Conclusions: Our findings extend those of a recently published study suggesting a lack of association between DBPs and pregnancy loss. C1 [MacLehose, Richard F.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Savitz, David A.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Herring, Amy H.] Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. [Hartmann, Katherine E.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Singer, Philip C.; Weinberg, Howard S.] Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. RP MacLehose, RF (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. EM maclehoser@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [P30ES10126] NR 33 TC 10 Z9 12 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2008 VL 19 IS 3 BP 451 EP 458 DI 10.1097/EDE.0b013e3l8l6a23eb PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 293DF UT WOS:000255314400017 PM 18379423 ER PT J AU Ram, PK Crump, JA Gupta, SK Miller, MA Mintz, ED AF Ram, P. K. Crump, J. A. Gupta, S. K. Miller, M. A. Mintz, E. D. TI Part II. Analysis of data gaps pertaining to Shigella infections in low and medium human development index countries, 1984-2005 SO EPIDEMIOLOGY AND INFECTION LA English DT Review ID TOXIGENIC ESCHERICHIA-COLI; HEMOLYTIC-UREMIC SYNDROME; HOUSEFLIES MUSCA-DOMESTICA; SHIGA-BACILLUS DYSENTERY; ACUTE DIARRHEAL DISEASE; YOUNG-CHILDREN; RISK-FACTORS; ANTIMICROBIAL RESISTANCE; PERSISTENT DIARRHEA; CHILDHOOD DIARRHEA AB The global incidence of Shigella infection has been estimated at 80-165 million episodes annually, with 99% of episodes Occurring in the developing world. To identify contemporary gaps in the understanding of the global epidemiology of shigellosis, we conducted a review of the English-language scientific literature from 1984 to 2005, restricting the search to low and medium human development countries. Out-review yielded I I population-based Studies of Shigella burden from seven countries. No population-based studies have been conducted in sub-Saharan Africa or in low human development Countries. In studies done in all age groups, Shigella incidence varied from 0 center dot 6 to 107 episodes/1000 person-years. S.flexneri was the most commonly detected subgroup in the majority of studies. Case-fatality rates ranged from 0% to 2 center dot 6% in population-based studies and from 0% to 21% in facility-based Studies. This review highlights the large gaps in data on the burden of Shigella infections for low human development index countries and, more specifically, for sub-Saharan Africa. C1 [Ram, P. K.] SUNY Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14214 USA. [Ram, P. K.; Crump, J. A.; Gupta, S. K.; Mintz, E. D.] Ctr Dis Control & Prevent, Enter Dis Epidemiol Branch, Natl Ctr Zoonot Vectorborne & Enter Dis, Atlanta, GA USA. [Miller, M. A.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Ram, PK (reprint author), SUNY Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Rm 273 Faber Hall,3435 Main St, Buffalo, NY 14214 USA. EM pkram@buffalo.edu FU U.S. National Institutes of Health Fogarty International Center; Bill and Melinda Gates Foundation [32143] FX This work was supported in part by the U.S. National Institutes of Health Fogarty International Center and by grant number 32143 from the Bill and Melinda Gates Foundation 'Assessment of diarrhea disease burden and public health programs to control diarrhea in Asian subcontinent and Africa'. NR 180 TC 33 Z9 34 U1 1 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD MAY PY 2008 VL 136 IS 5 BP 577 EP 603 DI 10.1017/S0950268807009351 PG 27 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 348GG UT WOS:000259198400001 PM 17686195 ER PT J AU Foglia, G Sateren, WB Renzullo, PO Bautista, CT Langat, L Wasunna, MK Singer, DE Scott, PT Robb, ML Birx, DL AF Foglia, G. Sateren, W. B. Renzullo, P. O. Bautista, C. T. Langat, L. Wasunna, M. K. Singer, D. E. Scott, P. T. Robb, M. L. Birx, D. L. TI High prevalence of HIV infection among rural tea plantation residents in Kericho, Kenya SO EPIDEMIOLOGY AND INFECTION LA English DT Article ID SUB-SAHARAN AFRICA; MALE CIRCUMCISION; VACCINE TRIALS; RISK; MEN; ACCEPTABILITY; FEASIBILITY AB Human immunodeficiency virus type 1 (HIV-1) epidemiology among residents of a rural agricultural plantation in Kericho, Kenya was studied. HIV-1 prevalence was 14 center dot 3%, and was higher among, women (19 center dot 1%) than men (11 center dot 3%). Risk factors associated with HIV-1 for men were age (>= 25 years), marital history (one or more marriages), age difference from current spouse (>= 5 years), Luo ethnicity, sexually transmitted infection (STI) symptomis In the past 6 months. circumcision (protective). and sexual activity (>= 7 years). Among women. risk factors associated with HIV-1 were age (25-29 years. >= 35 years), marital history (one or more marriages), age difference from current spouse (>= 10 years). Luo ethnicity, STI symptoms in the past 6 months, and a STI history in the past 5 years. Most participants (96%) expressed a willingness to participate in a future HIV vaccine study. These findings will facilitate targeted intervention and prevention measures for HIV-1 infection in Kericho. C1 [Sateren, W. B.; Singer, D. E.; Scott, P. T.; Birx, D. L.] Walter Reed Army Med Ctr, Div Retrovirol, Rockville, MD 20850 USA. [Foglia, G.; Langat, L.] USA, Med Res Unit, Nairobi, Kenya. [Renzullo, P. O.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Bautista, C. T.; Robb, M. L.] Henry M Jackson Fdn Advancement Mil Med Inc, US Mil HIV Res Program, Rockville, MD USA. [Wasunna, M. K.] Kenya Govt Med Res Ctr, Nairobi, Kenya. RP Sateren, WB (reprint author), Walter Reed Army Med Ctr, Div Retrovirol, 1 Taft Court,Suite 250, Rockville, MD 20850 USA. EM WSateren@hivresearch.org RI Bautista, Christian/B-2812-2011 FU Walter Reed Army Institute of Research; Kenya Medical Research Institute, Nairobi, Kenya FX This study was supported and approved by the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research (WRAIR protocol #855, RV142), and by the Kenya Medical Research Institute, Nairobi, Kenya. The material has been reviewed by the Walter Reed Army Institute of Research and there is no objection to its presentation and/or publication. The authors Would like to thank the management and employees of James K. Finlay LLC (formerly African Highlands Produce) for their invaluable assistance and cooperation during the conduct of this research among plantation emloyees and their dependants. We thank Dr Nelson L. Michael at the Walter Reed Army Institute of Research For manuscript review. NR 24 TC 12 Z9 12 U1 1 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD MAY PY 2008 VL 136 IS 5 BP 694 EP 702 DI 10.1017/S0950268807009028 PG 9 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 348GG UT WOS:000259198400013 PM 17599780 ER PT J AU Fan, T Schmidtmann, A Xi, S Briones, V Zhu, HM Suh, HC Gooya, J Keller, JR Xu, H Roayaei, J Anver, M Ruscetti, S Muegge, K AF Fan, Tao Schmidtmann, Anja Xi, Sichuan Briones, Victorino Zhu, Heming Suh, Hyung Chan Gooya, John Keller, Jonathan R. Xu, Hong Roayaei, Jean Anver, Miriam Ruscetti, Sandra Muegge, Kathrin TI DNA hypomethylation caused by Lsh deletion promotes erythroleukemia development SO EPIGENETICS LA English DT Article DE DNA methylation; chromatin; Lsh; SNF2; leukemia; hematopoiesis ID INTESTINAL NEOPLASIA; METHYLATION PATTERNS; FAMILY-MEMBER; SNF2 FAMILY; MICE; GENE; SUPPRESSION; ELEMENTS; CANCER; INDUCTION AB Hematopoietic malignancies are frequently associated with DNA hypomethylation but the molecular mechanisms involved in tumor formation remain poorly understood. Here we report that mice lacking Lsh develop leukemia associated with DNA hypomethylation and oncogene activation. Lsh is a member of the SNF2 chromatin remodeling family and is required for de novo methylation of genomic DNA. Mice that received Lsh deficient hematopoietic progenitors showed severe impairment of hematopoiesis, suggesting that Lsh is necessary for normal hematopoiesis. A subset of mice developed erythroleukemia, a tumor that does not spontaneously occur in mice. Tumor tissues were CpG hypomethylated and showed a modest elevation of the transcription factor PU.1, an oncogene that is crucial for Friend virus induced erythroleukemia. Analysis of Lsh(-/-) hematopoietic progenitors revealed widespread DNA hypomethylation at repetitive sequences and hypomethylation at specific retroviral elements within the PU.1 gene. Wild type cells showed Lsh and Dnmt3b binding at the retroviral elements located within the PU.1 gene. On the other hand, Lsh deficient cells had no detectable Dnmt3b association suggesting that Lsh is necessary for recruitment of Dnmt3b to its target. Furthermore, Lsh-/- hematopoietic precursors showed impaired suppression of retroviral elements in the PU.1 gene, an increase of PU.1 transcripts and protein levels. Thus DNA hypomethylation caused by Lsh depletion is linked to transcriptional upregulation of retroviral elements and oncogenes such as PU.1 which in turn may promote the development of erythroleukemia in mice. C1 [Fan, Tao; Schmidtmann, Anja; Xi, Sichuan; Briones, Victorino; Zhu, Heming; Suh, Hyung Chan; Gooya, John; Keller, Jonathan R.; Xu, Hong; Ruscetti, Sandra; Muegge, Kathrin] NCI, Lab Canc Prevent, SAIC FCRDC, Basic Res Program, Frederick, MD 21701 USA. [Roayaei, Jean] NCI, Comp & Stat Serv, Frederick, MD 21701 USA. [Anver, Miriam] NCI, Pathol Histotechnol Lab, SAIC Frederick, Frederick, MD 21701 USA. RP Muegge, K (reprint author), NCI, Lab Canc Prevent, SAIC FCRDC, Basic Res Program, BLDG 469,Rm 243, Frederick, MD 21701 USA. EM muegge@ncifcrf.gov FU Intramural NIH HHS [Z01 BC010014-12]; PHS HHS [N01-C0-12400] NR 47 TC 19 Z9 22 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1559-2294 J9 EPIGENETICS-US JI Epigenetics PD MAY-JUN PY 2008 VL 3 IS 3 BP 134 EP 142 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319RG UT WOS:000257180900005 PM 18487951 ER PT J AU Punkkinen, O Naji, A Podgornik, R Vattulainen, I Hansen, PL AF Punkkinen, O. Naji, A. Podgornik, R. Vattulainen, I. Hansen, P. -L. TI Ionic cloud distribution close to a charged surface in the presence of salt SO EPL LA English DT Article ID POISSON-BOLTZMANN; FIELD-THEORY; SOFT MATTER; COUNTERIONS; ELECTROLYTES; FORCES AB Despite its importance, the understanding of ionic cloud distribution close to a charged macroion under physiological salt conditions has remained very limited especially for strongly coupled systems with, for instance, multivalent counterions. Here we present a formalism that predicts both counterion and coion distributions in the vicinity of a charged macroion for an arbitrary amount of added salt and in both limits of mean field and strong coupling. The distribution functions are calculated explicitly for ions next to an infinite planar charged wall. We present a schematic phase diagram identifying different physical regimes in terms of electrostatic coupling parameter and bulk salt concentration. Copyright (c) EPLA, 2008. C1 [Punkkinen, O.; Vattulainen, I.] Aalto Univ, Phys Lab, FI-02015 Espoo, Finland. [Punkkinen, O.; Vattulainen, I.] Aalto Univ, Helsinki Inst Phys, FI-02015 Espoo, Finland. [Punkkinen, O.; Vattulainen, I.; Hansen, P. -L.] Univ So Denmark, Dept Chem & Phys, Memphys Ctr Biomembrane Phys, DK-5230 Odense M, Denmark. [Naji, A.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Naji, A.] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Podgornik, R.; Hansen, P. -L.] NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. [Podgornik, R.] Univ Ljubljana, Fac Math & Phys, Dept Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. [Vattulainen, I.] Tampere Univ Technol, Inst Phys, FI-33101 Tampere, Finland. RP Punkkinen, O (reprint author), Aalto Univ, Phys Lab, POB 1100, FI-02015 Espoo, Finland. EM olli.punkkinen@tkk.fi RI Naji, Ali/F-6352-2010; Podgornik, Rudolf/C-6209-2008; Vattulainen, Ilpo/G-4224-2014; OI Naji, Ali/0000-0003-3436-1499; Podgornik, Rudolf/0000-0002-3855-4637; Vattulainen, Ilpo/0000-0001-7408-3214 NR 28 TC 18 Z9 18 U1 0 U2 3 PU EPL ASSOCIATION, EUROPEAN PHYSICAL SOCIETY PI MULHOUSE PA 6 RUE DES FRERES LUMIERE, MULHOUSE, 68200, FRANCE SN 0295-5075 J9 EPL-EUROPHYS LETT JI EPL PD MAY PY 2008 VL 82 IS 4 AR 48001 DI 10.1209/0295-5075/82/48001 PG 6 WC Physics, Multidisciplinary SC Physics GA 307EN UT WOS:000256300900029 ER PT J AU Haldar, D Kamakaka, RT AF Haldar, Devyani Kamakaka, Rohinton T. TI Schizosaccharomyces pombe Hst4 functions in DNA damage response by regulating histone H3K56 acetylation SO EUKARYOTIC CELL LA English DT Article ID H3 LYSINE-56 ACETYLATION; STRAND BREAK REPAIR; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; GENOME INTEGRITY; CELL-CYCLE; CRYSTAL-STRUCTURE; BINDING-PROTEIN; EXCISION-REPAIR; SIR2 HOMOLOG AB The packaging of eukaryotic DNA into chromatin is likely to be crucial for the maintenance of genomic integrity. Histone acetylation and deacetylation, which alter chromatin accessibility, have been implicated in DNA damage tolerance. Here we show that Schizosaccharomyces pombe Hst4, a homolog of histone deacetylase Sir2, participates in S-phase-specific DNA damage tolerance. Hst4 was essential for the survival of cells exposed to the genotoxic agent methyl methanesulfonate (MMS) as well as for cells lacking components of the DNA damage checkpoint pathway. It was required for the deacetylation of histone H3 core domain residue lysine 56, since a strain with a point mutation of its catalytic domain was unable to deacetylate this residue in vivo. Hst4 regulated the acetylation of H3 K56 and was itself cell cycle regulated. We also show that MMS treatment resulted in increased acetylation of histone H3 lysine 56 in wild-type cells and hst4 Delta mutants had constitutively elevated levels of histone H3 K56 acetylation. Interestingly, the level of expression of Hst4 decreased upon MMS treatment, suggesting that the cell regulates access to the site of DNA damage by changing the level of this protein. Furthermore, we find that the phenotypes of both K56Q and K56R mutants of histone H3 were similar to those of hst4 Delta mutants, suggesting that proper regulation of histone acetylation is important for DNA integrity. We propose that Hst4 is a deacetylase involved in the restoration of chromatin structure following the S phase of cell cycle and DNA damage response. C1 [Haldar, Devyani] Univ Hyderabad, Div Discovery Res, Inst Life Sci, Hyderabad 500046, Andhra Pradesh, India. [Haldar, Devyani; Kamakaka, Rohinton T.] NICHD, Unit Chromatin & Transcript, NIH, Bethesda, MD 20892 USA. [Kamakaka, Rohinton T.] Univ Calif Santa Cruz, Dept MCD Biol, Santa Cruz, CA 95064 USA. RP Haldar, D (reprint author), Univ Hyderabad, Div Discovery Res, Inst Life Sci, Hyderabad 500046, Andhra Pradesh, India. EM devyanih@ilsresearch.org FU NIH [GM078068] FX We thank S. Grewal, L. Pillus, H. Levin, J. P. Javerzat, N. Rhind, P. Russell, S. Sazer, T. Wang, K. Hardwick, T. Kouzarides, S. Yasuhira, A. M. Carr, S. Forsburg, M. Bjoras, and A. Klar for various plasmids and strains. We also thank Henry Levin for protocols and technical help. We thank Krishnaveni Mishra for allowing us to use her lab space and resources in HCU in India. We acknowledge help from the NCI FACS facility. We also thank Namrita Dhillon and Sanjeev Galande for helpful comments and suggestions.; This work was supported by a grant from the NIH to R. T. K. (GM078068). NR 57 TC 31 Z9 31 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD MAY PY 2008 VL 7 IS 5 BP 800 EP 813 DI 10.1128/EC.00379-07 PG 14 WC Microbiology; Mycology SC Microbiology; Mycology GA 340SV UT WOS:000258666200006 PM 18344406 ER PT J AU Protchenko, O Shakoury-Elizeh, M Keane, P Storey, J Androphy, R Philpott, CC AF Protchenko, Olga Shakoury-Elizeh, Minoo Keane, Patricia Storey, Joshua Androphy, Rachel Philpott, Caroline C. TI Role of PUG1 in inducible porphyrin and heme transport in Saccharomyces cerevisiae SO EUKARYOTIC CELL LA English DT Article ID CANDIDA-ALBICANS; IRON UPTAKE; STAPHYLOCOCCUS-AUREUS; PLASMA-MEMBRANE; YEAST; IDENTIFICATION; GENE; DELETION; PATHWAYS; BINDING AB Unlike pathogenic fungi, the budding yeast Saccharomyces cerevisiae is not efficient at using heme as a nutritional source of iron. Here we report that for this yeast, heme uptake is induced under conditions of heme starvation. Heme synthesis requires oxygen, and yeast grown anaerobically exhibited an increased uptake of hemin. Similarly, a strain lacking aminolevulinate synthase exhibited a sixfold increase in hemin uptake when grown without 2-aminolevulinic acid. We used microarray analysis of cells grown under reduced oxygen tension or reduced intracellular heme conditions to identify candidate genes involved in heme uptake. Surprisingly, overexpression of PUG1 (protoporphyrin uptake gene 1) resulted in reduced utilization of exogenous heme by a heme-deficient strain and, conversely, increased the utilization of protoporphyrin IX. Pug1p was localized to the plasma membrane by indirect immunofluorescence and subcellular fractionation. Strains overexpressing PUG1 exhibited decreased accumulation of [Fe-55] hemin but increased accumulation of protoporphyrin IX compared to the wild-type strain. To measure the effect of PUG1 overexpression on intracellular heme pools, we used a CYC1-lacZ reporter, which is activated in the presence of heme, and we monitored the activity of a heme-containing metalloreductase, Fre1p, expressed from a constitutive promoter. The data from these experiments were consistent with a role for Pug1p in inducible protoporphyrin IX influx and heme efflux. C1 [Protchenko, Olga; Shakoury-Elizeh, Minoo; Keane, Patricia; Storey, Joshua; Androphy, Rachel; Philpott, Caroline C.] Natl Inst Diabet & Digest & Kidney Dis, Genet & Metab Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Philpott, CC (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Genet & Metab Sect, Liver Dis Branch, NIH, Rm 9B-16,Bldg 10, Bethesda, MD 20892 USA. EM carolinep@intra.niddk.nih.gov FU Intramural NIH HHS NR 47 TC 32 Z9 35 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD MAY PY 2008 VL 7 IS 5 BP 859 EP 871 DI 10.1128/EC.00414-07 PG 13 WC Microbiology; Mycology SC Microbiology; Mycology GA 340SV UT WOS:000258666200011 PM 18326586 ER PT J AU Mahabir, S Ettinger, S Johnson, L Baer, DJ Clevidence, BA Hartman, TJ Taylor, PR AF Mahabir, S. Ettinger, S. Johnson, L. Baer, D. J. Clevidence, B. A. Hartman, T. J. Taylor, P. R. TI Measures of adiposity and body fat distribution in relation to serum folate levels in postmenopausal women in a feeding study SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE adiposity and folate; postmenopausal women; feeding study ID BREAST-CANCER RISK; MODERATE ALCOHOL-CONSUMPTION; FOLIC-ACID; HOMOCYSTEINE LEVELS; CARRIER GENE; MASS INDEX; PLASMA; DEFICIENCY; METABOLISM; CELLS AB Objective: To assess the associations between serum folate concentration and measures of adiposity in postmenopausal women. Design: This study was conducted as a cross-sectional analysis within the control segment of a randomized, crossover trial in which postmenopausal women (n = 51) consumed 0 g (control), 15 g (one drink) and 30 g (two drinks) alcohol (ethanol)/day for 8 weeks as part of a controlled diet. Subjects in one treatment arm were crossed-over to another arm after a 2- to 5-week washout period. Body mass index (BMI) was measured, and dual energy X-ray absorptiometry (DEXA) scan administered to the women during the control (0 g alcohol) treatment, and a blood sample from this group was collected at baseline and week 8 of each diet period and analyzed for folate, B12, homocysteine and methylmalonic acid. Setting: This study was conducted at the Beltsville Human Nutrition Research Center, MD, USA. Results: In multivariate analysis, women who were overweight had a 12% lower, and obese women had a 22% lower serum folate concentrations compared to normal weight women (P-trend 0.02). Vitamin B12 also decreased with increasing BMI (P-trend 0.08). Increased BMI, percent body fat, and absolute amounts of central and peripheral fat were all significantly associated with decreased serum folate, but were unrelated to serum B12, homocysteine or methylmalonic acid. Conclusions: Our data show that adiposity is associated with lower serum folate levels in postmenopausal women. With obesity at epidemic proportions, these data, if confirmed by prospective or randomized controlled studies, have important public health implications. C1 [Mahabir, S.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Ettinger, S.] Columbia Univ, New York Obes Res Ctr, St Lukes Hosp Ctr, New York, NY 10027 USA. [Johnson, L.] NCCAM, NIH, Bethesda, MD USA. [Baer, D. J.; Clevidence, B. A.] ARS, USDA, Beltsville, MD USA. [Hartman, T. J.] Penn State Univ, Dept Nutr, Philadelphia, PA USA. [Taylor, P. R.] NIH, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Mahabir, S (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM smahabir@mdanderson.org FU Intramural NIH HHS [Z01 CP000101-03] NR 50 TC 23 Z9 24 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAY PY 2008 VL 62 IS 5 BP 644 EP 650 DI 10.1038/sj.ejcn.1602771 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 297AL UT WOS:000255587500009 PM 17457338 ER PT J AU Porter, FD AF Porter, Forbes D. TI Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE Smith-Lemli-Opitzsyndrome; DHCR7; cholesterol; 7-dehydrocholesterol; inborn error of cholesterol synthesis ID MOUSE MODEL; SYNDROME SLOS; 7-DEHYDROCHOLESTEROL REDUCTASE; CHOLESTEROL SUPPLEMENTATION; DELTA-7-STEROL REDUCTASE; SIMVASTATIN TREATMENT; SYNDROME FIBROBLASTS; PRENATAL-DIAGNOSIS; MATERNAL URINE; DHCR7 MUTATION AB Smith-Lemli-Opitzsyndrome ( SLOS) is a malformation syndrome due to a deficiency of 7- dehydrocholesterol reductase ( DHCR7). DHCR7 primarily catalyzes the reduction of 7- dehydrocholesterol ( 7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS. C1 NICHHD, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHHD, Sect Mol Dysmorphol, Program Dev Endocrinol & Genet, NIH,DHHS, Bld 10,Rm 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov FU Intramural NIH HHS NR 50 TC 108 Z9 112 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAY PY 2008 VL 16 IS 5 BP 535 EP 541 DI 10.1038/ejhg.2008.10 PG 7 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 292IU UT WOS:000255260500003 PM 18285838 ER PT J AU Mistry, RB Isaac, JTR Crabtree, JW AF Mistry, Rajen B. Isaac, John T. R. Crabtree, John W. TI Two differential frequency-dependent mechanisms regulating tonic firing of thalamic reticular neurons SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE glutamatergic inputs; intrareticular inhibition; synaptic plasticity; thalamic reticular nucleus; Wistar rat ID LATERAL GENICULATE-NUCLEUS; TERM SYNAPTIC PLASTICITY; METABOTROPIC GLUTAMATE RECEPTORS; POSTERIOR MEDIAL THALAMUS; RAT VENTROBASAL THALAMUS; RELAY CELLS; CORTICOTHALAMIC PROJECTIONS; PERIGENICULATE NUCLEUS; INHIBITORY INTERACTIONS; DISTINGUISHING DRIVERS AB Transmission through the thalamus activates circuits involving the GABAergic neurons of the thalamic reticular nucleus (TRN). TRN cells receive excitatory inputs from thalamocortical and corticothalamic cells and send inhibitory projections to thalamocortical cells. The inhibitory output of TRN neurons largely depends on the level of excitatory drive to these cells but may also be partly under the control of mechanisms intrinsic to the TRN. We examined two such possible mechanisms, short-term plasticity at glutamatergic synapses in the TRN and intra-TRN inhibition. In rat brain slices, responses of TRN neurons to brief trains of stimuli applied to glutamatergic inputs were recorded in voltage- or current-clamp mode. In voltage clamp, TRN cells showed no change in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory postsynaptic current amplitudes to stimulation at non-gamma frequencies (< 30 Hz), simulating background activity, but exhibited short-term depression in these amplitudes to stimulation at gamma frequencies (> 30 Hz), simulating sensory transmission. In current clamp, TRN cells increased their spike outputs in burst and tonic firing modes to increasing stimulus-train frequencies. These increases in spike output were most likely due to temporal summation of excitatory postsynaptic potentials. However, the frequency-dependent increase in tonic firing was attenuated at gamma stimulus frequencies, indicating that the synaptic depression selectively observed in this frequency range acts to suppress TRN cell output. In contrast, intra-TRN inhibition reduced spike output selectively at non-gamma stimulus frequencies. Thus, our data indicate that two intrinsic mechanisms play a role in controlling the tonic spike output of TRN neurons and these mechanisms are differentially related to two physiologically meaningful stimulus frequency ranges. C1 [Mistry, Rajen B.; Isaac, John T. R.; Crabtree, John W.] Univ Bristol, Sch Med Sci, Dept Anat, Med Res Council Ctr Synapt Plastic, Bristol BS8 1TD, Avon, England. [Mistry, Rajen B.] Univ Warwick, Dept Biol Sci, Coventry CV4 7AL, W Midlands, England. [Isaac, John T. R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Crabtree, JW (reprint author), Univ Bristol, Sch Med Sci, Dept Anat, Med Res Council Ctr Synapt Plastic, Bristol BS8 1TD, Avon, England. EM j.w.crabtree@bristol.ac.uk FU Wellcome Trust NR 64 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD MAY PY 2008 VL 27 IS 10 BP 2643 EP 2656 DI 10.1111/j.1460-9568.2008.06246.x PG 14 WC Neurosciences SC Neurosciences & Neurology GA 308MX UT WOS:000256395800016 PM 18547248 ER PT J AU Kramer-Marek, G Kiesewetter, DO Martiniova, L Jagoda, E Lee, SB Capala, J AF Kramer-Marek, Gabriela Kiesewetter, Dale O. Martiniova, Lucia Jagoda, Elaine Lee, Sang Bong Capala, Jacek TI [(18)F]FBEM-Z(HER2 : 342) - Affibody molecule - a new molecular tracer for in vivo monitoring of HER2 expression by positron emission tomography SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE breast cancer; molecular imaging; HER2; PET; F-18 ID BREAST-CANCER; ANTIBODY FRAGMENTS; MALIGNANT-TUMORS; TRASTUZUMAB; THERAPY; PET; XENOGRAFTS; DISEASE; AGENT; DRUGS AB Purpose The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET). Materials and methhods The HER2-binding Z(HER2:342)-Cys Affibody molecule was conjugated with N-2-(4-[(18)F]fluorobenzamido)ethylmaleimide ([(18)F]FBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled Z(HER2:342)-Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner. Results In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled Z(HER2:342)-Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones. Conclusion Our results suggest that the [(18)F]FBEM-Z(HER2:342) radioconjugate can be used to assess HER2 expression in vivo. C1 [Kramer-Marek, Gabriela; Lee, Sang Bong; Capala, Jacek] NCI, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kiesewetter, Dale O.; Jagoda, Elaine] Natl Inst Biomed Imaging & Bioengn, Natl Inst Hlth, Bethesda, MD USA. [Martiniova, Lucia] NICHHD, Natl Inst Hlth, Bethesda, MD USA. RP Capala, J (reprint author), NCI, Natl Inst Hlth, 10 Ctr Dr,Bldg 10 Rm 1B-37A, Bethesda, MD 20892 USA. EM capalaj@mail.nih.gov FU Intramural NIH HHS [Z01 BC010727-01, Z01 BC010727-02]; NCI NIH HHS [N02CO12401, N01CO12400, N01-CO-12400, N01-CO-12401] NR 38 TC 93 Z9 94 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD MAY PY 2008 VL 35 IS 5 BP 1008 EP 1018 DI 10.1007/s00259-007-0658-0 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 287FP UT WOS:000254902700016 PM 18157531 ER PT J AU Roelke, ME Johnson, WE Millan, J Palomares, F Revilla, E Rodriguez, A Calzada, J Ferreras, P Leon-Vizcaino, L Delibes, M O'Brien, SJ AF Roelke, Melody E. Johnson, Warren E. Millan, Javier Palomares, Francisco Revilla, Eloy Rodriguez, Alejandro Calzada, Javier Ferreras, Pablo Leon-Vizcaino, Luis Delibes, Miguel O'Brien, Stephen J. TI Exposure to disease agents in the endangered Iberian lynx (Lynx pardinus) SO EUROPEAN JOURNAL OF WILDLIFE RESEARCH LA English DT Article DE andalusia; conservation; disease risk; serosurvey; Spain ID FELINE LEUKEMIA-VIRUS; TOXOPLASMA-GONDII INFECTION; FREE-LIVING POPULATIONS; RANGING EURASIAN LYNX; DONANA-NATIONAL-PARK; CANINE PARVOVIRUS; IMMUNODEFICIENCY VIRUS; WILD CARNIVORES; ORYCTOLAGUS-CUNICULUS; LATEX AGGLUTINATION AB The Iberian lynx (Lynx pardinus) is the most endangered felid species in the world. Lynx populations have decreased dramatically in size and distribution in the last four decades, thus becoming increasingly vulnerable to catastrophic events such as epizooties. From 1989 to 2000, serum samples were obtained from 48 free-ranging lynx captured in the Donana National Park (DNP, n=31) and mountains of Sierra Morena (SM, n=17) in southern Spain. Samples were tested for antibodies against Toxoplasma gondii, feline herpesvirus 1 (FHV-1), feline calicivirus (FCV), feline/canine parvovirus (FPV/CPV), feline coronavirus, feline immunodeficiency virus (FIV), feline leukaemia virus and canine distemper virus (CDV) and for FeLV p27 antigen, to document baseline exposure levels. Antibodies against T. gondii were detected in 44% of lynx, with a significantly greater prevalence in DNP (61%) than in SM (12%). In DNP, prevalence was significantly higher in adult (81%) than in juvenile and sub-adult (41%) lynx, but no such difference was observed in SM. Low prevalences (<= 11%) of minimally positive titres were found for FHV-1, FCV and FPV/CPV. This, combined with the lack of evidence for exposure to CDV, FIV and FeLV, suggests that these lynx populations are naive and might be vulnerable to a disease outbreak in the future. Because of the reduced size of lynx populations, the documented low level of genetic variation (particularly in the DNP population) coupled with the recently documented state of immune depletion in a majority of necropsied lynx, it is important to better understand the threat and potential impact that disease agents might pose for the conservation of this endangered species. Future surveillance programs must include possible disease reservoir hosts such as domestic cats and dogs and other wild carnivores. C1 [Millan, Javier; Palomares, Francisco; Revilla, Eloy] CSIC, Dept Conservat Biol, Estac Biol Donana, Seville 41013, Spain. [Roelke, Melody E.; Johnson, Warren E.; O'Brien, Stephen J.] NCI, Lab Genom Divers, SAIC Frederick, Frederick, MD 21702 USA. [Calzada, Javier] Univ Huelva, Dept Biol Ambiental & Salud Publ, Fac Ciencias Expt, Huelva 21071, Spain. [Ferreras, Pablo] IREC CSIC UCLM JCCM, Ciudad Real 13071, Spain. [Leon-Vizcaino, Luis] Univ Murcia, Infect Dis Area, Fac Vet Med, E-30100 Murcia, Spain. RP Millan, J (reprint author), CSIC, Dept Conservat Biol, Estac Biol Donana, Seville 41013, Spain. EM syngamustrachea@hotmail.com RI Revilla, Eloy/B-5100-2008; Millan, Javier/B-5399-2008; Rodriguez, Alejandro/E-7709-2011; Ferreras, Pablo/A-6017-2009; Johnson, Warren/D-4149-2016; CSIC, EBD Donana/C-4157-2011; Palomares, Francisco/F-5327-2016; Delibes, Miguel/K-2744-2014 OI Revilla, Eloy/0000-0001-5534-5581; Millan, Javier/0000-0001-5608-781X; Rodriguez, Alejandro/0000-0001-9367-3420; Ferreras, Pablo/0000-0002-1116-6706; Johnson, Warren/0000-0002-5954-186X; CSIC, EBD Donana/0000-0003-4318-6602; Palomares, Francisco/0000-0002-4655-7205; Delibes, Miguel/0000-0002-3569-567X NR 71 TC 17 Z9 17 U1 1 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1612-4642 J9 EUR J WILDLIFE RES JI Eur. J. Wildl. Res. PD MAY PY 2008 VL 54 IS 2 BP 171 EP 178 DI 10.1007/s10344-007-0122-2 PG 8 WC Ecology; Zoology SC Environmental Sciences & Ecology; Zoology GA 289ZB UT WOS:000255091300002 ER PT J AU Schlom, J Gulley, JL Arlen, PM AF Schlom, Jeffrey Gulley, James L. Arlen, Philip M. TI Paradigm shifts in cancer vaccine therapy SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Review DE cancer vaccines; immunotherapy; combination therapy; prostate cancer ID PROSTATE-SPECIFIC ANTIGEN; COLONY-STIMULATING FACTOR; RENAL-CELL CARCINOMA; HIGH-DOSE INTERLEUKIN-2; ACTIVATED KILLER-CELLS; PHASE-III TRIAL; CARCINOEMBRYONIC ANTIGEN; ANDROGEN-DEPRIVATION; METASTATIC MELANOMA; COMBINATION THERAPY AB Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance " between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated. C1 [Schlom, Jeffrey; Gulley, James L.; Arlen, Philip M.] NIH, Tumor Immunol & Biol Lab, CCR, NCI, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NIH, Tumor Immunol & Biol Lab, CCR, NCI, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 72 TC 36 Z9 37 U1 0 U2 4 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAY PY 2008 VL 233 IS 5 BP 522 EP 534 DI 10.3181/0708-MR-226 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 293FR UT WOS:000255321300006 PM 18375829 ER PT J AU Zhou, ZX Liu, J Song, ZY Mcclain, CJ Kang, YJ AF Zhou, Zhanxiang Liu, Jie Song, Zhenyuan Mcclain, Craig J. Kang, Y. James TI Zinc supplementation inhibits hepatic apoptosis in mice subjected to a long-term ethanol exposure SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE zinc; apoptosis; oxidative stress; death receptors; alcoholic liver disease ID ALCOHOLIC LIVER-DISEASE; NECROSIS-FACTOR-ALPHA; ELEVATED S-ADENOSYLHOMOCYSTEINE; INDUCED HEPATOCYTE APOPTOSIS; CELLS EXPRESSING CYP2E1; OXIDATIVE STRESS; POSSIBLE INVOLVEMENT; INTRACELLULAR ZINC; METALLOTHIONEIN; INJURY AB Hepatocyte apoptosis has been documented in both clinical and experimental alcoholic liver disease. This study was undertaken to examine the effect of dietary zinc supplementation on hepatic apoptosis in mice subjected to a long-term ethanol exposure. Male adult 129S6 mice fed an ethanol-containing liquid diet for 6 months developed hepatitis, as indicated by neutrophil infiltration and elevation of hepatic keratinocyte chemoattractant (KC) and monocyte chemoattractant protein-1 (MCP-1) levels. Apoptotic cell death was detected in ethanol-exposed mice by a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and was confirmed by the increased activities of caspase-3 and -8. Zinc supplementation attenuated alcoholic hepatitis and reduced the number of TUNEL-positive cells in association with inhibition of caspase activities. Ethanol exposure caused oxidative stress, as indicated by reactive oxygen species accumulation, mitochondrial glutathione depletion, and decreased metallothionein levels in the liver, which were suppressed by zinc supplementation. The mRNA levels of tumor necrosis factor (TNF)-alpha, TNF-R1, FasL, Fas, Fas-associated factor-1, and caspase-3 in the liver were upregulated by ethanol exposure, which were attenuated by zinc supplementation. Zinc supplementation also prevented ethanol-elevated serum and hepatic TNF-alpha levels and TNF-R1 and Fas proteins in the liver. In conclusion, zinc supplementation prevented hepatocyte apoptosis in mice subjected to long-term ethanol exposure, and the action of zinc is likely through suppression of oxidative stress and death receptor-mediated pathways. C1 [Zhou, Zhanxiang; Song, Zhenyuan; Mcclain, Craig J.; Kang, Y. James] Univ Louisville, Sch Med, Dept Med, Louisville, KY 40292 USA. [Mcclain, Craig J.; Kang, Y. James] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Mcclain, Craig J.] Louisville Vet Affairs Med Ctr, Louisville, KY 40202 USA. [Liu, Jie] NIEHS, Natl Canc Inst, Res Triangle Pk, NC 27709 USA. RP Zhou, ZX (reprint author), Univ Louisville, Sch Med, Dept Med, 511 S Floyd St,MDR Room 529, Louisville, KY 40292 USA. EM z0zhou01@louisville.edu FU Intramural NIH HHS NR 50 TC 26 Z9 29 U1 0 U2 1 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAY PY 2008 VL 233 IS 5 BP 540 EP 548 DI 10.3181/0710-RM-265 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 293FR UT WOS:000255321300008 PM 18375824 ER PT J AU Manson, SC Wegner, C Filippi, M Barkhof, F Beckmann, C Ciccarelli, O De Stefano, N Enzinger, C Fazekas, F Agosta, F Gass, A Hirsch, J Johansen-Berg, H Kappos, L Korteweg, T Polman, C Mancini, L Manfredonia, F Marino, S Miller, DH Montalban, X Palace, J Rocca, M Ropele, S Rovira, A Smith, S Thompson, A Thornton, J Yousry, T Frank, JA Matthews, PM AF Manson, S. C. Wegner, C. Filippi, M. Barkhof, F. Beckmann, C. Ciccarelli, O. De Stefano, N. Enzinger, Christian Fazekas, F. Agosta, F. Gass, A. Hirsch, J. Johansen-Berg, H. Kappos, L. Korteweg, T. Polman, C. Mancini, L. Manfredonia, F. Marino, S. Miller, D. H. Montalban, X. Palace, J. Rocca, M. Ropele, S. Rovira, A. Smith, S. Thompson, A. Thornton, J. Yousry, T. Frank, J. A. Matthews, P. M. TI Impairment of movement-associated brain deactivation in multiple sclerosis: further evidence for a functional pathology of interhemispheric neuronal inhibition SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE fMRI; multiple sclerosis; movement; inhibitory neurotransmission ID CORTICAL MOTOR REORGANIZATION; SINGLE CLINICAL ATTACK; MRI CHANGES; DISTINCT MECHANISMS; ALZHEIMERS-DISEASE; AXONAL PATHOLOGY; CEREBRAL-CORTEX; ACTIVATION; MS; FMRI AB Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control. C1 [Manson, S. C.; Wegner, C.; Beckmann, C.; Johansen-Berg, H.; Palace, J.; Smith, S.; Matthews, P. M.] Univ Oxford, Ctr Funct Magnet Resonance Imaging Brain, Oxford, England. [Manson, S. C.; Frank, J. A.] Natl Inst Hlth, Bethesda, MD USA. [Filippi, M.; Agosta, F.; Rocca, M.] Univ Ospedale San Raffaele, Inst Sci, Dept Neurol, Neuroimaging Res Unit, Milan, Italy. [Barkhof, F.; Korteweg, T.; Polman, C.] Vrije Univ Amsterdam Med Ctr, Dept Radiol, Amsterdam, Netherlands. [Ciccarelli, O.; Mancini, L.; Manfredonia, F.; Miller, D. H.; Thompson, A.; Thornton, J.; Yousry, T.] UCL, Inst Neurol, NMR Res Unit, London, England. [De Stefano, N.; Marino, S.] Univ Siena, Dept Neurol & Behav sci, I-53100 Siena, Italy. [Enzinger, Christian; Fazekas, F.; Ropele, S.] Med Univ Graz, Dept Neurol, Graz, Austria. [Gass, A.; Hirsch, J.; Kappos, L.] Univ Basel Hosp, Dept Neurol, Kantonsspital Basel, CH-4031 Basel, Switzerland. [Mancini, L.] UCLH NHS Fdn Trust, Dept Neuroradiol, Natl Hosp Neurol & Neurosurg, London, England. [Montalban, X.; Rovira, A.] Hosp Gen Valle Hebron, Dept Radiol, Magnet Resonance Unit, Barcelona, Spain. [Matthews, P. M.] Univ London Imperial Coll Sci Technol & Med, Dept Clin Neurosci, London, England. [Matthews, P. M.] Hammersmith Hosp, Clim Imaging Ctr, Clin Pharmacol & Discovery Med, GlaxoSmithKline, London, England. RP Matthews, PM (reprint author), Univ Oxford, Ctr Funct Magnet Resonance Imaging Brain, S Parks Rd, Oxford, England. EM paul_m_matthews@hotmail.co.uk RI Yousry, Tarek/B-3417-2009; Thompson, Alan/C-2654-2008; Beckmann, Christian/E-6374-2012; Agosta, Federica/J-9908-2016; OI Smith, Stephen/0000-0001-8166-069X; Thornton, John/0000-0003-3248-8437; Thompson, Alan/0000-0002-4333-8496; Agosta, Federica/0000-0003-3121-4979; Johansen-Berg, Heidi/0000-0002-4134-9730; Matthews, Paul M/0000-0002-1619-8328 FU Intramural NIH HHS [Z01 CL090001-15]; Medical Research Council; Multiple Sclerosis Society [748]; Wellcome Trust [078204] NR 45 TC 38 Z9 38 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD MAY PY 2008 VL 187 IS 1 BP 25 EP 31 DI 10.1007/s00221-008-1276-1 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 289MK UT WOS:000255058400003 PM 18236036 ER PT J AU Harding, RL Howley, S Baker, LJ Murphy, TR Archer, WE Wistow, G Hyde, DR Vihtelic, TS AF Harding, Rachel L. Howley, Sinead Baker, Lee J. Murphy, Taylor R. Archer, William E. Wistow, Graeme Hyde, David R. Vihtelic, Thomas S. TI Lengsin expression and function during zebrafish lens formation SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE ocular lens; secondary fiber cells; lens development; zebralish; morpholino ID INTERMEDIATE-FILAMENT PROTEINS; SEQUENCE TAG ANALYSIS; ALPHA-B-CRYSTALLIN; DANIO-RERIO; EYE LENS; CYTOSKELETAL PROTEIN; VERTEBRATE LENS; FIBER CELLS; DIFFERENTIATION; FAMILY AB A zebrafish ortholog of human lengsin was identified by EST analysis of an adult lens cDNA library. During zebrafish development, lengsin transcription is first detected at 24 h post-fertilization (hpf). Immunolocalization, using polyclonal antiserum generated against a Lengsin bacterial fusion protein, detects lens-specific protein in whole-mount embryos at 30 hpf. Lengsin expression in zebrafish follows the temporal expression of the alpha A-alpha B1- and beta B1-crystallin proteins in the lens. At 72 hpf, Lengsin is localized to a subpopulation of differentiating secondary fiber cells, while no expression is detected in the lens epithelial cells or central lens fibers. In the adult lens, Lengsin is restricted to a narrow band of cortical fibers and co-localizes with actin at the lateral faces of these interdigitating cells. Stable transgenic lines, using a 3 kb lengsin genomic fragment to regulate EGFP expression, recapitulate the Lengsin temporal and spatial expression patterns. Lengsin function in zebrafish lens formation was examined by antisense morpholino-mediated translation and mRNA splice inhibition. At 72 hpf, the lengsin morphant lenses are reduced in size and exhibit separations within the cortex due to defects in secondary fiber morphogenesis. The location of the morphant lens defects correlates with the Lengsin protein localization at this age. These results demonstrate Lengsin is required for proper fiber cell differentiation by playing roles in either cell elongation or the establishment of cell interactions. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Harding, Rachel L.; Howley, Sinead; Baker, Lee J.; Murphy, Taylor R.; Archer, William E.; Hyde, David R.; Vihtelic, Thomas S.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. [Harding, Rachel L.; Howley, Sinead; Baker, Lee J.; Murphy, Taylor R.; Archer, William E.; Hyde, David R.; Vihtelic, Thomas S.] Galvin Life Sci Ctr, Ctr Zebrafish Res, Notre Dame, IN 46556 USA. [Wistow, Graeme] NEI, Natl Inst Hlth, Sect Mol Struct & Funct Genom, Bethesda, MD 20892 USA. RP Vihtelic, TS (reprint author), Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. EM tvihteli@nd.edu FU Intramural NIH HHS [Z01 EY000433-03, Z01 EY000320-09]; NEI NIH HHS [R01 EY014455-05, R01 EY014455] NR 41 TC 11 Z9 11 U1 0 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD MAY PY 2008 VL 86 IS 5 BP 807 EP 818 DI 10.1016/j.exer.2008.02.009 PG 12 WC Ophthalmology SC Ophthalmology GA 314PT UT WOS:000256822000012 PM 18406404 ER PT J AU Zarate, CA Manji, HK AF Zarate, Carlos A., Jr. Manji, Husseini K. TI The Role of AMPA receptor modulation in the treatment of neuropsychiatric diseases SO EXPERIMENTAL NEUROLOGY LA English DT Editorial Material DE aging; AMPA; antidepressant; cognition; depression; glutamate; plasticity; treatment ID IN-VIVO; MEMORY; POTENTIATION; HIPPOCAMPAL; MECHANISMS; EXPRESSION; DEPRESSION; PLASTICITY C1 [Zarate, Carlos A., Jr.] NIH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Res Program, Bethesda, MD USA. RP Zarate, CA (reprint author), Mark O Hatfield CRC, Unit 7 SE, 10 Ctr Dr,Rm 7-3445, Bethesda, MD 20892 USA. EM zaratcc@mail.nih.gov FU Intramural NIH HHS [Z01 MH002857-03] NR 29 TC 51 Z9 52 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2008 VL 211 IS 1 BP 7 EP 10 DI 10.1016/j.expneurol.2008.01.011 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 298ZM UT WOS:000255725600002 PM 18291371 ER PT J AU Stack, CM Lim, MA Cuasay, K Stone, MA Seibert, KM Spivak-Pohis, I Crawley, JN Waschek, JA Hill, JM AF Stack, Conor M. Lim, Maria A. Cuasay, Katrina Stone, Madeleine A. Seibert, Kimberly M. Spivak-Pohis, Irit Crawley, Jacqueline N. Waschek, James A. Hill, Joanna M. TI Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice SO EXPERIMENTAL NEUROLOGY LA English DT Article DE autism; Morris water maze; mouse model; neurodevelopmental disorder; neuropeptide; sex differences; sociability; social approach; spatial reversal learning; vasoactive intestinal peptide ID VASOACTIVE-INTESTINAL-PEPTIDE; DEPENDENT NEUROTROPHIC FACTOR; EMBRYONIC GROWTH; DORSOMEDIAL STRIATUM; NEUROPROTECTIVE PEPTIDE; KNOCKOUT MICE; MOUSE; RECEPTOR; RAT; AUTISM AB Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism. Published by Elsevier Inc. C1 [Stack, Conor M.; Lim, Maria A.; Cuasay, Katrina; Stone, Madeleine A.; Seibert, Kimberly M.; Crawley, Jacqueline N.; Hill, Joanna M.] NIH, NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. [Spivak-Pohis, Irit] Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. [Waschek, James A.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA USA. RP Hill, JM (reprint author), NIH, NIMH, Lab Behav Neurosci, 35-1C903, Bethesda, MD 20892 USA. EM hiilljoa@mail.nih.gov FU Intramural NIH HHS [, NIH0010150863]; PHS HHS [NIH0010150863] NR 67 TC 22 Z9 23 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2008 VL 211 IS 1 BP 67 EP 84 DI 10.1016/j.expneurol.2008.01.003 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 298ZM UT WOS:000255725600010 PM 18316078 ER PT J AU Choi, SH Langenbach, R Bosetti, F AF Choi, Sang Ho Langenbach, Robert Bosetti, Francesca TI Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury SO FASEB JOURNAL LA English DT Article DE microglia; astrocytes; prostaglandin; NADPH oxidase; oxidative stress ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PROSTAGLANDIN E-2 SYNTHESIS; NEURONAL OXIDATIVE DAMAGE; CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; NADPH OXIDASE; HIPPOCAMPAL-NEURONS; ACTIVATED MICROGLIA; CONTROLLED-TRIAL; RAT HIPPOCAMPUS AB Cyclooxygenase (COX) -1 and -2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major players in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX-2, the contribution of COX-1 to the inflammatory response is unclear. In the present study, the contribution of COX-1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX-1 deficient (COX-1 ) mice or wild-type (COX-1(+/+)) mice pretreated with SC-560, a selective COX-1 inhibitor. Twenty-four hours after lipopolysaccharide (LPS) injection, COX-1(-/-) mice showed decreased protein oxidation and LPS-induced neuronal damage in the hippocampus compared with COX-1(+/+) mice. COX-1(-/-) mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX-2, inducible NOS, and NADPH oxidase. The transcriptional down-regulation of cytokines and other inflammatory markers in COX-1(-/-) mice was mediated by a reduced activation of NF-kappa B and signal transducer and activator of transcription 3. Administration of SC-560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E-2, PGD(2), PGF(2 alpha), and thromboxane B-2, as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX-1 plays a previously unrecognized role in neuroinflammatory damage. C1 [Choi, Sang Ho; Bosetti, Francesca] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Langenbach, Robert] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU Intramural NIH HHS [Z01 AG000423-04] NR 54 TC 95 Z9 96 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2008 VL 22 IS 5 BP 1491 EP 1501 DI 10.1096/fj.07-9411com PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 301LW UT WOS:000255898700021 PM 18162486 ER PT J AU Schmidt, M Drgon, T Bowers, B Cabib, E AF Schmidt, Martin Drgon, Tomas Bowers, Blair Cabib, Enrico TI Hyperpolarized growth of Saccharomyces cerevisiae cak1(P212S) and cla4 mutants weakens cell walls and renders cells dependent on chitin synthase 3 SO FEMS YEAST RESEARCH LA English DT Article DE morphogenesis; yeast cell wall; stress chitin; chitin synthase 3 ID ACTIVATING KINASE CAK; BUDDING YEAST; PROTEIN-KINASE; CYCLE; MORPHOGENESIS; INTEGRITY; LOCALIZATION; PATHWAY; RING; PHOSPHORYLATION AB In a screen for cell wall defects in Saccharomyces cerevisiae, we isolated a strain carrying a mutation in the Cdc28-activating kinase CAK1. The cak1(P212S) mutant cells exhibit multiple, elongated and branched buds, beta(1,3)glucan-poor regions of the cell periphery and lysed upon osmotic shock after treatment with the chitin synthase III inhibitor Nikkomycin Z. Ultrastructural examination of cak1(P212S) mutants revealed a thin, uneven cell wall and marked abnormalities in septum formation. In all of the above aspects, the cak1(P212S) mutants are similar to previously described cla4 mutants, suggesting that the cell wall defects are common to mutants with hyperpolarized growth. In cak1M(P212S) mutants, chitin accumulates all over the surface of the cells and glucan synthase activity is located preferentially to the tips of elongated buds. We conclude that the cell wall weakness in cak1(P212S) mutants is caused by hyperpolarized secretion of glucan synthase and lack of reinforcement of the lateral cell walls. Showing that the defect depends at least in part on Cdc28, the cak1(P212S) hyperpolarized growth phenotype can be suppressed by a Cak1-independent Cdc28-allele. The results underline the importance of a minor cell wall component, the chitin of lateral walls, for the integrity of the cell in a stress situation. C1 [Schmidt, Martin] Des Moines Univ, Dept Biochem & Nutr, Des Moines, IA 50311 USA. [Drgon, Tomas] NIDA, Mol Neurobiol Branch, NIH IRP, Baltimore, MD USA. [Bowers, Blair] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Cabib, Enrico] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD USA. RP Schmidt, M (reprint author), Des Moines Univ, Dept Biochem & Nutr, 3200 Grand Ave, Des Moines, IA 50311 USA. EM mschmidt@dmu.edu NR 42 TC 6 Z9 6 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1567-1356 J9 FEMS YEAST RES JI FEMS Yeast Res. PD MAY PY 2008 VL 8 IS 3 BP 362 EP 373 DI 10.1111/j.1567-1364.2008.00368.x PG 12 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA 291QO UT WOS:000255212100004 PM 18373684 ER PT J AU Whitcomb, BW Schisterman, EF Ruopp, MD Collins, TC AF Whitcomb, Brian W. Schisterman, Enrique F. Ruopp, Marcus D. Collins, Tara C. TI Validity of block randomized clinical trials - Reply SO FERTILITY AND STERILITY LA English DT Letter C1 [Whitcomb, Brian W.; Schisterman, Enrique F.; Ruopp, Marcus D.; Collins, Tara C.] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Whitcomb, BW (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAY PY 2008 VL 89 IS 5 BP 1281 EP 1282 DI 10.1016/j.fertnstert.2008.02.156 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 303XY UT WOS:000256075700047 ER PT J AU Gibbs, AG Hoshizaki, DK AF Gibbs, Allen G. Hoshizaki, Deborah K. TI Life is a gas SO FLY LA English DT Editorial Material DE carbon dioxide; hypoxia; oxygen; respiration; trachea ID EXCHANGE; INSECTS; HYPOTHESIS C1 [Gibbs, Allen G.] Univ Nevada, Sch Life Sci, Las Vegas, NV 89154 USA. [Hoshizaki, Deborah K.] NIDDK, Bethesda, MD USA. RP Gibbs, AG (reprint author), Univ Nevada, Sch Life Sci, 4505 Maryland Parkway, Las Vegas, NV 89154 USA. EM allen.gibbs@unlv.edu RI Gibbs, Allen/D-6968-2011; Gibbs, Allen/G-6939-2014 NR 12 TC 1 Z9 1 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6934 J9 FLY JI Fly PD MAY-JUN PY 2008 VL 2 IS 3 BP 121 EP 122 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 336NW UT WOS:000258372900004 PM 18820454 ER PT J AU Huang, J Chen, KQ Gong, WH Dunlop, NM Wang, JM AF Huang, Jian Chen, Keqiang Gong, Wanghua Dunlop, Nancy M. Wang, Ji Ming TI G-protein coupled chemoattractant receptors and cancer SO FRONTIERS IN BIOSCIENCE LA English DT Review DE chemoattractants; chemokines; receptors; cancer; review ID CELL LUNG-CANCER; LYMPH-NODE METASTASIS; HUMAN BREAST-CANCER; CC-CHEMOKINE RECEPTOR-7; EPIDERMAL-GROWTH-FACTOR; MALIGNANT HUMAN GLIOMAS; HUMAN-MELANOMA CELLS; NF-KAPPA-B; TUMOR-GROWTH; CXC-CHEMOKINE AB Chemoattractant receptors are a group of seven transmembrane, G protein coupled receptors (GPCRs). They were initially identified mainly on leukocytes to mediate cell migration in response to pathogen or host-derived chemotactic factors. During the past decade, chemoattractant GPCRs have been discovered not only to mediate leukocyte chemotaxis thus promoting innate and adaptive host immune responses, but also to play essential roles in development, homeostasis, HIV infection, angiogenesis and wound healing. A growing body of evidence further indicates that chemoattractant GPCRs contribute to tumor growth, invasion, angiogenesis/angiostasis and metastasis. The diverse properties of GPCRs in the progression of malignant tumors have attracted intense interest in their potential as novel anti-tumor pharmacological targets. C1 [Huang, Jian; Chen, Keqiang; Dunlop, Nancy M.; Wang, Ji Ming] NCI, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD 21702 USA. [Gong, Wanghua] NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. [Huang, Jian] Third Mil Med Univ, Dept Pathophysiol, Chongqing, Peoples R China. RP Wang, JM (reprint author), NCI, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM wangji@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 118 TC 24 Z9 24 U1 0 U2 2 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2008 VL 13 BP 3352 EP 3363 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301GS UT WOS:000255885000011 PM 18508437 ER PT J AU Zheng, J Ma, BY Chang, Y Nussinov, R AF Zheng, Jie Ma, Buyong Chang, Yung Nussinov, Ruth TI Molecular dynamics simulations of Alzheimer A beta(40) elongation and lateral association SO FRONTIERS IN BIOSCIENCE LA English DT Article DE A beta; amyloid; peptide aggregation; molecular dynamics ID AMYLOID PEPTIDE AGGREGATION; BETA-PROTEIN; ION CHANNELS; FIBRILS; DISEASE; OLIGOMERS; STABILITY; KINETICS; MODELS AB Amyloid-beta (A beta) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic A beta models with different in-register intermolecular beta-sheet-beta-sheet associations. We probe structural stability, conformational dynamics, and association force of A beta oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an A beta oligomer that is laterally associated through the C-terminal-C-terminal interface is energetically more favorable than other oligomers with the N-terminal-N- terminal and C-terminal-N-terminal interfaces. We further develop a simple numerical model to describe the kinetics of A beta aggregation process by considering fibril elongation and lateral association using a Monte Carlo algorithm. Kinetic data suggest that fibril elongation and lateral association are mutually competitive. Single-point mutations of Glu22 or Met35 at the interfaces have profound negative effects on intermolecular beta-sheet-beta-sheet association. These disease-related mutants (E22K, E22Q, and M35O) display more flexible structures, weaker lateral association, and stronger elongation tendencies than the wild type, suggesting that amyloid oligomerization and neurotoxicity might be linked to fibril longitudinal growth. C1 [Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Ma, Buyong; Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Chang, Yung] Chung Yuan Christian Univ, Res & Dev Ctr Membrane Technol, Tao Yuan 320, Taiwan. [Chang, Yung] Chung Yuan Christian Univ, Dept Chem Engn, Tao Yuan 320, Taiwan. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Zheng, J (reprint author), Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. EM zhengj@uakron.edu RI Chang, Yung/B-4788-2011; Ma, Buyong/F-9491-2011; Zheng, Jie/B-5057-2013 OI Ma, Buyong/0000-0002-7383-719X; Zheng, Jie/0000-0003-1547-3612 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 38 TC 29 Z9 29 U1 0 U2 15 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2008 VL 13 BP 3919 EP 3930 DI 10.2741/2980 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301GS UT WOS:000255885000060 PM 18508486 ER PT J AU Furuichi, K Wada, T Kaneko, S Murphy, PM AF Furuichi, Kengo Wada, Takashi Kaneko, Shuichi Murphy, Philip M. TI Roles of chemokines in renal ischemia/reperfusion injury SO FRONTIERS IN BIOSCIENCE LA English DT Article DE chemokines; kidney; renal; ischemia; reperfusion; injury; review ID ISCHEMIA-REPERFUSION INJURY; NF-KAPPA-B; NECROSIS-FACTOR-ALPHA; RECEPTOR CXCR2; MYOCARDIAL-ISCHEMIA; EXPRESSION; KIDNEY; RATS; HYPOXIA; CELLS AB Ischemia-reperfusion injury (IR) is a common and an important clinical cause of renal disease, such as renal transplantation, renal artery stenosis and following shock from any cause. Inflammatory reaction after IR is regulated by various kinds of mediators. Chemokines are major mediators of the inflammation, and regulate pro-inflammatory cytokine and adhesion molecule expression, and leukocyte infiltration and activation. Chemokines are the key players of inflammation, angiogenesis and fibrosis. These inflammatory processes mediated by chemokines were observed in not only experimental animal models, but also in human renal diseases with ischemic injury. A number of challenges of chemokine targeted therapy is trying to prevent the ischemic injury, and will give some beneficial effect on the injury. C1 [Furuichi, Kengo; Kaneko, Shuichi] Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol & Nephrol, Kanazawa, Ishikawa, Japan. [Furuichi, Kengo; Wada, Takashi] Kanazawa Univ, Grad Sch Med Sci, Div Blood Purificat, Kanazawa, Ishikawa, Japan. [Murphy, Philip M.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Furuichi, K (reprint author), Kanazawa Univ, Grad Sch Med Sci, Dept Gastroenterol & Nephrol, Kanazawa, Ishikawa, Japan. NR 67 TC 15 Z9 27 U1 0 U2 1 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2008 VL 13 BP 4021 EP 4028 DI 10.2741/2990 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301GS UT WOS:000255885000070 PM 18508496 ER PT J AU Dulev, S Aragon, L Strunnikov, A AF Dulev, Stanimir Aragon, Luis Strunnikov, Alexander TI Unreplicated DNA in mitosis precludes condensin binding and chromosome condensation in S. cerevisiae SO FRONTIERS IN BIOSCIENCE LA English DT Article DE DNA replication; chromosome condensation; condensin; rDNA; nucleolus ID RIBOSOMAL-RNA GENE; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; SISTER CHROMATIDS; BUDDING YEAST; REPLICATION; PROTEIN; COMPLEX; SEGREGATION; RDNA AB Condensin is the core activity responsible for chromosome condensation in mitosis. In the yeast S. cerevisiae, condensin binding is enriched at the regions where DNA replication terminates. Therefore, we investigated whether DNA replication completion determines the condensin-binding proficiency of chromatin. In order to fulfill putative mitotic requirements for condensin activity we analyzed chromosome condensation and condensin binding to unreplicated chromosomes in mitosis. For this purpose we used pGAL:CDC6 cdc15-ts cells that are known to enter mitosis without DNA replication if CDC6 transcription is repressed prior to S-phase. Both the condensation of nucleolar chromatin and proper condensin targeting to rDNA sites failed when unreplicated chromosomes were driven in mitosis. We propose that the DNA replication results in structural and/or biochemical changes to replicated chromatin, which are required for two-phase condensin binding and proper chromosome condensation. C1 [Dulev, Stanimir; Strunnikov, Alexander] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. [Dulev, Stanimir] Paisij Hilendarski Univ Plovdiv, BG-4000 Plovdiv, Bulgaria. [Aragon, Luis] Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, MRC, Cell Cycle Grp, London, England. RP Strunnikov, A (reprint author), NICHD, NIH, LGRD, 18T Lib Dr,Room 106, Bethesda, MD 20892 USA. EM strunnik@mail.nih.gov OI Strunnikov, Alexander/0000-0002-9058-2256 FU Intramural NIH HHS [Z99 AI999999, Z01 HD001903-11]; Medical Research Council [, MC_U120074328] NR 48 TC 2 Z9 2 U1 0 U2 1 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2008 VL 13 BP 5838 EP 5846 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301GS UT WOS:000255885000200 PM 18508626 ER PT J AU Kang, H Han, K Jo, J Kim, J Choi, MY AF Kang, Hyuk Han, Kyungreem Jo, Junghyo Kim, Jinwoong Choi, Moo Young TI Systems of pancreatic beta-cells and glucose regulation SO FRONTIERS IN BIOSCIENCE LA English DT Article DE pancreatic islet; beta-cell; bursting action potential; size distribution; intercellular interaction; whole feedback model; glucose regulation; review ID ELECTRICAL-ACTIVITY; INSULIN-SECRETION; GLUCAGON-SECRETION; ENDOCRINE PANCREAS; ALPHA-CELLS; SIZE DISTRIBUTION; ISLET VOLUME; MOUSE; LANGERHANS; OSCILLATIONS AB We present mathematical models for systems of beta-cells in pancreatic islets. The first topic begins with the effects of noise and coupling strength on bursting action potentials of beta-cells. From the discussion, the regular bursts are produced by a proper amount of noise and coupling strength. Furthermore, the bursting duration and period depend on the cluster size of beta-cells. We also observe the real size of islets mostly consisting of beta-cells and obtain the size distribution of islets. In addition, we derive either log-normal or Weibull distributions of the islet sizes based on recent observation on islet growth. Islets of Langerhans are composed of several endocrine cells which interact with each other. Considering asymmetric and inhibitory interactions of these endocrine cells, we introduce a simple islet model consisting of alpha-, beta-, and delta- cells. Finally, a whole feedback model for glucose regulation is constructed, connecting the microscopic bursting mechanism and the macroscopic blood glucose regulation of the body. We analyzed these models via numerical simulations based on in vivo and in vitro experimental data. C1 [Choi, Moo Young] Seoul Natl Univ, Dept Phys, Seoul 151747, South Korea. [Choi, Moo Young] Seoul Natl Univ, Ctr Theoret Phys, Seoul 151747, South Korea. [Jo, Junghyo] NIH, Bethesda, MD 20892 USA. [Han, Kyungreem; Kim, Jinwoong] Seoul Natl Univ, Res Inst Pharmaceut Sci, Seoul 151747, South Korea. [Han, Kyungreem; Kim, Jinwoong] Seoul Natl Univ, Coll Pharm, Seoul 151747, South Korea. [Kang, Hyuk] Sungkyunkwan Univ, Inst Basic Sci, Suwon 404746, South Korea. RP Choi, MY (reprint author), Seoul Natl Univ, Dept Phys, Seoul 151747, South Korea. EM mychoi@snu.ac.kr RI Jo, Junghyo/D-4889-2011; Kim, Jinwoong/G-6289-2013; OI Choi, MooYoung/0000-0001-8070-7716 NR 64 TC 2 Z9 2 U1 0 U2 3 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI JI Front. Biosci. PD MAY PY 2008 VL 13 BP 6421 EP 6431 DI 10.2741/3163 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 301GS UT WOS:000255885000243 PM 18508669 ER PT J AU Au, WC Crisp, MJ DeLuca, SZ Rando, OJ Basrai, MA AF Au, Wei-Chun Crisp, Matthew J. DeLuca, Steven Z. Rando, Oliver J. Basrai, Munira A. TI Altered dosage and mislocalization of histone H3 and Cse4p lead to chromosome loss in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID BUDDING YEAST KINETOCHORE; CENP-A; CELL-CYCLE; CHROMATIN-STRUCTURE; CENTROMERIC NUCLEOSOME; ACTIVE CENTROMERES; VARIANT CSE4P; IN-VIVO; DNA; PROTEIN AB Cse4p is an essential histone H3 variant in Saccharomyces cerevisiae that defines centromere identity and is required for proper segregation of chromosomes. In this study, we investigated phenotypic consequences of Cse4p mislocalization and increased dosage of histone H3 and Cse4p, and established a direct link between histone stoichiometry, mislocalization of Cse4p, and chromosome segregation. Overexpression of the stable Cse4p mutant, cse4(K16R), resulted in its mislocalization, increased association with chromatin, and a high rate of chromosome loss, all of which were suppressed by constitutive expression of histone H3 (Delta 16H3). We determined that Delta 16H3 did not lead to increased chromosome loss; however, increasing the dosage of histone H3 (GALH3) resulted in significant chromosome loss due to reduced levels of centromere (CEN)-associated Cse4p and synthetic dosage lethality (SDL) in kinetochore mutants. These phenotypes were suppressed by GALCSE4. We conclude that the chromosome missegregation of GALcse4(K16R) and GALH3 strains is due to mislocalization and a functionally compromised kinetochore, respectively. Suppression of these phenotypes by histone Delta 16H3 and GALCSE4 supports the conclusion that proper stoichiometry affects the localization of histone H3 and Cse4p and is thus essential for accurate chromosome segregation. C1 [Au, Wei-Chun; Crisp, Matthew J.; DeLuca, Steven Z.; Basrai, Munira A.] NCI, Genet Branch Ctr Canc Res, NIH, Bethesda, MD 20889 USA. [Rando, Oliver J.] Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. RP Basrai, MA (reprint author), NCI, Genet Branch Ctr Canc Res, NIH, 8901 Wisconsin Ave,NNMC Bldg 8,Room 5101, Bethesda, MD 20889 USA. EM basraim@mail.nih.gov FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM079205, R01 GM079205-01A2] NR 66 TC 34 Z9 35 U1 0 U2 0 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2008 VL 179 IS 1 BP 263 EP 275 DI 10.1534/genetics.108.088518 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 307IG UT WOS:000256312000024 PM 18458100 ER PT J AU Cui, YH Kang, GL Sun, KL Qian, MP Romero, R Fu, WJ AF Cui, Yuehua Kang, Guolian Sun, Kelian Qian, Minping Romero, Roberto Fu, Wenjiang TI Gene-centric genomewide association study via entropy SO GENETICS LA English DT Article ID COMPLEMENT FACTOR-H; WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; MACULAR DEGENERATION; PREECLAMPSIA; SUSCEPTIBILITY; POLYMORPHISM; DISEASE; RISK; REPLICATION AB Genes are the functional units in most organisms. Compared to genetic variants located outside genes, genic variants are more likely to affect disease risk. The development of tire human HapMap project provides an unprecedented opportunity for genetic association studies at the genomewide level for elucidating disease etiology. Currently, most association studies at the single-nucleotide polymorphism (SNP) or the haplotype level rely on the linkage information between SNP markers and disease variants, with which association findings are difficult to replicate. Moreover, variants in genes might not be sufficiently covered by currently available methods. In this article, we present a gene-centric approach via entropy statistics for a genomewide association study to identify disease genes. The new entropy-based approach considers genic variants within one gene simultaneous]), and is developed on the basis of a joint genotype distribution among genetic variants for an association test. A grouping algorithm based on a penalized entropy measure is proposed to reduce the dimension of the test statistic. Type I error rates and power of the entropy test are evaluated through extensive Simulation studies. The results indicate that the entropy test has stable power under different disease models with a reasonable sample size. Compared to single SNP-based analysis, the gene-centric approach has greater power, especially when there is more than one disease variant in a gene. As the genomewide genic SNPs become available, our entropy-based gene-centric approach would provide a robust and computationally efficient way for gene-based genomewide association study. C1 [Cui, Yuehua; Kang, Guolian] Michigan State Univ, Dept Stat & Probabil, E Lansing, MI 48824 USA. [Sun, Kelian; Qian, Minping; Fu, Wenjiang] Michigan State Univ, Dept Epidemiol, E Lansing, MI 48824 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, Bethesda, MD USA. RP Cui, YH (reprint author), Michigan State Univ, Dept Stat & Probabil, A432 Wells Hall, E Lansing, MI 48824 USA. EM cui@stt.msu.edu FU Intramural NIH HHS NR 41 TC 24 Z9 24 U1 0 U2 1 PU GENETICS SOC AM PI BETHESDA PA 9650 ROCKVILLE AVE, BETHESDA, MD 20814 USA SN 0016-6731 J9 GENETICS JI Genetics PD MAY PY 2008 VL 179 IS 1 BP 637 EP 650 DI 10.1534/genetics.107.082370 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 307IG UT WOS:000256312000055 PM 18458106 ER PT J AU Faucett, WA Hart, S Pagon, RA Neall, LF Spinella, G AF Faucett, William Andrew Hart, Suzanne Pagon, Roberta A. Neall, Lisa Forman Spinella, Giovanna TI A model program to increase translation of rare disease genetic tests: collaboration, education, and test translation program SO GENETICS IN MEDICINE LA English DT Article DE test translation; rare diseases; model program; CETT; CLIA AB In 2006, The National Institutes of Health Office of Rare Diseases announced the Collaboration, Education, and Test Translation (CETT) Program, a pilot project to increase and improve the translation of genetic tests for rare diseases from research laboratories to clinical laboratories. The CETT Program created a new paradigm in which applicants must form a collaborative group consisting of a clinical laboratory, researcher, research laboratory, clinical expert, and disease-specific advocacy group. In addition, each collaborative group must assure that test results are written in a style and format appropriate for nonexpert clinicians; provide educational materials for clinicians and patients about the disease, as well as the use and limitations of the test in the care of persons with the disease; agree to collect clinical data necessary for test result interpretation; and store genotype information and clinical data in a publicly accessible deidentified database. C1 [Faucett, William Andrew] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Hart, Suzanne] NHGRI, NIH, Bethesda, MD 20892 USA. [Pagon, Roberta A.] Univ Washington, Dept Pediat & GeneTests, Seattle, WA 98195 USA. [Neall, Lisa Forman] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Spinella, Giovanna] NIH, Off Rare Dis, Bethesda, MD 20892 USA. RP Faucett, WA (reprint author), Emory Univ, Sch Med, Dept Human Genet, 615 Michael St,Suite 301, Atlanta, GA 30322 USA. EM afaucett@genetics.emory.edu FU Intramural NIH HHS NR 2 TC 13 Z9 14 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD MAY PY 2008 VL 10 IS 5 BP 343 EP 348 DI 10.1097/GIM.0b013e318172837c PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 303VU UT WOS:000256069800008 PM 18496033 ER PT J AU Litkouhi, B Litkouhi, B Fleming, E Welch, WR Berkowitz, RS Birrer, MJ Mok, SC AF Litkouhi, Behrang Litkouhi, Babak Fleming, Evelyn Welch, William R. Berkowitz, Ross S. Birrer, Michael J. Mok, Samuel C. TI Overexpression of CEACAM6 in borderline and invasive mucinous ovarian neoplasms SO GYNECOLOGIC ONCOLOGY LA English DT Article DE mucinous ovarian neoplasms; CEACAM6; gene expression ID PANCREATIC ADENOCARCINOMA CELLS; GENE-EXPRESSION; CANCER; ADHESION; TUMORS; TUMORIGENESIS; DETERMINANT; PROFILE AB Objective. Identifying markers specific for mucinous ovarian neoplasms (MON) is important for cancer diagnosis and surveillance, and will help improve our general understanding of the pathobiology of these tumors. CEACAM6 overexpression appears to be an early molecular event with prognostic significance in gastrointestinal carcinomas. Microarray analysis previously demonstrated high CEACAM6 overexpression in MON's and this study sought to validate this finding. Methods. Western blot compared CEACAM6 expression in normal human ovarian surface epithelium (HOSE) and ovarian cancer cell lines. Quantitative RT-PCR (qRT-PCR) was performed on 75 laser-microdissected HOSE and ovarian cancer tissue samples. Inummohistochemistry (IHC) was performed and slides were analyzed in a semi-quantitative manner. Results. CEACAM6 was expressed in 2 of 3 mucinous cancer cell lines. Expression was absent in all 2 HOSE, 7 serous cancer, and 2 clear cell cancer cell lines. 100-fold CEACAM6 overexpression (qRT-PCR) was demonstrated in 13/16 (81%) borderline, low-grade, and high-grade invasive MON's, compared to 5150 (10%) serous and 1/5 (20%) benign mucinous samples. CEACAM6 expression was not different between borderline and invasive MON's (p = 0.55) or across tumor stage (p = 0.76). CEACAM6 staining was present in 24/28 (86%) borderline, low-grade, and high-grade invasive MON's; 13/28 (46%) exhibited moderate-strong staining. Neither CEACAM6 expression (p=0.36) nor staining intensity (p=0.51) was different between borderline and invasive MON's. None of the serous or benign mucinous tumors exhibited CEACAM6 staining. Conclusions. CEACAM6 is overexpressed in borderline and invasive MON's. (c) 2008 Elsevier Inc. All rights reserved. C1 [Litkouhi, Babak; Fleming, Evelyn; Berkowitz, Ross S.; Mok, Samuel C.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol,Div Gynecol Onc, Boston, MA 02115 USA. [Litkouhi, Behrang] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Litkouhi, Babak; Fleming, Evelyn; Welch, William R.; Berkowitz, Ross S.; Mok, Samuel C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Boston, MA 02115 USA. [Welch, William R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Birrer, Michael J.] NCI, Cell & Canc Biol Branch, NIH, Rockville, MD USA. RP Mok, SC (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol,Div Gynecol Onc, BLI-447,221 Longwood Ave, Boston, MA 02115 USA. EM scmok@rics.bwh.harvard.edu FU Intramural NIH HHS; NCI NIH HHS [R33CA103595, P50CA165009] NR 26 TC 8 Z9 14 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2008 VL 109 IS 2 BP 234 EP 239 DI 10.1016/j.ygyno.2008.01.031 PG 6 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 305VJ UT WOS:000256205600015 PM 18331757 ER PT J AU Konecny, GE Agarwal, R Keeney, GA Winterhoff, B Jones, MB Mariani, A Riehle, D Neuper, C Dowdy, SC Wang, HJ Morin, PJ Podratz, KC AF Konecny, Gottfried E. Agarwal, Rachana Keeney, Gary A. Winterhoff, Boris Jones, Monica Brown Mariani, Andrea Riehle, Darren Neuper, Christina Dowdy, Sean C. Wang, He-Jing Morin, Patrice J. Podratz, Karl C. TI Claudin-3 and claudin-4 expression in serous papillary, clear-cell, and endometrioid endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article DE uterine serous papillary endometrial cancer; claudin-3; claudin-4; endometrial ID CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; RECEPTORS CLAUDIN-3; OVARIAN-CANCER; CARCINOMA; OVEREXPRESSION; PROTEINS; ADHESION; THERAPY; DISEASE; BREAST AB Objective. Tight junction (TJ) proteins claudin-3 and claudin-4 may be differentially expressed in uterine serous papillary carcinoma (USPC), a rare form of endometrial cancer characterized by a particularly poor prognosis. Our aim was to determine the expression pattern and prognostic relevance of claudin-3 and claudin-4 in a large cohort of endometrial cancer patients of diverse histological type and stage. Methods. Claudin-3 and claudin-4 expression was studied in a cohort of 287 patients with endometrial cancer including 137 cases of USPC or clear-cell histology using immunohistochemistry. Patients were completely surgically staged. Outcome data is available on all 287 patients. Results. The rate of claudin-3 and claudin-4 expression was significantly higher in USPC and clear-cell endometrial cancer compared to endometrioid endometrial cancer (claudin-3: 78% and 61% versus 38%, p <.0001; claudin-4: 56% and 44% versus 9%, p <.0001). Furthermore, expression of both TJ proteins was significantly associated with poor clinical outcome (claudin-3, DFS RR 1.70,p=.0087, OS RR 1.62,p=.0247; claudin-4, DFS RR 2.66,p < 0.0001, and OS RR 2.50,p < 0.0001). However, both markers did not maintain prognostic independence in multivariate analyses, as their expression was tightly associated with more advanced disease stages (p <.0001 for both), and higher nuclear grade (p <.0001 for both). Conclusion. These clinical observations confirm the hypothesis based on preclinical evidence that increased expression of claudin-3 and claudin-4 may contribute to the aggressive phenotype of endometrial cancer of serous papillary or clear-cell histology and suggest their potential utility as diagnostic biomarkers and possible targets for therapeutic intervention. (c) 2008 Elsevier Inc. All rights reserved. C1 [Podratz, Karl C.] Mayo Clin, Div Gynecol Surg, Dept Obstet & Gynecol, Rochester, MN 55905 USA. [Agarwal, Rachana] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Keeney, Gary A.; Riehle, Darren] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Wang, He-Jing] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biostat & Biomath, Los Angeles, CA 90095 USA. [Morin, Patrice J.] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Podratz, KC (reprint author), Mayo Clin, Div Gynecol Surg, Dept Obstet & Gynecol, 200 1st St SW, Rochester, MN 55905 USA. EM Podratz.Karl@mayo.edu FU Intramural NIH HHS [Z01 AG000512-10] NR 30 TC 38 Z9 44 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAY PY 2008 VL 109 IS 2 BP 263 EP 269 DI 10.1016/j.ygyno.2008.01.024 PG 7 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 305VJ UT WOS:000256205600019 PM 18313739 ER PT J AU Emanuel, EJ Grady, C AF Emanuel, Ezekiel J. Grady, Christine TI Is longer always better? Commentary SO HASTINGS CENTER REPORT LA English DT Editorial Material C1 [Emanuel, Ezekiel J.; Grady, Christine] NIH, Sect Human Subjects, Bioeth Dept, Ctr Clin, Bethesda, MD 20892 USA. [Emanuel, Ezekiel J.] Stanford Univ, FRESH Thinking Program Hlth Reform, Stanford, CA 94305 USA. RP Emanuel, EJ (reprint author), NIH, Sect Human Subjects, Bioeth Dept, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAY-JUN PY 2008 VL 38 IS 3 BP 10 EP 11 PG 2 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 308HM UT WOS:000256379300012 PM 18584850 ER PT J AU Menikoff, J AF Menikoff, Jerry TI Is longer always better? Commentary SO HASTINGS CENTER REPORT LA English DT Editorial Material C1 NIH, Off Human Subjects Res, Bethesda, MD 20892 USA. RP Menikoff, J (reprint author), NIH, Off Human Subjects Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAY-JUN PY 2008 VL 38 IS 3 BP 11 EP 12 PG 2 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 308HM UT WOS:000256379300013 PM 18581930 ER PT J AU Drozdovitch, V Bouville, A Doyon, F Brindel, P Cardis, E de Vathaire, F AF Drozdovitch, Vladimir Bouville, Andre Doyon, Francoise Brindel, Pauline Cardis, Elisabeth de Vathaire, Florent TI Reconstruction of individual radiation doses for a case-control study of thyroid cancer in french polynesia SO HEALTH PHYSICS LA English DT Article DE atmospheric testing; cancer; dose reconstruction; thyroid ID DOSIMETRY; FALLOUT; TESTS AB Forty-one atmospheric nuclear weapons tests (plus five safety tests) were conducted in French Polynesia between 1966 and 1974. To evaluate the potential role of atmospheric nuclear weapons testing on a high incidence of thyroid cancer observed since 1985 in French Polynesia, a population-based case-control study was performed. The study included 602 subjects, either cases or controls, all aged less than 40 y at the end of nuclear weapons testing in 1974. Radiation doses to the thyroids of the study subjects were assessed based on the available historical results of radiation measurements. These were mainly found in the annual reports on the radiological situation in French Polynesia that had been sent to the UNSCEAR Secretariat. For each atmospheric nuclear weapons test that contributed substantially to the local deposition of radionuclides, the radiation dose to the thyroid from I-131 intake was estimated. In addition, thyroid doses from the intake of short-lived radioiodines (I-132, I-133, I-135) and Te-132, external exposure from gamma-ernitted radionuclides deposited on the ground, and ingestion of long-lived (CS)-C-137 Were reconstructed. The mean thyroid dose among the study subjects was found to be around 3 mGy while the highest dose was estimated to be around 40 mGy. Doses from short-lived iodine and tellurium isotopes ranged up to 10 mGy. Thyroid doses from extemal exposure ranged up to 3 mGy, while those from internal exposure due to cesium ingestion did not exceed I mGy. The dose estimates that have been obtained are based on a rather limited number of radiation measurements performed on a limited number of islands and are highly uncertain. A thorough compilation of the results of all radiation monitoring that was performed in French Polynesia in 1966-1974 would be likely to greatly improve the reliability and the precision of the dose estimates. C1 [Drozdovitch, Vladimir; Bouville, Andre] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Drozdovitch, Vladimir; Cardis, Elisabeth] Int Agcy Res Canc, F-69372 Lyon, France. [Doyon, Francoise; Brindel, Pauline; de Vathaire, Florent] INSERM, Natl Inst Hlth & Med Res, U605, F-94800 Villejuif, France. [Doyon, Francoise; Brindel, Pauline; de Vathaire, Florent] Inst Gustave Roussy, F-94800 Villejuif, France. [Doyon, Francoise; Brindel, Pauline; de Vathaire, Florent] Univ Paris 11, F-94800 Villejuif, France. RP Drozdovitch, V (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-7100, Bethesda, MD 20892 USA. EM drozdovv@mail.nih.gov RI de Vathaire, Florent/L-2983-2016; Cardis, Elisabeth/C-3904-2017 FU Intramural NIH HHS [ZIA CP010132-18] NR 35 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD MAY PY 2008 VL 94 IS 5 BP 418 EP 433 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 288HJ UT WOS:000254976700002 PM 18403963 ER PT J AU Croyle, RT Backinger, CL AF Croyle, Robert T. Backinger, Cathy L. TI Psychosocial processes underlying smoking: Still more to learn - Commentaries SO HEALTH PSYCHOLOGY LA English DT Editorial Material C1 [Croyle, Robert T.; Backinger, Cathy L.] NCI, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, 6130 Executive Blvd,Room 6138, Bethesda, MD 20892 USA. EM croyler@mail.nih.gov NR 18 TC 1 Z9 1 U1 3 U2 8 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0278-6133 J9 HEALTH PSYCHOL JI Health Psychol. PD MAY PY 2008 VL 27 IS 3 SU S BP S185 EP S186 DI 10.1037/a0012916 PG 2 WC Psychology, Clinical; Psychology SC Psychology GA 326OM UT WOS:000257668800001 PM 18979969 ER PT J AU Lifson, AR Belloso, WH Carey, C Davey, RT Duprez, D El-Sadr, WM Gatell, JM Gey, DC Hoy, JF Krum, EA Nelson, R Nixon, DE Paton, N Pedersen, C Perez, G Price, RW Prineas, RJ Rhame, FS Sampson, J Worley, J AF Lifson, Alan R. Belloso, Waldo H. Carey, Cate Davey, Richard T. Duprez, Daniel El-Sadr, Wafaa M. Gatell, Jose M. Gey, Daniela C. Hoy, Jennifer F. Krum, Eric A. Nelson, Ray Nixon, Daniel E. Paton, Nick Pedersen, Court Perez, George Price, Richard W. Prineas, Ronald J. Rhame, Frank S. Sampson, James Worley, John CA INSIGHT Cause Death Writing Grp TI Determination of the underlying cause of death in three multicenter international HIV clinical trials SO HIV CLINICAL TRIALS LA English DT Article DE cause of death; endpoint review committees; clinical trials; HIV; mortality ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; INFARCTION END-POINTS; MYOCARDIAL-INFARCTION; INFECTED INDIVIDUALS; EVENTS COMMITTEE; LUNG-CANCER; BACTERIAL PNEUMONIA; SUICIDAL IDEATION; MORTALITY-RATES AB Purpose: Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials. Method: Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated. Results: Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached. Conclusion: ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths. C1 [Lifson, Alan R.; Duprez, Daniel; Krum, Eric A.; Nelson, Ray] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55454 USA. [Belloso, Waldo H.] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. [Carey, Cate] Univ New S Wales, Sydney, NSW, Australia. [Davey, Richard T.] NIH, Bethesda, MD 20892 USA. [El-Sadr, Wafaa M.] Columbia Univ, New York, NY USA. [Gatell, Jose M.] Univ Barcelona, Barcelona, Spain. [Duprez, Daniel] Univ Copenhagen, Copenhagen, Denmark. [Hoy, Jennifer F.] Alfred Hosp, Melbourne, Vic, Australia. [Hoy, Jennifer F.] Monash Univ, Melbourne, Vic 3004, Australia. [Nixon, Daniel E.] Richmond AIDS Consortium, Richmond, VA USA. [Paton, Nick] MRC, Clin Trials Unit, London, England. [Pedersen, Court] Odense Univ Hosp, DK-5000 Odense, Denmark. [Perez, George] N Jersey Community Res Initiat, Newark, NJ USA. [Price, Richard W.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Prineas, Ronald J.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Rhame, Frank S.] Abbott NW Hosp, Minneapolis, MN 55407 USA. [Sampson, James] Res & Educ Grp, Portland, OR USA. [Worley, John] Pk Nicollet Hlth Serv, St Louis Pk, MN USA. RP Lifson, AR (reprint author), Univ Minnesota, Div Epidemiol, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM lifso001@umn.edu FU Medical Research Council [MC_U122886352]; NIAID NIH HHS [U01 AI068641, U01 AI068641-01, U01 AI46957, U01 AI042170-07, U01 AI042170, U01 AI046362, U01 AI046957, U01 AI046957-05] NR 57 TC 31 Z9 31 U1 0 U2 0 PU THOMAS LAND PUBLISHERS, INC PI ST LOUIS PA 255 JEFFERSON RD, ST LOUIS, MO 63119 USA SN 1528-4336 J9 HIV CLIN TRIALS JI HIV Clin. Trials PD MAY-JUN PY 2008 VL 9 IS 3 BP 177 EP 185 DI 10.1310/hct0903-177 PG 9 WC Infectious Diseases; Pharmacology & Pharmacy SC Infectious Diseases; Pharmacology & Pharmacy GA 311OG UT WOS:000256608900004 PM 18547904 ER PT J AU Eisenhofer, G Siegert, G Kotzerke, J Bornstein, SR Pacak, K AF Eisenhofer, G. Siegert, G. Kotzerke, J. Bornstein, S. R. Pacak, K. TI Current progress and future challenges in the biochemical diagnosis and treatment of pheochromocytomas and paragangliomas SO HORMONE AND METABOLIC RESEARCH LA English DT Review DE pheochromocytorna; paraganglioma; metanephrines; m-iodobenzylguanidine; malignant pheochromocytorna; metastases ID TANDEM MASS-SPECTROMETRY; PLASMA-FREE METANEPHRINE; MALIGNANT PHEOCHROMOCYTOMA; NEUROENDOCRINE TUMORS; METASTATIC PHEOCHROMOCYTOMA; FRACTIONATED METANEPHRINES; NEUROBLASTOMA-CELLS; PROLONGED RETENTION; TRANSPORTER GENE; XENOGRAFT MODEL AB Findings from five independent studies - with close to 350 patients with pheochromocytoma and more than 2 500 in whom the tumor was excluded - indicate that measurements of plasma free metanephrines provide an overall diagnostic sensitivity of 98% and specificity of 92%. The recommendation that initial testing for the tumor should always include measurements of either plasma or urinary fractionated metanephrines results from recognition of the high diagnostic sensitivity of measurements of plasma metanephrines. The few patients with pheochromocytoma in whom the test may not yield a positive result include those with very small tumors or microscopic disease and others with tumors that do not produce norepinephrine and epinephrine. Such patients are typically normotensive and do not exhibit symptoms of catecholamine excess. Additional measurements of methoxytyramine can be useful for detecting those tumors that produce only dopamine. Suboptimal diagnostic specificity and difficulties in distinguishing true- from false-positive elevations of plasma metanephrines remain challenges for diagnosis. Improvements in analytical technology (e.g., liquid chromatography with tandem mass spectrometry) and new strategies for follow-up testing provide possible solutions to these problems. The single most important remaining clinical care challenge is the development of effective cures for patients with malignant disease. Current treatments, none of which are truly satisfactory, include chemotherapy and radiopharmaceutical therapy with I'll-labelled m-iodobenzylguanidine or radioactive somatostatin analogues. Improvements in treatment may in the future come from several fronts, but proof of efficacy ideally will require well-coordinated multicenter prospective trials in larger numbers of patients than in previous studies. C1 [Eisenhofer, G.; Siegert, G.] Univ Hosp Carl Gustav Carus Dresden, Inst Clin Chem & Lab Med, D-01307 Dresden, Germany. [Eisenhofer, G.; Bornstein, S. R.] Univ Hosp Carl Gustav Carus Dresden, Dept Internal Med 3, D-01307 Dresden, Germany. [Kotzerke, J.] Univ Hosp Carl Gustav Carus Dresden, Dept Nucl Med, D-01307 Dresden, Germany. [Pacak, K.] NICHHD, Reprod & Adult Endocrinol Program, NIH, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), Univ Hosp Carl Gustav Carus Dresden, Inst Clin Chem & Lab Med, Fetscherstr 74, D-01307 Dresden, Germany. EM graeme.eisenhofer@uniklinikum-dresden.de FU Intramural NIH HHS [Z01 HD008735-08] NR 73 TC 58 Z9 62 U1 0 U2 5 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2008 VL 40 IS 5 BP 329 EP 337 DI 10.1055/s-2008-1073156 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 310MJ UT WOS:000256533400007 PM 18491252 ER PT J AU Boikos, SA Horvath, A Heyerdahl, S Stein, E Robinson-White, A Bossis, I Bertherat, J Carney, JA Stratakis, CA AF Boikos, S. A. Horvath, A. Heyerdahl, S. Stein, E. Robinson-White, A. Bossis, I. Bertherat, J. Carney, J. A. Stratakis, C. A. TI Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE adrenal tumors; Cushing syndrome; protein kinase A; cyclic AMP; phosphodiesterases ID CARNEY COMPLEX; GENOMIC ORGANIZATION; REGULATORY SUBUNIT; CUSHINGS-SYNDROME; SPLICE VARIANTS; PROTEIN-KINASE; HUMAN TISSUES; PRKAR1A GENE; PDE11A; MUTATIONS AB A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (WAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11 A (PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues. C1 [Stratakis, C. A.] NICHHD, SEGEN, Pediat Endocrinol Training Program, DEB,NIH,Program Dev Endocrionol & Genet, Bethesda, MD 20892 USA. [Bertherat, J.] INSERM, U567, Paris, France. [Bertherat, J.] Hop Cochin, AP HP, Inst Cochin, Dept Endocrinol,Reference Ctr Rare Adrenal Dis, F-75674 Paris, France. [Carney, J. A.] Mayo Clin, Pathol Lab, Rochester, MN USA. RP Stratakis, CA (reprint author), NICHHD, SEGEN, Pediat Endocrinol Training Program, DEB,NIH,Program Dev Endocrionol & Genet, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov OI Stein, Erica/0000-0001-8778-8846 FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [Z01 HD000642, Z01-HD-000642-04] NR 24 TC 21 Z9 22 U1 0 U2 1 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAY PY 2008 VL 40 IS 5 BP 347 EP 353 DI 10.1055/s-2008-1076694 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 310MJ UT WOS:000256533400010 PM 18491255 ER PT J AU Heemskerk, B Liu, K Dudley, ME Johnson, LA Kaiser, A Downey, S Zheng, Z Shelton, TE Matsuda, K Robbins, PF Morgan, RA Rosenberg, SA AF Heemskerk, Bianca Liu, Ke Dudley, Mark. E. Johnson, Laura A. Kaiser, Andrew Downey, Stephanie Zheng, Zhili Shelton, Thomas E. Matsuda, Kant Robbins, Paul F. Morgan, Richard A. Rosenberg, Steven A. TI Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2 SO HUMAN GENE THERAPY LA English DT Article ID CD8(+) T-CELLS; IN-VIVO PERSISTENCE; METASTATIC MELANOMA; CANCER REGRESSION; SECONDARY EXPANSION; EXOGENOUS IL-2; GENE; MEMORY; PROLIFERATION; EFFECTOR AB Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% of patients with metastatic melanoma. In vivo persistence and telomere length of the transferred cells correlate with antitumor response. In an attempt to prolong the in vivo survival of the transferred cells, TILs were genetically engineered to produce interleukin (IL)-2. In vitro, these transduced TILs secreted IL-2 while retaining tumor specificity and exhibited prolonged survival after IL-2 withdrawal. In a phase I/II clinical trial, seven evaluable patients received transduced TILs and one patient experienced a partial response associated with in vivo persistence of IL-2-transduced TILs in circulating lymphocytes. An additional five patients received transduced TILs in conjunction with IL-2 administration. Persistence of IL-2-transduced TILs was observed in three patients, including one partial responder. The transgene DNA as well as vector-derived IL-2 mRNA could be detected for 4 months in responding patients. The low response rate in this trial was possibly due to a reduction in telomere length in cells as a result of prolonged in vitro culture. In this study, insertion of the IL-2 gene into antitumor TILs increased their ability to survive after IL-2 withdrawal in vitro but did not increase their in vivo persistence or clinical effectiveness. C1 [Heemskerk, Bianca; Liu, Ke; Dudley, Mark. E.; Johnson, Laura A.; Kaiser, Andrew; Downey, Stephanie; Zheng, Zhili; Shelton, Thomas E.; Robbins, Paul F.; Morgan, Richard A.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Liu, Ke] US FDA, Rockville, MD 20852 USA. [Matsuda, Kant] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, CRC 3W-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM sar@mail.nih.gov RI Kaiser, Andrew/C-2617-2012; Heemskerk, Bianca/C-4635-2012; Johnson, Laura/H-4861-2013; OI Liu, Kebin/0000-0003-1965-7240 FU Intramural NIH HHS [Z01 SC003811-33] NR 33 TC 65 Z9 66 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD MAY PY 2008 VL 19 IS 5 BP 496 EP 510 DI 10.1089/hum.2007.0171 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 308ZW UT WOS:000256430500009 PM 18444786 ER PT J AU Cook, MB Graubard, BI Quraishi, SM Yeager, M Chanock, SJ Crenshaw, A Erickson, RL Rubertone, MV Thomas, G McGlynn, KA AF Cook, Michael B. Graubard, Barry I. Quraishi, Sabah M. Yeager, Meredith Chanock, Stephen J. Crenshaw, Andrew Erickson, Ralph L. Rubertone, Mark V. Thomas, Gilles McGlynn, Katherine A. TI Genetic variants in the 8q24 locus and risk of testicular germ cell tumors SO HUMAN GENETICS LA English DT Article ID PROSTATE-CANCER RISK; GENOME-WIDE ASSOCIATION; ANDROGEN RECEPTOR GENE; COLORECTAL-CANCER; CHROMOSOME 8Q24; BREAST-CANCER; FAMILIAL AGGREGATION; SUSCEPTIBILITY LOCI; LOCALIZATION; CONFIRMATION AB Much evidence supports the premise that population genetic variation contributes significantly to the risk of testicular germ-cell tumor (TGCT). However, investigations of the association between genomic markers and TGCT susceptibility are scarce. Single nucleotide polymorphisms (SNPs) at the locus 8q24 have recently been found to be associated with prostate, colorectal and breast cancer. The US Servicemen's testicular tumor environmental and endocrine determinants (STEED) study was used to investigate the association of 15 specific 8q24 SNPs with TGCT and its two main histologic groups of seminoma and nonseminoma. Conditional and unconditional logistic regression models, adjusted for the matching variables of year of birth, race/ethnicity and serum date, were utilized to produce odds ratios (OR) and 95% confidence intervals (95%CI). The analysis included 680 controls and 568 TGCT cases. In the TGCT analysis, no SNP was associated with risk in both heterozygotes and variant homozygotes. When stratified by histology the seminoma analysis also showed no association with the 8q24 SNPs. Conversely, the analysis of nonseminomas had three tentative associations (rs6470494, OR(genotype AG) = 1.15, 95%CI: 0.86-1.54; OR(genotype GG) = 1.68, 95%CI: 1.04-2.73; p for trend = 0.04) (rs13254738, OR(genotype GT) = 1.04, 95%CI: 0.77-1.40; OR(genotype TT) = 1.62, 95%CI: 1.06-2.49; p for trend = 0.07) (rs10505476, OR(genotype CT) = 0.67, 95%CI: 0.50, 0.91; OR(genotype TT) = 0.81, 95%CI: 0.47-1.39; p for trend = 0.04). There was no linkage disequilibrium between any of the 8q24 SNPs analyzed in this population. In conclusion, this study has found little evidence for an association between the reported 8q24 SNPs and TGCTs, although the findings for nonseminoma may be worth further investigation. C1 [Cook, Michael B.; Graubard, Barry I.; Quraishi, Sabah M.; Yeager, Meredith; Chanock, Stephen J.; Crenshaw, Andrew; Thomas, Gilles; McGlynn, Katherine A.] NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Yeager, Meredith; Crenshaw, Andrew] NCI, SAIC Frederick Inc, Adv Technol Program, Core Genotyping Facil, Frederick, MD 21702 USA. [Erickson, Ralph L.] Walter Reed Army Inst Res, Global Emerging Infect Syst, Silver Spring, MD 20910 USA. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Washington, DC 20307 USA. RP Cook, MB (reprint author), NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural NIH HHS [Z99 CA999999] NR 55 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAY PY 2008 VL 123 IS 4 BP 409 EP 418 DI 10.1007/s00439-008-0491-y PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 288AW UT WOS:000254959600009 PM 18373104 ER PT J AU Hruska, KS LaMarca, ME Scott, CR Sidransky, E AF Hruska, Kathleen S. LaMarca, Mary E. Scott, C. Ronald Sidransky, Ellen TI Gaucher disease: Mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA) SO HUMAN MUTATION LA English DT Review DE gaucher disease; GBA; glucocerebrosidase; genotype-phenotype; recombinant alleles; comparative genomics; genetic modifiers ID ACID-BETA-GLUCOSIDASE; PYRUVATE-KINASE PKLR; GRADIENT GEL-ELECTROPHORESIS; LYSOSOMAL STORAGE DISORDERS; NON-JEWISH PATIENTS; X-RAY-STRUCTURE; MUTANT ALLELES; HETEROLOGOUS EXPRESSION; JAPANESE PATIENTS; GENOTYPE/PHENOTYPE CORRELATIONS AB Gaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase. C1 [Hruska, Kathleen S.; LaMarca, Mary E.; Sidransky, Ellen] NHGRI, Sect Mol Neurogenet, Med Genet Branch, Bethesda, MD 20892 USA. [Scott, C. Ronald] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, Bldg 35,Room 1A-213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov NR 182 TC 203 Z9 214 U1 5 U2 23 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2008 VL 29 IS 5 BP 567 EP 583 DI 10.1002/humu.20676 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 294DZ UT WOS:000255385800001 PM 18338393 ER PT J AU Tarazona-Santos, E Bernig, T Burdett, L Magalhaes, WCS Fabbri, C Liao, J Redondo, RAF Welch, R Yeager, M Chanock, SJ AF Tarazona-Santos, Eduardo Bernig, Toralf Burdett, Laurie Magalhaes, Wagner C. S. Fabbri, Cristina Liao, Jason Redondo, Rodrigo A. F. Welch, Robert Yeager, Meredith Chanock, Stephen J. TI CYBB, an NADPH-Oxidase gene: Restricted diversity in humans and evidence for differential long-term purifying selection on transmembrane and cytosollic domains SO HUMAN MUTATION LA English DT Article DE population genetics; haplotypes; respiratory burst; tag-SNPs; linkage disequilibrium; innate immunity; CYBB ID CHRONIC GRANULOMATOUS-DISEASE; DNA-SEQUENCE VARIATION; CELL-LINE PANEL; LINKAGE DISEQUILIBRIUM; X-CHROMOSOME; HUMAN GENOME; HAPLOTYPE STRUCTURE; MAXIMUM-LIKELIHOOD; POLYMORPHISM; PATTERNS AB CYBB encodes the gp91-phox protein of the phagocytic NADPH oxidase; the innate immunity-related enzymatic complex responsible for the respiratory burst. Mutations in CYBB can cause chronic granulomatous disease (CGD), a primary immunodeficiency characterized by ineffective microbicidal activity, for which over 150 family-specific mutations have been described. It is also plausible that common SNPs in CYBB alter the expression or function of gp91-phox, determining differences in susceptibility to complex disorders such as autoimmune or infectious diseases. We have resequenced the exons, UTRs, and intronic regions of CYBB in 102 ethnically diverse individuals and genotyped nine tag-SNPs in 942 individuals from 52 worldwide populations. The 28 observed SNPs (none of which nonsynonymous) reside on 28 haplotypes that can be collapsed into five clades. CYBB shows lower diversity than other X-chromosome genes and most of the between-population genetic variance was observed among Africans and non-Africans. The African population shows the highest diversity and the lowest linkage disequilibrium (LD). Because there is extensive shared LD among non,Africans, tag-SNPs can be effectively employed in gene,centric association studies and are portable across Eurasian and Native American populations. Comparison of CYBB coding sequences among mammals evidences the action of long-term purifying selection, which is stronger on the C-terminal cytosolic domain than on the N-terminal transmembrane domain of gp91-phox. C1 [Tarazona-Santos, Eduardo; Bernig, Toralf; Liao, Jason; Chanock, Stephen J.] NCI, Sect Genom Variat, Pediat Oncol Branch, NIH, Gaithersburg, MD USA. [Tarazona-Santos, Eduardo; Magalhaes, Wagner C. S.; Redondo, Rodrigo A. F.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, Belo Horizonte, MG, Brazil. NCI, Intramural Res Support Program, SAIC Frederick, Frederick, MD USA. NCI, Core Genotype Fac, NIH, Gaithersburg, MD USA. [Fabbri, Cristina] Univ Bologna, Dipartimento Biol Evoluzionist & Sperimentale, Area Antropol, Bologna, Italy. RP Chanock, SJ (reprint author), NCI, Adv Technol Ctr, Pediat Oncol Branch, 8717 Grovemont Circle, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov RI Magalhaes, Wagner/D-8822-2015 FU Intramural NIH HHS NR 54 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2008 VL 29 IS 5 BP 623 EP 632 DI 10.1002/humu.20667 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 294DZ UT WOS:000255385800007 PM 18278805 ER PT J AU Greene, EL Horvath, AD Nesterova, M Giatzakis, C Bossis, I Stratakis, CA AF Greene, Elizabeth L. Horvath, Anelia D. Nesterova, Maria Giatzakis, Christoforos Bossis, Ioannis Stratakis, Constantine A. TI In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay SO HUMAN MUTATION LA English DT Article DE PRKAR1A; Carney complex; mutations; functional studies; PKA; cAMP; expressed mutations ID DEPENDENT PROTEIN-KINASE; FAMILIAL CARDIAC MYXOMAS; CARNEY-COMPLEX; REGULATORY SUBUNIT; ENDOCRINE OVERACTIVITY; SPOTTY PIGMENTATION; CAMP; GENE; SCHWANNOMAS; HOLOENZYME AB Patients presenting with primary pigmented nodular adrenocortical disease (PPNAD), Carney complex (CNC), or sporadic tumors were previously found to carry germline mutations in the human type lot regulatory subunit (RI alpha) of adenosine 3',5'-cyclic monophosphate (cyclic AMP [cAMP])-dependent protein kinase (PKA; PRKAR1A). Although about 90% of disease,causing PRKAR1A mutations lead to premature stop codon generation and subsequent degradation of the mutant message by nonsense-mediated mRNA decay (NMD), here we describe seven PRKAR1A mutations whose mRNAs do not seem to undergo NMD and instead result in an expressed mutant RI alpha protein. The expressed mutations (p.Ser9Asn, p.Glu60(-)Lys116del [Delta-exon 3], p.Arg74Cys, p.Arg146Ser, p.Asp183Tyr, p.Ala213Asp, and p.Gly289Trp) were spread over all the functional RIa domains, and all of them exhibited increased PKA activity, which we attribute to decreased binding to cAMP and/or the catalytic subunit. Our data further corroborate the previous finding that altered PRKAR1A function, not only haploinsufficiency, is enough to elevate PYA activity which is apparently associated with tumorigenesis in tissues affected by CNC. In some cases, as with the Delta-exon 3 mutation, we may even conclude that the presence of a mutant PRKAR1A protein may be more harmful than allelic loss. C1 [Greene, Elizabeth L.; Horvath, Anelia D.; Nesterova, Maria; Giatzakis, Christoforos; Bossis, Ioannis; Stratakis, Constantine A.] NICHD, SEGEN, DEB, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, SEGEN, DEB, NIH, 10 Ctr Dr,Bldg 10-CRC,Room 1E-3330,MSC 1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS NR 19 TC 35 Z9 37 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2008 VL 29 IS 5 BP 633 EP 639 DI 10.1002/humu.20688 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 294DZ UT WOS:000255385800008 PM 18241045 ER PT J AU Welch, RA Lazaruk, K Haque, KA Hyland, F Xiao, NQ Wronka, L Burdett, L Chanock, SJ Ingber, D De La Vega, FM Yeager, M AF Welch, Robert A. Lazaruk, Katherine Haque, Kashif A. Hyland, Fiona Xiao, Nianqing Wronka, Loni Burdett, Laura Chanock, Stephen J. Ingber, Daniel De La Vega, Francisco M. Yeager, Meredith TI Validation of the performance of a comprehensive genotyping assay panel of single nucleotide polymorphisms in drug metabolism enzyme genes SO HUMAN MUTATION LA English DT Article DE genetic variation; assay validation; drug metabolizing enzyme; DME; multiethnic control samples ID HUMAN GENOME; PHASE-I; ASSOCIATION; SEQUENCE AB A class of genes, known as drug metabolism enzymes (DMEs) are responsible for the metabolism and transport of drugs and other xenobiotics. Variation in DME genes most likely accounts for a proportion of the variability in drug response in humans, and may contribute to complex diseases such as cancer (Nebert DW, Dieter MZ. Pharmacology 2000;61:124-135). To date, assessing the extent of this variation has proven difficult, especially because of sequence paralogy issues that cause difficulty when attempting to genotype polymorphisms in very closely-related gene families (Murphy ME Pharmacogenomics 2000;1:115-123; Ingelman-Sundberg M. Drug Metab Rev 1999;31:449-459). We have developed and genotyped a panel of N = 2,325 individual TaqMan (R) genotyping assays for polymorphisms in > 200 DME genes; many of the variants in the panel are single nucleotide polymorphisms (SNPs) that are of known or putative function (e.g., missense, nonsense or frameshift). Using these assays, we have examined genetic variation among several groups of populations, including: 1) the two SNP500 Cancer population panels (http://snp500cancer.nci.nih.gov; last accessed: 11 December 2007); and 2) the panel used in the International HapMap Project panel (www.hapmap.org; last accessed: 11 December 2007). We have developed a comprehensive validation strategy to ensure reproducibility and accuracy of the assays and estimated minor allele frequencies. Here, we present the results of these analyses, which strongly suggest that this panel of DME assays are of extremely high quality and produce robust, accurate, and reproducible results. C1 [Welch, Robert A.; Haque, Kashif A.; Xiao, Nianqing; Wronka, Loni; Burdett, Laura; Chanock, Stephen J.; Yeager, Meredith] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Gaithersburg, MD 20877 USA. [Welch, Robert A.; Haque, Kashif A.; Xiao, Nianqing; Wronka, Loni; Burdett, Laura; Yeager, Meredith] NCI, SAIC, Adv Technol Program, Frederick, MD USA. [Hyland, Fiona; Ingber, Daniel; De La Vega, Francisco M.] Appl Biosyst Inc, Foster City, CA 94404 USA. [Chanock, Stephen J.] NCI, Sect Genom Variat, Pediat Oncol Branch,DHHS, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Yeager, M (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM yeagerm@mail.nih.gov RI De La Vega, Francisco/H-3832-2011 FU NCI NIH HHS [N01-CO-12400] NR 10 TC 3 Z9 3 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD MAY PY 2008 VL 29 IS 5 BP 750 EP 756 DI 10.1002/humu.20703 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 294DZ UT WOS:000255385800021 PM 18327779 ER PT J AU Ruopp, MD Whitcomb, BW Schisterman, EF AF Ruopp, Marcus D. Whitcomb, Brain W. Schisterman, Enrique F. TI Is it time for meta-analysis? SO HUMAN REPRODUCTION UPDATE LA English DT Letter C1 [Ruopp, Marcus D.; Whitcomb, Brain W.; Schisterman, Enrique F.] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Rockville, MD 20852 USA. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, 6100 Execut Blvd, Rockville, MD 20852 USA. EM schistee@mail.nih.gov NR 4 TC 3 Z9 3 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1355-4786 J9 HUM REPROD UPDATE JI Hum. Reprod. Update PD MAY-JUN PY 2008 VL 14 IS 3 BP 289 EP 289 DI 10.1093/humupd/dmm044 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 290VS UT WOS:000255151400008 PM 18258788 ER PT J AU Pandana, H Aschenbach, KH Lenski, DR Fuhrer, MS Khan, J Gomez, RD AF Pandana, Herman Aschenbach, Konrad H. Lenski, Daniel R. Fuhrer, Michael S. Khan, Javed Gomez, Rome D. TI A versatile biomolecular charge-based sensor using oxide-gated carbon nanotube transistor arrays SO IEEE SENSORS JOURNAL LA English DT Article DE biosensor; carbon nanotube; label-free deoxyribonucleic acid (DNA) detection; transistor ID FIELD-EFFECT TRANSISTORS; DNA; HYBRIDIZATION; MOLECULES AB Label-free deoxyribonucleic acid (DNA) hybridization detection using carbon nanotube transistor (CNT) arrays is demonstrated. The present scheme is distinguished from other CNT sensing methods as it uses a gate oxide overlayer on top of the carbon nanotubes, which function solely as charge sensors but are not participants in the chemical binding process. Because it involves DNA probe attachment on the gate oxide rather than on the CNT, this approach allows the use of conventional DNA functionalization and bioassay protocols, and is less prone to false positives. The signal sought is a few tens of millivolts in threshold voltage shift due to the increase of surface charges after target hybridization. The hybridization detection is shown to be highly specific and sensitive to a minimum concentration of about 30 nM of 61-mer DNA. Despite differences in the transistor properties due to the spread in the CNT parameters during fabrication, the yields are very high and the sensing characteristics are uniformly consistent in nearly all transistors. C1 [Pandana, Herman; Aschenbach, Konrad H.; Gomez, Rome D.] Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. Univ Maryland, Dept Phys, College Pk, MD 20742 USA. Univ Maryland, Ctr Nanophys & Adv Mat, College Pk, MD 20742 USA. [Khan, Javed] Natl Canc Inst, Pediat Oncol Branch, Natl Inst Hlth, Gaithersburg, MD 20877 USA. RP Pandana, H (reprint author), Univ Maryland, Dept Elect & Comp Engn, College Pk, MD 20742 USA. EM hpandana@glue.umd.edu; konrad@umd.edu; lenski@umd.edu; mfuhrer@umd.edu; khanjav@mail.nih.gov; rdgomez@ece.umd.edu RI Fuhrer, Michael/E-7634-2010 OI Fuhrer, Michael/0000-0001-6183-2773 FU National Institute of Health [0701097058]; Laboratory for Physical Sciences [H98230-04-C-0470] FX Manuscript received August 3, 2007; revised October 26, 2007; accepted January 15, 2008. This work was supported in part by the National Institute of Health under SAIC Grant 0701097058, and in part by the Laboratory for Physical Sciences under Grant H98230-04-C-0470. The associate editor coordinating the review of this paper and approving it for publication was Dr. James Jensen. NR 15 TC 5 Z9 5 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 1530-437X J9 IEEE SENS J JI IEEE Sens. J. PD MAY-JUN PY 2008 VL 8 IS 5-6 BP 655 EP 660 DI 10.1109/JSEN.2008.922724 PG 6 WC Engineering, Electrical & Electronic; Instruments & Instrumentation; Physics, Applied SC Engineering; Instruments & Instrumentation; Physics GA 342CW UT WOS:000258763200033 ER PT J AU Shah, VP Younan, NH King, RL AF Shah, Vijay P. Younan, Nicolas H. King, Roger L. TI An efficient pan-sharpening method via a combined adaptive PCA approach and contourlets SO IEEE TRANSACTIONS ON GEOSCIENCE AND REMOTE SENSING LA English DT Article DE contourlets; image fusion; pan-sharpening; principal component analysis (PCA); wavelets ID SPECTRAL RESOLUTION IMAGES; WAVELET TRANSFORM; FUSION; DECOMPOSITION; ALGORITHMS AB High correlation among the neighboring pixels both spatially and spectrally in a multispectral image makes it necessary to use an efficient data transformation approach before performing pan-sharpening. Wavelets and principal component analysis (PCA) methods have been a popular choice for spatial and spectral transformations, respectively. Current PCA-based pan-sharpening methods make an assumption that the first principal component (PC) of high variance is an ideal choice for replacing or injecting it with high spatial details from the high-resolution histogram-matched panchromatic (PAN) image. This paper presents a combined adaptive PCA-contourlet approach for pan-sharpening, where the adaptive PCA is used to reduce the spectral distortion and the use of nonsubsampled contourlets for spatial transformation in pan-sharpening is incorporated to overcome the limitation of the wavelets in representing the directional information efficiently and capturing intrinsic geometrical structures of the objects. The efficiency of the presented method is tested by performing pan-sharpening of the high-resolution (IKONOS and QuickBird) and the medium-resolution (Landsat-7 Enhanced Thematic Mapper Plus) datasets. The evaluation of the pan-sharpened images using global validation indexes reveal that the adaptive PCA approach helps reducing the spectral distortion, and its merger with contourlets provides better fusion results. C1 [Shah, Vijay P.; Younan, Nicolas H.; King, Roger L.] Mississippi State Univ, Dept Elect & Comp Engn, Mississippi State, MS 39762 USA. [Shah, Vijay P.; Younan, Nicolas H.; King, Roger L.] Mississippi State Univ, GeoResources Inst, Mississippi State, MS 39762 USA. RP Shah, VP (reprint author), SAIC Frederick Inc, NCI, NIH, Bethesda, MD 20814 USA. EM vijaypshah@yahoo.com; younan@ece.msstate.edu; rking@engr.msstate.edu RI Shah, Vijay/D-4083-2014 OI Shah, Vijay/0000-0003-3856-156X NR 35 TC 147 Z9 161 U1 3 U2 18 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0196-2892 J9 IEEE T GEOSCI REMOTE JI IEEE Trans. Geosci. Remote Sensing PD MAY PY 2008 VL 46 IS 5 BP 1323 EP 1335 DI 10.1109/TGRS.2008.916211 PG 13 WC Geochemistry & Geophysics; Engineering, Electrical & Electronic; Remote Sensing; Imaging Science & Photographic Technology SC Geochemistry & Geophysics; Engineering; Remote Sensing; Imaging Science & Photographic Technology GA 291UQ UT WOS:000255222800005 ER PT J AU McCullough, DP Gudla, PR Harris, BS Collins, JA Meaburn, KJ Nakaya, MA Yamaguchi, TP Misteli, T Lockett, SJ AF McCullough, Dean P. Gudla, Prabhakar R. Harris, Bradley S. Collins, Jason A. Meaburn, Karen J. Nakaya, Masa-Aki Yamaguchi, Terry P. Misteli, Tom Lockett, Stephen J. TI Segmentation of whole cells and cell nuclei from 3-D optical microscope images using dynamic programming SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE confocal microscopy; dynamic programming; segmentation; three-dimensional image analysis ID 3-DIMENSIONAL SEGMENTATION; ACTIVE CONTOURS; TISSUE-SECTIONS; MODEL; VALIDATION; SURFACES; TRACKING AB Communications between cells in large part drive tissue development and function, as well as disease-related processes such as tumorigenesis. Understanding the mechanistic bases of these processes necessitates quantifying specific molecules in adjacent cells or cell nuclei of intact tissue. However, a major restriction on such analyses is the lack of an efficient method that correctly segments each object (cell or nucleus) from 3-D images of an intact tissue specimen. We report a highly reliable and accurate semi-automatic algorithmic method for segmenting fluorescence-labeled cells or nuclei from 3-D tissue images. Segmentation begins with semi-automatic, 2-D object delineation in a user-selected plane, using dynamic programming (DP) to locate the border with an accumulated intensity per unit length greater that any other possible border around the same object. Then the two surfaces of the object in planes above and below the selected plane are found using an algorithm that combines DP and combinatorial searching. Following segmentation, any perceived errors can be interactively corrected. Segmentation accuracy is not significantly affected by intermittent labeling of object surfaces, diffuse surfaces, or spurious signals away from surfaces. The unique strength of the segmentation method was demonstrated on a variety of biological tissue samples where all cells, including irregularly shaped cells, were accurately segmented based on visual inspection. C1 [Gudla, Prabhakar R.; Harris, Bradley S.; Collins, Jason A.; Lockett, Stephen J.] NCI, SAIC Frederick, Image Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. [McCullough, Dean P.] High Performance Technol Inc, Reston, VA 20190 USA. [Meaburn, Karen J.; Misteli, Tom] NCI, Cell Biol & Genomes Grp, Bethesda, MD 20892 USA. [Nakaya, Masa-Aki; Yamaguchi, Terry P.] NCI, Canc & Dev Bio Lab, Frederick, MD 21702 USA. RP Lockett, SJ (reprint author), NCI, SAIC Frederick, Image Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. EM dmccullough@hpti.com; reddyg@ncifcrf.gov; bharris@zeiss.com; jas.a.collins@verizon.net; meaburnk@mail.nih.gov; mnakaya@basic.m.kanazawa-u.ac.jp; tyamaguchi@ncifcrf.gov; mistelit@mail.nih.gov; slockett@ncifcrf.gov OI Meaburn, Karen/0000-0002-1327-5957 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 38 TC 35 Z9 35 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD MAY PY 2008 VL 27 IS 5 BP 723 EP 734 DI 10.1109/TMI.2007.913135 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 294VD UT WOS:000255433500013 PM 18450544 ER PT J AU Teng, G Hakimpour, P Landgraf, P Rice, A Tuschl, T Casellas, R Papavasiliou, FN AF Teng, Grace Hakimpour, Paul Landgraf, Pablo Rice, Amanda Tuschl, Thomas Casellas, Rafael Papavasiliou, F. Nina TI MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase SO IMMUNITY LA English DT Article ID MATURE B-CELLS; SOMATIC HYPERMUTATION; GENE-EXPRESSION; ANTIBODY DIVERSIFICATION; AID; PHOSPHORYLATION; TARGETS; RNA; LYMPHOMAS; MIR-150 AB B lymphocytes perform somatic hypermutation and class-switch recombination (CSR) of the immunoglobulin locus to generate an antibody repertoire diverse in both affinity and function. These somatic diversification processes are catalyzed by activation-induced cytidine deaminase (AID), a potent DNA mutator whose expression and function are highly regulated. Here we show that AID was regulated post-transcriptionally by a lymphocyte-specific microRNA, miR-155. We found that miR-155 was upregulated in murine B lymphocytes undergoing CSR and that it targeted a conserved site in the 3'-untranslated region of the mRNA encoding AID. Disruption of this target site in vivo resulted in quantitative and temporal deregulation of AID expression, along with functional consequences for CSR and affinity maturation. Thus, miR-155, which has recently been shown to play important roles in regulating the germinal-center reaction, does so in part by directly downmodulating AID expression. C1 [Teng, Grace; Hakimpour, Paul; Papavasiliou, F. Nina] Rockefeller Univ, Lab Lymphocyte Biol, New York, NY 10065 USA. [Landgraf, Pablo; Rice, Amanda; Tuschl, Thomas] Rockefeller Univ, Howard Hughes Med Inst, Lab RNA Mol Biol, New York, NY 10065 USA. [Casellas, Rafael] NIAMS, Genom Integr & Immun, NIH, Bethesda, MD 20892 USA. RP Papavasiliou, FN (reprint author), Rockefeller Univ, Lab Lymphocyte Biol, 1230 York Ave, New York, NY 10065 USA. EM papavasiliou@rockefeller.edu FU Intramural NIH HHS [Z01 AR041149-03]; NCI NIH HHS [R01 CA098495, CA098495, R01 CA098495-05]; NIGMS NIH HHS [GM066699] NR 42 TC 258 Z9 273 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAY PY 2008 VL 28 IS 5 BP 621 EP 629 DI 10.1016/j.immuni.2008.03.015 PG 9 WC Immunology SC Immunology GA 302XS UT WOS:000256003900009 PM 18450484 ER PT J AU Freeman, AF Holland, SM AF Freeman, Alexandra F. Holland, Steven M. TI The hyper-IgE syndromes SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article ID HYPERIMMUNOGLOBULIN-E SYNDROME; INFECTION JOBS SYNDROME; IMMUNOGLOBULIN-E SYNDROME; RECURRENT INFECTIONS; INTERFERON-GAMMA; BONE-RESORPTION; INNATE IMMUNITY; CROHNS-DISEASE; CYTOKINE; PATIENT AB The hyper IgE syndromes (HIES) are rare primary immune deficiencies characterized by elevated serum IgE, rash, and recurrent bacterial infections of the skin and lung. Autosomal dominant HIES, the most common disease in this group, results from STAT3 mutations and has a variety of connective tissue and skeletal abnormalities. The genetic etiologies of the more rare autosomal recessive forms still need delineation. Treatment of these syndromes has relied on prophylactic and therapeutic antimicrobial agents and aggressive skin care. The new and evolving genetic and immunologic understandings of this previously elusive set of diseases should lead to more effective disease-specific therapies. C1 [Freeman, Alexandra F.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, Bldg 10,CRC B3-4141,MSC 1684,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural NIH HHS [Z01 AI000647-16, Z99 AI999999]; NCI NIH HHS [N01-CO12400] NR 49 TC 66 Z9 72 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD MAY PY 2008 VL 28 IS 2 BP 277 EP + DI 10.1016/j.iac.2008.01.005 PG 16 WC Allergy; Immunology SC Allergy; Immunology GA 305KC UT WOS:000256176300005 PM 18424333 ER PT J AU Su, HC Lenardo, MJ AF Su, Helen C. Lenardo, Michael J. TI Genetic defects of apoptosis and primary immunodeficiency SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article ID AUTOIMMUNE-LYMPHOPROLIFERATIVE-SYNDROME; NF-KAPPA-B; ABNORMAL LYMPHOCYTE APOPTOSIS; BONE-MARROW-TRANSPLANTATION; DENDRITIC CELL APOPTOSIS; CD4(-)CD8(-) T-CELLS; SYNDROME ALPS; FAS MUTATIONS; MYCOPHENOLATE-MOFETIL; DOMINANT EXPRESSION AB Programmed cell death is important for maintaining lymphocyte homeostasis. Several human-inherited diseases with impaired apoptosis have been identified at the genetic level: autoimmune lymphoproliferative syndrome, caspase-8 deficiency state, and X-linked lymphoproliferative syndrome. These diseases feature excess lymphocyte accumulation, autoimmunity, or immunodeficiency. Elucidating their molecular pathogenesis has also provided new insights into the signaling mechanisms regulating apoptosis and lymphocyte activation. C1 [Su, Helen C.] NIAID, Human Immunol Dis Unit, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Lenardo, Michael J.] NIAID, Mol Dev Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Su, HC (reprint author), NIAID, Human Immunol Dis Unit, Host Def Lab, NIH, Bldg 10 CRC,Room 5W-3932,10 Ctr Dr,MSC 1456, Bethesda, MD 20892 USA. EM hsu@niaid.nih.gov RI Su, Helen/H-9541-2015 OI Su, Helen/0000-0002-5582-9110 FU Intramural NIH HHS [Z99 AI999999] NR 92 TC 14 Z9 14 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD MAY PY 2008 VL 28 IS 2 BP 329 EP + DI 10.1016/j.iae.2008.01.002 PG 24 WC Allergy; Immunology SC Allergy; Immunology GA 305KC UT WOS:000256176300008 PM 18424336 ER PT J AU Stewart, PE Bestor, A Cullen, JN Rosa, PA AF Stewart, Philip E. Bestor, Aaron Cullen, Jonah N. Rosa, Patricia A. TI A tightly regulated surface protein of Borrelia burgdorferi is not essential to the mouse-tick infectious cycle SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; MAMMALIAN HOST; GENE-EXPRESSION; FACTOR-H; EXTRACHROMOSOMAL DNAS; CIRCULAR PLASMID; IXODES-DAMMINI; LIFE-CYCLE; VLSE LOCUS; LUXS GENE AB Borrelia burgdorferi synthesizes a variety of differentially regulated outer surface lipoproteins in the tick vector and in vertebrate hosts. Among these is OspD, a protein that is highly induced in vitro by conditions that mimic the tick environment. Using genetically engineered strains in which ospD is deleted, we demonstrate that this protein is not required for B. burgdorferi survival and infectivity in either the mouse or the tick. However, examination of both transcript levels and protein expression indicates that OspD expression is limited to a discrete window of time during B. burgdorferi replication within the tick. This time frame corresponds to tick detachment from the host following feeding, and expression of OspD continues during tick digestion of the blood meal but is low or undetectable after the tick has molted. The high level of OspD production correlates to the highest cell densities that B. burgdorferi is known to reach in vivo. Although OspD is nonessential to the infectious cycle of B. burgdorferi, the tight regulation of expression suggests a beneficial contribution of OspD to the spirochete during bacterial replication within the tick midgut. C1 [Stewart, Philip E.; Bestor, Aaron; Cullen, Jonah N.; Rosa, Patricia A.] NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. RP Stewart, PE (reprint author), NIAID, Rocky Mt Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov FU Intramural NIH HHS NR 62 TC 33 Z9 33 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2008 VL 76 IS 5 BP 1970 EP 1978 DI 10.1128/IAI.00714-07 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 292LJ UT WOS:000255267200018 PM 18332210 ER PT J AU Zhang, P Skurnik, M Zhang, SS Schwartz, O Kalyanasundaram, R Bulgheresi, S He, JJ Klena, JD Hinnebusch, BJ Chen, T AF Zhang, Pei Skurnik, Mikael Zhang, Shu-Sheng Schwartz, Olivier Kalyanasundaram, Ramaswarny Bulgheresi, Silvia He, Johnny J. Klena, John D. Hinnebusch, B. Joseph Chen, Tie TI Human dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin (CD209) is a receptor for Yersinia pestis that promotes phagocytosis by dendritic cells SO INFECTION AND IMMUNITY LA English DT Article ID LIPOPOLYSACCHARIDE O-ANTIGEN; GONOCOCCAL OPACITY PROTEINS; ESCHERICHIA-COLI K-12; DC-SIGN CD209; NEISSERIA-GONORRHOEAE; CORE LIPOPOLYSACCHARIDE; PLASMINOGEN-ACTIVATOR; ENTERIC BACTERIA; EPITHELIAL-CELLS; BLOOD MONOCYTES AB Yersinia pestis is the etiologic agent of bubonic and pneumonic plagues. It is speculated that K pestis hijacks antigen-presenting cells (APCs), such as dendritic cells (DCs) and alveolar macrophages, in order to be delivered to lymph nodes. However, how APCs initially capture the bacterium remains uncharacterized. It is well known that HIV-1 uses human DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) (CD209) receptor, expressed by APCs, to be captured and delivered to target cell, such as CD4+ lymphocytes. Several gram-negative bacteria utilize their core lipopolysaccharides (LPS) as ligands to interact with the human DC-SIGN. Therefore, it is possible that Y. pestis, whose core LPS is naturally exposed, might exploit DC-SIGN to invade APCs. We demonstrate in this study that Y. pestis directly interacts with DC-SIGN and invades both DCs and alveolar macrophages. In contrast, when engineered to cover the core LPS, Y. pestis loses its ability to invade DCs, alveolar macrophages, and DC-SIGN-expressing transfectants. The interaction between Y. pestis and human DCs can be reduced by a combination treatment with anti-CD209 and anti-CD207 antibodies. This study shows that human DC-SIGN is a receptor for Y. pestis that promotes phagocytosis by DCs in vitro. C1 [Zhang, Pei; Zhang, Shu-Sheng; Kalyanasundaram, Ramaswarny; Chen, Tie] Univ Illinois, Coll Med, Dept Biomed Sci, Rockford, IL 61107 USA. [Skurnik, Mikael] Univ Helsinki, Haartman Inst, Dept Bacteriol & Immunol, FIN-00014 Helsinki, Finland. [Skurnik, Mikael] Univ Helsinki, Cent Hosp, Diagnost Lab, FIN-00014 Helsinki, Finland. [Schwartz, Olivier] Inst Pasteur, Dept Virol, Virus & Immun Grp, Paris, France. [Bulgheresi, Silvia] Univ Vienna, Fac Life Sci, Dept Marine Biol, Vienna, Austria. [He, Johnny J.] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Klena, John D.] Univ Canterbury, Sch Biol Sci, Christchurch 1, New Zealand. [Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Chen, T (reprint author), Univ Illinois, Coll Med, Dept Biomed Sci, 1601 Parkview Ave, Rockford, IL 61107 USA. EM tiechen@uic.edu RI Bulgheresi, Silvia/B-8972-2009; Bulgheresi, Silvia/C-3128-2013; OI Skurnik, Mikael/0000-0001-8791-9260 FU NIAID NIH HHS [R01 AI039066, R01 AI039066-08] NR 64 TC 24 Z9 25 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAY PY 2008 VL 76 IS 5 BP 2070 EP 2079 DI 10.1128/IAI.01246-07 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 292LJ UT WOS:000255267200029 PM 18285492 ER PT J AU Calvo, E Pham, VM Ribeiro, JMC AF Calvo, E. Pham, V. M. Ribeiro, J. M. C. TI An insight into the sialotranscriptome of the non-blood feeding Toxorhynchites amboinensis mosquito SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE salivary glands; transcriptome; mosquito; hematophagy ID ADULT FEMALE MOSQUITO; SALIVARY-GLAND TRANSCRIPTS; VECTOR ANOPHELES-GAMBIAE; AEDES-AEGYPTI; MALARIA VECTOR; SEQUENCE ALIGNMENT; PROTEIN FAMILIES; SIALOME; DATABASE; CATALOG AB All adult mosquitoes take sugar meals, and most adult females also take blood meals to develop eggs. Salivary glands (SG) of males are thus much smaller and do not contain many of the antihemostatic and antiinflammatory compounds found in females. In the past 5 years, transcriptome analyses have identified nearly 70 different genes expressed in adult female SG. For most of these, no function can be assigned in either blood or sugar feeding. Exceptionally, Toxorhynchites mosquitoes are unusual in that they never feed on blood, and the SG of adults are identical in both sexes. Transcriptome analysis of the adult SG of this mosquito was performed to increase knowledge of the evolution of blood feeding-and to identify polypeptide families associated with sugar feeding-in mosquitoes. Published by Elsevier Ltd. C1 [Ribeiro, J. M. C.] NIAID, LMVR, NIH, Rockville, MD 20852 USA. [Calvo, E.; Pham, V. M.; Ribeiro, J. M. C.] NIAID, Lab Malaria & Vector Res, Sect Vector Biol, NIH, Rockville, MD 20852 USA. RP Ribeiro, JMC (reprint author), NIAID, LMVR, NIH, Twinbrook 3,12735 Twinbrook Pkwy,Room 2E32D, Rockville, MD 20852 USA. EM jribeiro@nih.gov OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z01 AI001012-01] NR 47 TC 12 Z9 12 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD MAY PY 2008 VL 38 IS 5 BP 499 EP 507 DI 10.1016/j.ibmb.2007.12.006 PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 300HU UT WOS:000255815700001 PM 18405828 ER PT J AU Lee, TL Yeh, J Friedman, J Yan, B Yang, XP Yeh, NT Van Waes, C Chen, Z AF Lee, Tin Lap Yeh, Jason Friedman, Jay Yan, Bin Yang, Xinping Yeh, Ning T. Van Waes, Carter Chen, Zhong TI A signal network involving coactivated NF-kappa B and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE NF-kappa B; STAT3; p53; BCL-XL; BAX; HNSCC ID PROTEASOME INHIBITOR BORTEZOMIB; GROWTH-FACTOR RECEPTOR; BCL-2 FAMILY PROTEINS; TUMOR-SUPPRESSOR P53; CANCER-CELLS; IN-VIVO; CONSTITUTIVE ACTIVATION; CISPLATIN SENSITIVITY; TRANSCRIPTION FACTORS; THERAPEUTIC TARGET AB Abrogation of apoptosis to sustain cell survival is an essential step in development of cancer. Aberrant activation of signal transcription factors NF-kappa B or STAT3, alterations in p53 status, or BCL/BAX family expression have each been reported to affect cell survival in cancer, including head and neck squamous cell carcinomas (HNSCC). However, molecular targeting of these alterations individually has yielded disappointing results. In our study, we examined the hypothesis that alterations in a signal network involving NF-kappa B, STAT3 and p53 modulates expression of proapoptotic BAX and antiapoptotic BCL-XL proteins, and promotes cell survival of HNSCC. We found that NF-kappa B and STAT3 are coactivated together, and with cytokine stimulation or siRNA knock-down, both modulate BAX/BCL-XL. Greater modulation among HNSCC lines expressing low wt p53 than those over-expressing mt p53 protein suggested that decreased p53 expression might enhance activation of NF-kappa B, STAT3 and BCL-XL. Reexpression of wt p53 suppressed NF-kappa B and STAT3 nuclear binding activity, and BCL-XL expression, while inducing p21 and BAX. Over-expression of p53 together with inhibition of NF-kappa B or STAT3 induced greater increase in the BAX/BCL-XL ratio and apoptosis than modulation of these transcription factors individually. Conversely, NF-kappa B or STAT3 inducing cytokines decreased the BAX/BCL-XL ratio. Thus, a network involving signal coactivation of NF-kappa B and STAT3, differentially modified by p53 inactivation or mutation, promotes altered BAX/BCL-XL expression and cell survival in HNSCC. Inhibition of signal activation of both NF-kappa B and STAT3 together with reexpression of p53 could be the most effective strategy to restore BAX/BCL-XL regulation and for cytotoxic therapy of HNSCC. (C) 2008 Wiley-Liss, Inc. C1 [Lee, Tin Lap; Yeh, Jason; Friedman, Jay; Yan, Bin; Yang, Xinping; Yeh, Ning T.; Van Waes, Carter; Chen, Zhong] NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), NIDCD, Tumor Biol Sect, Head & Neck Surg Branch, NIH, 10-5D55,MSC 1419, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS NR 66 TC 60 Z9 65 U1 0 U2 1 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 MAY 1 PY 2008 VL 122 IS 9 BP 1987 EP 1998 DI 10.1002/ijc.23324 PG 12 WC Oncology SC Oncology GA 277OR UT WOS:000254224100010 PM 18172861 ER PT J AU Willett, EV Morton, LM Hartge, P Becker, N Bernstein, L Boffetta, P Bracci, P Cerhan, J Chiu, BCH Cocco, P Dal Maso, L Davis, S De Sanjose, S Smedby, KE Ennas, MG Foretova, L Holiy, EA La Vecchia, C Matsuo, K Maynadie, M Melbye, M Negri, E Nieters, A Severson, R Slager, SL Spinelli, JJ Staines, A Talamini, R Vornanen, M Weisenburger, DD Roman, E AF Willett, Eleanor V. Morton, Lindsay M. Hartge, Patricia Becker, Nikolaus Bernstein, Leslie Boffetta, Paolo Bracci, Paige Cerhan, James Chiu, Brian C. -H. Cocco, Pierluigi Dal Maso, Luigino Davis, Scott De Sanjose, Silvia Smedby, Karin Ekstrom Ennas, Maria Grazia Foretova, Lenka Holiy, Elizabeth A. La Vecchia, Carlo Matsuo, Keitaro Maynadie, Marc Melbye, Mads Negri, Eva Nieters, Alexandra Severson, Richard Slager, Susan L. Spinelli, John J. Staines, Anthony Talamini, Renato Vornanen, Martine Weisenburger, Dennis D. Roman, Eve CA Interlymph Consortium TI Non-Hodgkin lymphoma and obesity: A pooled analysis from the InterLymph consortium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE non-Hodgkin lymphoma; lymphoma; body mass index weight; height; epidemiology ID BODY-MASS INDEX; FORMER COLLEGE-STUDENTS; CANCER-RISK; MALIGNANT-LYMPHOMA; LYMPHOHEMATOPOIETIC MALIGNANCIES; ALCOHOL-CONSUMPTION; PHYSICAL-ACTIVITY; SCANDINAVIAN MEN; UNITED-STATES; WOMEN AB Nutritional status is known to alter immune function, a suspected risk factor for non-Hodgkin lymphoma (NHL). To investigate whether long-term over, or under, nutrition is associated with NHL, self-reported anthropometric data on weight and height from over 10,000 cases of NHL and 16,000 controls were pooled across 18 case-control studies identified through the International Lymphoma Epidemiology Consortium. Study-specific odds ratios (OR) were estimated using logistic regression and combined using a random-effects model. Severe obesity, defined as BMI of 40 kg m(-2) or more, was not associated with NHL overall (pooled OR = 1.00, 95% confidence interval (CI) 0.70-1.41) or the majority of NHL subtypes. An excess was however observed for diffuse large B-cell lymphoma (pooled OR = 1.80, 95% CI 1.24-2.62), although not all study-specific ORs were raised. Among the overweight (BMI 25-29.9 kg m(-2)) and obese (BMI 30-39.9 kg m(-2)), associations were elevated in some studies and decreased in others, while no association was observed among the underweight (BMI < 18.5 kg m(-2)). There was little suggestion of increasing ORs for NHL or its subtypes with every 5 kg m(-2) rise in BMI above 18.5 kg m(-2). BMI components height and weight were also examined, and the tallest men, but not women, were at marginally increased risk (pooled OR = 1.19, 95% CI 1.06-1.34). In summary, whilst we conclude that there is no evidence to support the hypothesis that obesity is a determinant of all types of NHL combined, the association between severe obesity and diffuse large B-cell lymphoma may warrant further investigation. (C) 2007 Wiley-Liss, Inc. C1 [Willett, Eleanor V.; Interlymph Consortium] Univ York, Dept Hlth Sci, Epidemiol & Genet Unit, York YO10 5DD, N Yorkshire, England. [Morton, Lindsay M.; Hartge, Patricia] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Becker, Nikolaus; Nieters, Alexandra] German Canc Res Ctr, Div Clin Epidemiol, D-6900 Heidelberg, Germany. [Bernstein, Leslie] Cancer Surveillance Program, Los Angeles, CA USA. [Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Bracci, Paige; Holiy, Elizabeth A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Cerhan, James; Slager, Susan L.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. [Chiu, Brian C. -H.] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. [Cocco, Pierluigi] Univ Cagliari, Occupat Hlth Sect, Dept Publ Hlth, I-09124 Cagliari, Italy. [Dal Maso, Luigino; Talamini, Renato] Aviano Canc Ctr, Epidemiol & Biostat Unit, I-33081 Aviano, Italy. [Davis, Scott] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Epidemiol, Seattle, WA 98104 USA. [Davis, Scott] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [De Sanjose, Silvia] Catalan Inst Oncol, Epidemiol & Canc Registry Unit, Barcelona, Spain. [Smedby, Karin Ekstrom] Karolinska Univ Hosp, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden. [Ennas, Maria Grazia] Univ Cagliari, Dept Cytomophol, Cagliari, Italy. [Foretova, Lenka] Masaryk Mem Canc Inst, Brno, Czech Republic. [La Vecchia, Carlo] Univ Milan, Ist Ric Farmacol Mario Negri, Milan, Italy. [La Vecchia, Carlo] Univ Milan, Ist Stat Med & Biometria, Milan, Italy. [Matsuo, Keitaro] Aichi Canc Ctr, Div Epidemiol & Prevent, Nagoya, Aichi 464, Japan. [Maynadie, Marc] Registre Hemopathies Malignes Cote Or, U Bourgogne EA 4184, Dijon, France. [Melbye, Mads] Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. [Negri, Eva] Ist Ric Farmacol Mario Negri, I-20156 Milan, Italy. [Severson, Richard] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Severson, Richard] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Spinelli, John J.] BC Canc Agcy, Canc Control res Program, Vancouver, BC, Canada. [Staines, Anthony] Publ Hlth Univ Coll, Sch Publ Hlth, Dublin, Ireland. [Vornanen, Martine] Pathol Tampere Univ Hosp, Tampere, Finland. [Weisenburger, Dennis D.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. RP Willett, EV (reprint author), Univ York, Dept Hlth Sci, Epidemiol & Genet Unit, Seebohm Rowntree Bldg, York YO10 5DD, N Yorkshire, England. EM eleanor.willett@egu.york.ac.uk RI Kane, Eleanor/B-4349-2009; Slager, Susan/B-6756-2009; Spinelli, John/B-6210-2013; Negri, Eva/B-7244-2013; de Sanjose Llongueras, Silvia/H-6339-2014; Morton, Lindsay/B-5234-2015; OI Negri, Eva/0000-0001-9712-8526; Ennas, Maria Grazia/0000-0002-9448-715X; Matsuo, Keitaro/0000-0003-1761-6314; Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X; Staines, Anthony/0000-0001-9161-1357; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X FU Intramural NIH HHS [ZIA CP010170-13]; NCI NIH HHS [CA50850, CA92153, 5R01 CA69269-02, N01 PC065064, N01 PC067008, N01 PC067009, N01 PC067009-025, N01 PC067010, PC65064, PC67008, PC67009, PC67010, PC71105, R01 CA051086, R01 CA051086-03, R01 CA069269, R01 CA092153]; Associazione Italiana per la Ricerca sul Cancro NR 54 TC 58 Z9 65 U1 0 U2 4 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 MAY 1 PY 2008 VL 122 IS 9 BP 2062 EP 2070 DI 10.1002/ijc.23344 PG 9 WC Oncology SC Oncology GA 277OR UT WOS:000254224100020 PM 18167059 ER PT J AU Roblick, UJ Bader, FG Lenander, C Hellman, U Zimmermann, K Becker, S Ost, A Alaiya, A Bruch, HP Keller, R Mirow, L Franzen, B Ried, T Auer, G Habermann, JK AF Roblick, U. J. Bader, F. G. Lenander, C. Hellman, U. Zimmermann, K. Becker, S. Ost, A. Alaiya, A. Bruch, H. -P. Keller, R. Mirow, L. Franzen, B. Ried, T. Auer, G. Habermann, J. K. TI Undifferentiated pelvic adenocarcinomas: diagnostic potential of protein profiling and multivariate analysis SO INTERNATIONAL JOURNAL OF COLORECTAL DISEASE LA English DT Article DE proteomics; colon cancer; ovarian cancer; pelvic carcinoma; 2-DE; differential diagnosis; principal component analysis ID HUMAN BREAST-LESIONS; 2-DIMENSIONAL GEL-ELECTROPHORESIS; POLYPEPTIDE EXPRESSION; UNKNOWN PRIMARY; MASS-SPECTROMETRY; OVARIAN-CARCINOMA; MALIGNANT-TUMORS; CANCER; IDENTIFICATION; BENIGN AB Background and aims Despite improved techniques, the determination of tumor origin in poorly differentiated adenocarcinomas still remains a challenge for the pathologist. Here we report the use of protein profiling combined with principal component analysis to improve diagnostic decision-making in tumor samples, in which standard pathologic investigations cannot present reliable results. Materials and methods A poorly differentiated adenocarcinoma of unknown origin located in the pelvis, infiltrating the sigmoid colon as well as the ovary, served as a model to evaluate our proteomic approach. Firstly, we characterized the protein expression profiles from eight advanced colon and seven ovarian adenocarcinomas using two-dimensional gel electrophoresis (2-DE). Qualitative and quantitative patterns were recorded and compared to the tumor of unknown origin. Based on these protein profiles, match sets from the different tumors were created. Finally, a multivariate principal component analysis was applied to the entire 2-DE data to disclose differences in protein patterns between the different tumors. Results Over 89% of the unknown tumor sample spots could be matched with the colon standard gel, whereas only 63% of the spots could be matched with the ovarian standard. In addition, principal component analysis impressively displayed the clustering of the unknown case within the colon cancer samples, whereas this case did not cluster at all within the group of ovarian adenocarcinomas. Conclusion These results show that 2-DE protein expression profiling combined with principal component analysis is a sensitive method for diagnosing undifferentiated adenocarcinomas of unknown origin. The described approach can contribute greatly to diagnostic decision-making and, with further technical improvements and a higher throughput, become a powerful tool in the armentarium of the pathologist. C1 [Roblick, U. J.; Bader, F. G.; Zimmermann, K.; Bruch, H. -P.; Keller, R.; Mirow, L.; Habermann, J. K.] Univ Hosp Schleswig Holstein, Dept Surg, Surg Res Lab, D-23538 Lubeck, Germany. [Roblick, U. J.; Bader, F. G.; Lenander, C.; Becker, S.; Ost, A.; Auer, G.] Karolinska Biom Ctr, Karolinska Inst, KBC, Stockholm, Sweden. [Hellman, U.] Uppsala Univ, Ludwig Inst Canc Res, Uppsala, Sweden. [Alaiya, A.] King Faisal Hosp, Dept Biol & Med Res, Proteom Res Unit, Riyadh, Saudi Arabia. [Franzen, B.] AstraZeneca AB, Preclin R&D, Sodertalje, Sweden. [Ried, T.] NIH, Natl Canc Inst, Dept Genet, Bethesda, MD 20892 USA. RP Roblick, UJ (reprint author), Univ Hosp Schleswig Holstein, Dept Surg, Surg Res Lab, Campus Lubeck,Ratzeburgerallee 160, D-23538 Lubeck, Germany. EM DrDr.UJRoblick@t-online.de RI Bruch, Hans-Peter/E-7731-2010; Habermann, Jens/E-2968-2010 NR 35 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0179-1958 EI 1432-1262 J9 INT J COLORECTAL DIS JI Int. J. Colorectal Dis. PD MAY PY 2008 VL 23 IS 5 BP 483 EP 491 DI 10.1007/s00384-008-0448-6 PG 9 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 277GO UT WOS:000254200900005 PM 18293003 ER PT J AU Li, YC Bao, YM Jiang, B Wang, Z Liu, YX Zhang, C An, LJ AF Li, Yachen Bao, Yongming Jiang, Bo Wang, Zhuo Liu, Yuxin Zhang, Cen An, Lijia TI Catalpol protects primary cultured astrocytes from in vitro ischemia-induced damage SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Article DE catalpol; astrocyte; ischemia; ROS; iNOS ID NITRIC-OXIDE SYNTHASE; CEREBRAL-ARTERY OCCLUSION; REACTIVE OXYGEN RADICALS; SUPEROXIDE-DISMUTASE; BRAIN-INJURY; OXIDATIVE STRESS; NEURONAL DEATH; CELL-DEATH; GENE-EXPRESSION; FOCAL ISCHEMIA AB Catalpol, an iridoid glycoside abundant in the roots of Rehmannia glutinosa, has been previously found to prevent the loss of CA1 hippocampal neurons and to reduce working errors in gerbils after ischemia-reperfusion injury. In the present study, we investigated the effects of catalpol on astrocytes in an ischemic model to further characterize its neuroprotective mechanisms. Primary cultured astrocytes exposed to oxygen-glucose deprivation (OGD) followed by reperfusion (adding back oxygen and glucose, OGD-R), were used as an in vitro ischemic model. Treatment of the astrocytes with catalpol during ischemia-reperfusion increased astrocyte survival significantly in a concentration-dependent manner, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release and morphological observation. In addition, catalpol prevented the decrease in mitochondrial membrane potential, inhibited the formation of reactive oxygen species (ROS) and the production of nitric oxide (NO), decreased the level of lipid peroxide and the activity of inducible nitric oxide synthase (iNOS), and elevated the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and the content of glutathione (GSH). Our results suggest that catalpol exerts the most significant cytoprotective effect on astrocytes by suppressing the production of free radicals and elevating antioxidant capacity. (C) 2008 ISDN. Published by Elsevier Ltd. All rights reserved. C1 [Li, Yachen; Bao, Yongming; Jiang, Bo; Wang, Zhuo; An, Lijia] Dalian Univ Technol, Sch Environm & Biol Sci & Technol, Dalian 116024, Peoples R China. [Liu, Yuxin; Zhang, Cen] NIEHS, Natl Inst Hlth, Lab Pharmacol & Chem, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. RP An, LJ (reprint author), Dalian Univ Technol, Sch Environm & Biol Sci & Technol, 2 Linggong Rd, Dalian 116024, Peoples R China. EM lijiaan97@yahoo.com NR 65 TC 46 Z9 54 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD MAY-JUN PY 2008 VL 26 IS 3-4 BP 309 EP 317 DI 10.1016/j.ijdevneu.2008.01.006 PG 9 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 300VL UT WOS:000255853200008 PM 18337048 ER PT J AU Ludani, S Gonzdles, A Munoz, S Jeronimo, J Robdes, S AF Ludani, Sidvana Gonzdles, AAiguet Munoz, Sergio Jeronimo, Jose Robdes, Sytvia TI Effectiveness of cryotherapy treatment for cervical intraepithelial neoplasia SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Article DE cervical cancer prevention; cervical precancer treatment; cryotherapy; low-resource settings ID LOW-RESOURCE SETTINGS; VISUAL INSPECTION; CANCER PREVENTION; ACCEPTABILITY; CYTOLOGY; SAFETY; INDIA; PERU; CARE AB Objective: To assess the effectiveness of cryotherapy treatment delivered by general practitioners in primary care settings, as part of a screen-and-treat approach for cervical cancer prevention. Method: Women aged between 25 and 49 years residing in San Martin, Peru, who were positive on visual inspection screening were treated, if eligible, with cryotherapy following biopsy. At 12 months post cryotherapy treatment the participants were evaluated for treatment effectiveness and examined by visual inspection and Papanicolaou test and, if positive, referred to a gynecologist for colposcopy and biopsy. Results: Cryotherapy treatment was performed for 1398 women; of these, 531 (38%) had a histology result of cervical intraepithelial neoplasia (CIN). Cryotherapy effectively cured CIN in 418 (88%) women, including 49 (70%) women with a baseline diagnosis of CIN 3. Conclusion: Cryotherapy is an effective treatment for cervical precancerous lesions; it can easily be administered by general practitioners in primary care settings following visual inspection screening. (c) 2007 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Ludani, Sidvana] Pan Amer Hlth Org, Unit Non Communicable Dis, Washington, DC USA. [Gonzdles, AAiguet] Pan Amer Hlth Org Representat Peru, Hlth Surveillance & Dis Management, Lima, Peru. [Munoz, Sergio] Univ La Frontera, Clin Epidemiol Res & Training Ctr, Temuco, Chile. [Jeronimo, Jose] NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Robdes, Sytvia] World Bank, Human Dev Network, Washington, DC USA. RP Ludani, S (reprint author), Pan Amer Hlth Org, Unit Non Communicable Dis, Washington, DC USA. EM lucianis@paho.org NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD MAY PY 2008 VL 101 IS 2 BP 172 EP 177 DI 10.1016/j.ijgo.2007.11.013 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300IE UT WOS:000255816700012 ER PT J AU Karila, L Gorelick, D Weinstein, A Noble, F Benyamina, A Coscas, S Blecha, L Lowenstein, W Martinot, JL Reynaud, M Lepine, JP AF Karila, Laurent Gorelick, David Weinstein, Aviv Noble, Florence Benyamina, Amine Coscas, Sarah Blecha, Lisa Lowenstein, William Martinot, Jean Luc Reynaud, Michel Lepine, Jean Pierre TI New treatments for cocaine dependence: a focused review SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE addiction; clinical trials; cocaine; dependence; pharmacotherapy(ies) ID PLACEBO-CONTROLLED TRIAL; GAMMA-VINYL-GABA; CONTROLLED DRUG-INTERACTION; CONTROLLED SCREENING TRIAL; PITUITARY-ADRENAL AXIS; 2 DOUBLE-BLIND; RHESUS-MONKEYS; INTRAVENOUS COCAINE; NUCLEUS-ACCUMBENS; SEEKING BEHAVIOR AB Cocaine, already a significant drug problem in North and South America, has become a more prominent part of the European drug scene. Cocaine dependence has major somatic, psychological, psychiatric, socio-economic, and legal implications. No specific effective pharmacological treatment exists for cocaine dependence. Recent advances in neurobiology have identified various neuronal mechanisms implicated in cocaine addiction and suggested several promising pharmacological approaches. Data were obtained from Medline, EMBASE, and PsycINFO searches of English-language articles published between 1985 and June 2007 using the key words: cocaine, addiction, cocaine dependence, clinical trials, pharmacotherapy(ies) singly and in combination. Large well-controlled studies with appropriate statistical methods were preferred. Pharmacological agents such as GABA agents (topiramate, tiagabine, baclofen and vigabatrin) and agonist replacement agents (modafinil, disulfiram, methylphenidate) seem to be the most promising in treatment of cocaine dependence. The results from trials of first- and second-generation neuroleptics are largely negative. Aripiprazole, a partial dopaminergic agonist that may modulate the serotonergic system, shows some promise. Preliminary results of human studies with anti-cocaine vaccine, N-acetylcysteine, and ondansetron, are promising, as are several compounds in preclinical development. While no medication has received regulatory approval for the treatment of cocaine dependence, several medications marketed for other indications have shown efficacy in clinical trials. An anti-cocaine vaccine and several compounds in preclinical development have also shown promise. Findings from early clinical trials must be confirmed in larger, less selective patient populations. C1 [Karila, Laurent; Martinot, Jean Luc] CEA IFR49, Res Unit Neuroimaging & Psychiat, Neuroimaging & Psychiat Unit, Hosp Dept Frederic Joliot,12BM,U797, Orsay, France. [Karila, Laurent; Benyamina, Amine; Coscas, Sarah; Blecha, Lisa; Reynaud, Michel] Hop Univ Paul Brousse, AP HP, Ctr Enseignement Rech & Traitement Addict, F-94808 Villejuif, France. [Karila, Laurent; Martinot, Jean Luc] Univ Paris 05, F-75270 Paris 06, France. [Gorelick, David] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD USA. [Weinstein, Aviv] Hadassah Hosp Ein Kerem, Dept Med Biophys & Nucl Med, Jerusalem, Israel. [Noble, Florence; Lepine, Jean Pierre] Univ Paris 05, Fac Pharm Neuropsychopharmacol Addict, CNRS, UMR7157, Paris, France. [Karila, Laurent; Benyamina, Amine; Coscas, Sarah; Blecha, Lisa; Reynaud, Michel] Univ Paris Sud, INSERM, U669, F-75014 Paris, France. [Lowenstein, William] Montevideo Clin, Boulogne, France. [Lepine, Jean Pierre] Univ Paris 07, AP HP, INSERM, Hop Fernand Widal,Serv Psychiat,U705, F-75010 Paris, France. RP Karila, L (reprint author), CERTA, Hop Paul Brousse, 12 Ave Paul Vaillant Couturier, F-94800 Villejuif, France. EM laurent.karila@pbr.aphp.fr FU US National Institutes of Health, National Institute on Drug Abuse FX Preparation of this review was supported in part by the Intramural Research Program, US National Institutes of Health, National Institute on Drug Abuse. NR 144 TC 112 Z9 114 U1 4 U2 15 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD MAY PY 2008 VL 11 IS 3 BP 425 EP 438 DI 10.1017/S1461145707008097 PG 14 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 350LZ UT WOS:000259355300013 PM 17927843 ER PT J AU Moore, SC Mayne, ST Graubard, BI Schatzkin, A Albanes, D Schairer, C Hoover, RN Leitzmann, MF AF Moore, S. C. Mayne, S. T. Graubard, B. I. Schatzkin, A. Albanes, D. Schairer, C. Hoover, R. N. Leitzmann, M. F. TI Past body mass index and risk of mortality among women SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE body mass; weight; overweight; mortality; life expectancy; epidemiology ID BREAST-CANCER DETECTION; PROSPECTIVE COHORT; UNITED-STATES; WEIGHT CHANGE; MIDDLE-AGE; US ADULTS; FOLLOW-UP; OLD-AGE; OBESITY; OVERWEIGHT AB Background: Epidemiologic studies of body mass index (BMI) in relation to mortality commonly exclude persons with health conditions and/or a history of smoking to prevent bias resulting from illness-related weight loss ('reverse causation'). Analysis of BMI from an earlier time period may minimize reverse causation without requiring exclusion of participants based on disease or smoking history. Methods: We prospectively examined BMI based on technician measurements of weight and height from 10 years prior to start of follow-up in relation to subsequent mortality in a cohort of 50 186 women who were 40-93 years old at baseline in 1987-1989. Deaths were ascertained through the US National Death Index. Proportional hazards regression was used to estimate hazard ratios (HRs) of mortality, adjusted for age, education, race/ethnicity, income, menopausal hormone use, smoking and physical activity. Results: During 10 years of follow-up through 1997, 5201 women died. Overall, we observed a J-shaped association between BMI and mortality, with increased risk for women who were underweight, overweight or obese. The HRs and 95% confidence intervals of mortality for BMI categories of <18.5, 18.5-20.9, 21.0-23.4 (reference), 23.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9 and 35.0+ kg m(-2) were 1.43 (1.19, 1.72), 1.07 (0.98, 1.17), 1.00 (reference), 1.10 (1.00, 1.20), 1.20 (1.11, 1.31), 1.23 (1.11, 1.37), 1.60 (1.44, 1.77) and 1.92 (1.64, 2.24). There was little evidence that pre-existing conditions (heart disease, diabetes and/or cancer) or smoking history modified the past BMI and mortality relation (P = 0.54 and 0.76). Conclusions: In this large cohort of women, BMI based on technician measurements of weight and height from 10 years prior to baseline showed increased risk for mortality across the range of overweight and obesity, regardless of disease and smoking history. Observed associations between overweight, obesity and mortality in healthy individuals may also apply to persons with a history of disease or smoking. C1 [Moore, S. C.; Schatzkin, A.; Albanes, D.; Leitzmann, M. F.] Natl Canc Inst, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Moore, S. C.; Mayne, S. T.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Graubard, B. I.; Schairer, C.] Natl Canc Inst, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hoover, R. N.] Natl Canc Inst, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Moore, SC (reprint author), Natl Canc Inst, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, EPS S,Room 3033,6120 Execut Blvd, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU Intramural NIH HHS; NCI NIH HHS [TU2 CA105666, TU2 CA105666-01] NR 41 TC 20 Z9 20 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 IS 5 BP 730 EP 739 DI 10.1038/sj.ijo.0803801 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 299LB UT WOS:000255756000002 PM 18209736 ER PT J AU Hallgreen, CE Hall, KD AF Hallgreen, C. E. Hall, K. D. TI Allometric relationship between changes of visceral fat and total fat mass SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE weight loss; visceral adipose tissue; body composition; fat mass; allometry ID SUBCUTANEOUS ADIPOSE-TISSUE; OBESE POSTMENOPAUSAL WOMEN; CORONARY-HEART-DISEASE; PREDICT INSULIN SENSITIVITY; LIFE-STYLE INTERVENTION; METABOLIC RISK-FACTORS; MODERATE WEIGHT-LOSS; PREMENOPAUSAL WOMEN; ABDOMINAL OBESITY; AEROBIC EXERCISE AB Objective: To elucidate the mathematical relationship between changes of visceral adipose tissue (VAT) and total body fat mass (FM) during weight loss. Design: We hypothesized that changes of VAT mass are allometrically related to changes of FM, regardless of the type of weight-loss intervention, as defined by the differential equation dVAT/dFM = k x VAT/FM, where k is a dimensionless constant. We performed a systematic search of the published literature for studies that included measurements of VAT changes via magnetic resonance imaging (MRI) or computed tomography (CT) imaging along with measurements of FM changes by dual-energy X-ray absorptiometry, hydrodensitometry, air-displacement plethysmography or whole-body MRI or CT imaging. We then examined whether or not the data could be explained by the allometric model. Result: We found 37 published studies satisfying our search criteria, representing 1407 men and women of various ethnicities, degrees of adiposity and weight-loss interventions. The hypothesized allometric equation relating changes of VAT and FM accurately modeled the data for both men and women and for all methods of weight loss studied. The best-fit value for the dimensionless constant was k = 1.3 +/- 0.1 and the resulting model had an R(2) = 0.73. Conclusion: This is the first report to reveal an allometric relationship between changes of VAT and FM that holds for both genders as well as a wide variety of weight-loss interventions including bariatric surgery, caloric restriction with or without exercise and exercise alone. We conclude that changes of VAT are primarily determined by FM changes as well as the initial VAT to FM ratio. C1 [Hallgreen, C. E.] Tech Univ Denmark, Dept Phys, DK-2800 Lyngby, Denmark. [Hall, K. D.] NIDDK, NIH, Lab Biol Modelling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, NIH, Lab Biol Modelling, 12A S Dr,Room 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010 FU Intramural NIH HHS [Z01 DK013036-01] NR 53 TC 28 Z9 30 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 IS 5 BP 845 EP 852 DI 10.1038/sj.ijo.0803783 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 299LB UT WOS:000255756000017 PM 18087265 ER PT J AU Flegal, KM Graubard, BI Williamson, DF Gail, MH AF Flegal, K. M. Graubard, B. I. Williamson, D. F. Gail, M. H. TI Simple examples should not be extrapolated to the US population SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Letter ID OBESITY; DEATHS; UNDERWEIGHT; OVERWEIGHT; FRACTIONS C1 [Flegal, K. M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Graubard, B. I.; Gail, M. H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Williamson, D. F.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 6 TC 2 Z9 2 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 IS 5 BP 875 EP 875 DI 10.1038/sj.ijo.0803788 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 299LB UT WOS:000255756000021 PM 18197183 ER PT J AU Hall, KD Hallgreen, CE AF Hall, K. D. Hallgreen, C. E. TI Changes of visceral fat are allometrically related to total body fat independently of gender or weight loss intervention SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 16th European Congress on Obesity CY MAY 14-17, 2008 CL Geneva, SWITZERLAND C1 [Hall, K. D.] NIH, Bethesda, MD 20892 USA. [Hallgreen, C. E.] Tech Univ Denmark, Copenhagen, Denmark. RI Hall, Kevin/F-2383-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 SU 1 BP S134 EP S134 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 300JM UT WOS:000255820100533 ER PT J AU Hall, KD AF Hall, K. D. TI What is the energy deficit required per unit weight loss? SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 16th European Congress on Obesity CY MAY 14-17, 2008 CL Geneva, SWITZERLAND C1 [Hall, K. D.] NIH, Bethesda, MD 20892 USA. RI Hall, Kevin/F-2383-2010 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 SU 1 BP S99 EP S99 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 300JM UT WOS:000255820100391 ER PT J AU Meruvu, S Hugendubler, L Mueller, E AF Meruvu, S. Hugendubler, L. Mueller, E. TI Identification of a novel n-terminal ppar gamma coactivator involved in adipogenesis SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Meeting Abstract CT 16th European Congress on Obesity CY MAY 14-17, 2008 CL Geneva, SWITZERLAND C1 [Meruvu, S.; Hugendubler, L.; Mueller, E.] NIDDK, NIH, GDDB Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD MAY PY 2008 VL 32 SU 1 BP S16 EP S16 PG 1 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 300JM UT WOS:000255820100058 ER PT J AU Thangapazham, RL Puri, A Tele, S Blumenthal, R Maheshwari, RK AF Thangapazham, Rajesh L. Puri, Anu Tele, Shrikant Blumenthal, Robert Maheshwari, Radha K. TI Evaluation of a nanotechnology-based carrier for delivery of curcumin in prostate cancer cells SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE nanotechnology; curcumin; prostate cancer ID CHEMOPREVENTIVE AGENT CURCUMIN; IN-VIVO; DIETARY CURCUMIN; LIPOSOMES; APOPTOSIS; VITRO; PROLIFERATION; ANGIOGENESIS; FORESTOMACH; METABOLITES AB We have initiated studies to enhance targeted delivery of an anticancer agent, curcumin, for prostate cancer treatment by incorporating this agent into the liposomes (nanodelivery vehicles primarily composed of phospholipids) coated with prostate membrane specific antigen specific antibodies. We prepared curcumin-loaded liposomes of various lipid compositions by sonication at an average size of 100-150 nm. Un-entrapped curcumin was removed by size exclusion chromatography. Data show that curcumin preferentially partitioned into liposomes prepared from dimyristoyl phosphatidyl choline (DMPQ and cholesterol among the various compositions tested. The anti-proliferative activity of liposomal curcumin was studied using two human prostate cancer cell lines (LNCaP and C4-2B) by a tetrazolium dye-based (MTT) assay. Treatment of cells with liposomal curcumin (5-10 mu M) for 24-48 h at 37 degrees C resulted in at least 70-80% inhibition of cellular proliferation without affecting their viability. On the other hand, free curcumin exhibited similar inhibition only at 10-fold higher doses (> 50 mu M). We also observed that LNCaP cells were relatively more sensitive to liposomal curcumin mediated block of cellular proliferation than C4-2B cells. We are currently developing liposome formulations with targeting ability to further improve the efficacy of curcumin in vivo. C1 [Thangapazham, Rajesh L.; Maheshwari, Radha K.] Uniformed Serv Univ Hlth Sci, Dept Pathol, Ctr Combat Casualty & Life Sustainment Res, Bethesda, MD 20814 USA. [Thangapazham, Rajesh L.] Birla Inst Technol & Sci, Pilani 333031, Rajasthan, India. [Puri, Anu; Tele, Shrikant; Blumenthal, Robert] Natl Canc Inst, NIH, CCR Nanobiol Program, Frederick, MD USA. RP Maheshwari, RK (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, Ctr Combat Casualty & Life Sustainment Res, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM rmaheshwari@usuhs.mil FU Intramural NIH HHS [Z01 BC010652-03, Z99 CA999999] NR 25 TC 88 Z9 94 U1 7 U2 31 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD MAY PY 2008 VL 32 IS 5 BP 1119 EP 1123 PG 5 WC Oncology SC Oncology GA 293EY UT WOS:000255319300019 PM 18425340 ER PT J AU Thurman, AR Holden, AEC Shain, R Perdue, S Piper, J AF Thurman, Andrea Ries Holden, Alan E. C. Shain, Rochelle Perdue, Sondra Piper, Jeanna TI Partner notification of sexually transmitted infections among pregnant women SO INTERNATIONAL JOURNAL OF STD & AIDS LA English DT Article DE partner notification; pregnancy; STD exposure ID CHLAMYDIA-TRACHOMATIS INFECTION; MINORITY WOMEN; PRIVATE-SECTOR; UNITED-STATES; GONORRHEA; RECURRENT; STD; PREVENTION; SEATTLE; HEALTH AB The object of this study was to determine the factors associated with partner notification (PN) of sexually transmitted infection (STI) exposure among pregnant, low income, Mexican-American (MA) and African-American (AA) women and their male sexual partners. We used a cross-sectional analysis of 166 pregnant women with an STI, enrolled in a randomized controlled trial of behavioural intervention to prevent recurrent STIs. The primary outcome, PN, is notification of, or intent to notify male sexual partner(s) of STI exposure. Pregnant women with one (n=136) versus multiple (n=30) partners reported PN for 88.2% and 54.5% of male partners, respectively (P < 0.001). Multivariate logistic regression demonstrated three variables that independently predicted PN: a steady relationship, with one male sexual partner and recent (< 30 days) intercourse with the partner. Among the low income, pregnant MA and AA women, the three relationship variables predicted 81.6% of PN and correctly classified 78.5% of males notified and 65.7% of males not notified. C1 [Thurman, Andrea Ries; Holden, Alan E. C.; Shain, Rochelle; Perdue, Sondra] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Piper, Jeanna] NIAID, NIH, Bethesda, MD 20892 USA. RP Thurman, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, 7703 Floyd Curl Dr,Mail Code 7836, San Antonio, TX 78229 USA. EM thurmana@uthscsa.edu FU NIAID NIH HHS [U01 AI 40029] NR 33 TC 2 Z9 2 U1 3 U2 3 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0956-4624 J9 INT J STD AIDS JI Int. J. STD AIDS PD MAY PY 2008 VL 19 IS 5 BP 309 EP 315 DI 10.1258/ijsa.2007.007295 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 305KI UT WOS:000256176900005 PM 18482960 ER PT J AU Visco, AG Brubaker, L Nygaard, I Richter, HE Cundiff, G Fine, P Zyczynski, H Brown, MB Weber, AM AF Visco, Anthony G. Brubaker, Linda Nygaard, Ingrid Richter, Holly E. Cundiff, Geoffrey Fine, Paul Zyczynski, Halina Brown, Morton B. Weber, Anne M. CA Pelvic Floor Disorders Network TI The role of preoperative urodynamic testing in stress-continent women undergoing sacrocolpopexy: the Colpopexy and Urinary Reduction Efforts (CARE) randomized surgical trial SO INTERNATIONAL UROGYNECOLOGY JOURNAL LA English DT Article DE occult incontinence; urodynamics; prolapse reduction; sacrocolpopexy ID PELVIC ORGAN PROLAPSE; ENDOPELVIC FASCIA PLICATION; VAGINAL VAULT PROLAPSE; GENITOURINARY PROLAPSE; UTEROVAGINAL PROLAPSE; BURCH COLPOSUSPENSION; INCONTINENCE; PREVALENCE; SURGERY; PESSARY AB The aim of this study is to describe results of reduction testing in stress-continent women undergoing sacrocolpopexy and to estimate whether stress leakage during urodynamic testing with prolapse reduction predicts postoperative stress incontinence. Three hundred twenty-two stress-continent women with stages II-IV prolapse underwent standardized urodynamics. Five prolapse reduction methods were tested: two at each site and both performed for each subject. Clinicians were masked to urodynamic results. At sacrocolpopexy, participants were randomized to Burch colposuspension or no Burch (control). P-values were computed by two-tailed Fisher's exact test or t-test. Preoperatively, only 12 of 313 (3.7%) subjects demonstrated urodynamic stress incontinence (USI) without prolapse reduction. More women leaked after the second method than after the first (22% vs. 16%; p = 0.012). Preoperative detection of USI with prolapse reduction at 300ml was pessary, 6% (5 of 88); manual, 16% (19 of 122); forceps, 21% (21 of 98); swab, 20% (32 of 158); and speculum, 30% (35 of 118). Women who demonstrated preoperative USI during prolapse reduction were more likely to report postoperative stress incontinence, regardless of concomitant colposuspension (controls 58% vs. 38% (p = 0.04) and Burch 32% vs. 21% (p = 0.19)). In stress-continent women undergoing sacrocolpopexy, few women demonstrated USI without prolapse reduction. Detection rates of USI with prolapse reduction varied significantly by reduction method. Preoperative USI leakage during reduction testing is associated with a higher risk for postoperative stress incontinence at 3 months. Future research is warranted in this patient population to evaluate other treatment options to refine predictions and further reduce the risk of postoperative stress incontinence. C1 [Visco, Anthony G.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, Durham, NC 27710 USA. [Brubaker, Linda] Loyola Univ, Ctr Med, Dept Obstet & Gynecol, Maywood, IL 60153 USA. [Brubaker, Linda] Loyola Univ, Ctr Med, Dept Urol, Maywood, IL 60153 USA. [Nygaard, Ingrid] Univ Utah, Salt Lake City, UT USA. [Richter, Holly E.] Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. [Cundiff, Geoffrey] Providence Hlth Care, Vancouver, BC, Canada. [Fine, Paul] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Zyczynski, Halina] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Brown, Morton B.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Weber, Anne M.] NICHHD, Rockville, MD 20847 USA. RP Visco, AG (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Urogynecol & Reconstruct Pelv Surg, Durham, NC 27710 USA. EM anthony.visco@duke.edu FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U01 HD041249-06, U10 HD041248, U10 HD041248-05, U10 HD041250, U10 HD041250-06, U10 HD041261, U10 HD041261-05, U10 HD041263, U10 HD041263-05, U10 HD041267, U10 HD041267-07, U10 HD041268-05, U10 HD041269-03] NR 25 TC 72 Z9 79 U1 0 U2 4 PU SPRINGER LONDON LTD PI ARTINGTON PA ASHBOURNE HOUSE, THE GUILDWAY, OLD PORTSMOUTH ROAD, ARTINGTON GU3 1LP, GUILDFORD, ENGLAND SN 0937-3462 J9 INT UROGYNECOL J JI Int. Urogynecol. J. PD MAY PY 2008 VL 19 IS 5 BP 607 EP 614 DI 10.1007/s00192-007-0498-2 PG 8 WC Obstetrics & Gynecology; Urology & Nephrology SC Obstetrics & Gynecology; Urology & Nephrology GA 285AZ UT WOS:000254751000002 PM 18185903 ER PT J AU Davis, J Davis, D Norman, B Piatigorsky, J AF Davis, Janine Davis, Dionne Norman, Barbara Piatigorsky, Joram TI Gene expression of the mouse corneal crystallin Aldh3a1: Activation by Pax6, Oct1, and p300 SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALPHA-A-CRYSTALLIN; MULTIFUNCTIONAL LENS CRYSTALLINS; MAF TRANSCRIPTION FACTORS; DICKIES SMALL EYE; ALDEHYDE DEHYDROGENASE; EPITHELIAL-CELLS; C-MAF; FUNCTIONAL INTERACTIONS; LETHAL MUTATION; RETINOIC ACID AB PURPOSE. Aldehyde dehydrogenase 3a1 (Aldh3a1) represents similar to 50% of the water-soluble protein of the mouse corneal epithelial cells and thus, by analogy with the abundant lens crystallins, is considered a corneal crystallin. This study was conducted to examine the developmental pattern and transcriptional activation of Aldh3a1 gene expression in the mouse cornea. METHODS. Aldh3a1 mRNA and protein were analyzed by quantitative (Q)-PCR and Western immunoblot analysis. Functional promoter analysis was examined by cotransfecting plasmids containing variable portions of the Aldh3a1 promoter fused to the luciferase reporter gene into COS-7 cells with selected transcription factors. Transcription factor binding sites were identified by electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation assays (ChIP). In situ hybridization and immunohistochemistry were used to assess expression of Aldh3a1, Pax6, and Oct1 in the cornea. RESULTS. Aldh3a1 expression is temporally regulated in the cornea beginning at birth and increasing 100-fold by 6 weeks of age. Pax6, Oct1, and p300 synergistically activate the Aldh3a1 promoter similar to 116-fold. One Pax6 and two Oct1 binding sites were identified in vitro and in vivo in the Aldh3a1 promoter fragment analyzed. Pax6 and Oct1 are both present in the nuclei of corneal epithelial cells of the 6-week-old mouse. Finally, a reduction of Aldh3a1 correlated with reduced Pax6 in the corneas of heterozygous Small eye Pax6+/- mice. CONCLUSIONS. Pax6, Oct1, and p300 activate gene expression of the corneal crystallin Aldh3a1 in the mouse. These transcription factors are also implicated in the high expression of crystallin genes in the lens, consistent with the "refracton hypothesis" unifying many aspects of the lens and cornea. C1 [Davis, Janine; Davis, Dionne; Norman, Barbara; Piatigorsky, Joram] NIH, Mol & Dev Biol Lab, NEI, Bethesda, MD USA. RP Davis, J (reprint author), Bldg 7 Rm 137 7 Mem Dr,MSC 0704, Bethesda, MD USA. EM davisj@nei.nih.gov NR 100 TC 16 Z9 17 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2008 VL 49 IS 5 BP 1814 EP 1826 DI 10.1167/iovs.07-1057 PG 13 WC Ophthalmology SC Ophthalmology GA 292UH UT WOS:000255291100012 PM 18436815 ER PT J AU Zhou, Y Grinchuk, O Tomarev, SI AF Zhou, Yu Grinchuk, Oleg Tomarev, Stanislav I. TI Transgenic mice expressing the Tyr437His mutant of human myocilin protein develop glaucoma SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID OPEN-ANGLE GLAUCOMA; TRABECULAR MESHWORK CELLS; NORMAL-TENSION GLAUCOMA; RETINAL GANGLION-CELLS; INTRAOCULAR-PRESSURE; MUTATED MOUSE; NON-SECRETION; OPTIC-NERVE; GENE; OLFACTOMEDIN AB PURPOSE. To developed a genetic mouse model of primary open-angle glaucoma induced by expression of mutated human myocilin in transgenic mice and to test whether expression of mutated human myocilin in the eye angle structures produces more significant damage to the eye than does mutated mouse myocilin. METHODS. Recombineering in Escherichia coli was used to introduce the Tyr437His point mutation into a BAC carrying the full-length human MYOCILIN ( MYOC) gene and long flanking regions. This BAC was used to produce transgenic mice. The expression of myocilin in the iridocorneal angle tissues and aqueous humor was studied by immunohistochemistry and Western blot analysis. Intraocular pressure was measured non-invasively with a fiber optic transducer. Retinal ganglion cells were retrograde labeled with fluorescent gold, and counted 5 days after labeling. RESULTS. BAC transgenic mice expressed elevated levels of myocilin in tissues of the iridocorneal angle. Expression of mutated myocilin induced its intracellular accumulation and prevented secretion of both mutated and wild-type myocilin into the aqueous humor. Transgenic mice demonstrated a moderate elevation of intraocular pressure, which was more pronounced at night than in daytime. In the peripheral retina, transgenic mice lost 20% of the retinal ganglion cells and 55% of large retinal ganglion cells. Axonal degeneration was observed at the periphery of the optic nerve. CONCLUSIONS. Expression of equivalent levels of mutated human or mouse myocilin in the eyes of transgenic mice produce comparable pathologic changes that are similar to those observed in patients with glaucoma. C1 [Zhou, Yu; Grinchuk, Oleg; Tomarev, Stanislav I.] NEI, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, NIH,DHHS, Bethesda, MD 20814 USA. RP Tomarev, SI (reprint author), NEI, Sect Mol Mech Glaucoma, Mol & Dev Biol Lab, NIH,DHHS, Bldg 7,Room 103, Bethesda, MD 20814 USA. EM tomarevs@nei.nih.gov FU Intramural NIH HHS [Z01 EY000318-10, Z99 EY999999] NR 40 TC 64 Z9 65 U1 0 U2 2 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2008 VL 49 IS 5 BP 1932 EP 1939 DI 10.1167/iovs.07-1339 PG 8 WC Ophthalmology SC Ophthalmology GA 292UH UT WOS:000255291100026 PM 18436825 ER PT J AU Cortes, LM Mattapallil, MJ Silver, PB Donoso, LA Liou, GI Zhu, W Chan, CC Caspi, RR AF Cortes, Lizette M. Mattapallil, Mary J. Silver, Phyllis B. Donoso, Larry A. Liou, Gregory I. Zhu, Wei Chan, Chi-Chao Caspi, Rachel R. TI Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2(b)) and B10.RIII (H-2(r)) mice SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID RETINOID-BINDING-PROTEIN; EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; MECHANISMS; DISEASE; RESPONSES; UVEITIS; GENE; IDENTIFICATION; EXPRESSION; INDUCTION AB PURPOSE. Interphotoreceptor retinoid binding protein (IRBP) is the major uveitogenic retinal antigen eliciting experimental autoimmune uveoretinitis (EAU) in mice. The most frequently used mouse strains are B10.RIII and C57BL/6, but to date only one uveitogenic epitope for each has been identified. The purpose of this study was to identify and characterize additional uveitogenic epitopes in B10.RIII and C57BL/6 mice and to compare epitope recognition in wild-type versus IRBP-deficient mice on both backgrounds. METHODS. Mice were immunized with IRBP. Spleen cells were stimulated in culture with overlapping peptides representing the entire IRBP molecule, and lymphocyte proliferative responses were measured. Peptides determined to be immunodominant were used to immunize mice for EAU. Cytokine profile and proliferation of the CD4 versus CD8 subsets were analyzed for the most pathogenic peptides. RESULTS. Two new major pathogenic epitopes were identified in WT C57BL/6 mice, residues 461-480 and 651-670. These epitopes induced EAU of severity similar to that induced by the previously known peptide, 1-20. Several other peptides elicited mild disease with lower incidence. Some peptides elicited EAU only in WT recipients of IRBP KO splenocytes. In the B10.RIII strain, two major new uveitogenic peptides were identified, 171-190 and 541-560, and several others elicited moderate disease. Unlike in C57BL/6 mice, adoptive transfer of WT B10.RIII with IRBP KO splenocytes did not reveal additional uveitogenic epitopes. Both CD4 and CD8 lymphocyte subsets proliferated to pathogenic peptides. CONCLUSIONS. Several new pathogenic peptides of IRBP were identified in C57BL/6 and B10.RIII mice. Differences in epitope recognition between WT and IRBP KO mice were observed in C57BL/6 mice, but not in B10.RIII mice, suggesting more extensive culling of the repertoire in C57BL/6 mice by endogenously expressed IRBP. C1 [Cortes, Lizette M.; Mattapallil, Mary J.; Silver, Phyllis B.; Zhu, Wei; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Donoso, Larry A.] Philadelphia Retina Endowment Fund, Philadelphia, PA USA. [Liou, Gregory I.] Med Coll Georgia, Dept Ophthalmol, Augusta, GA 30912 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N222, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS [Z01 EY000184-25, Z99 EY999999] NR 26 TC 21 Z9 21 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2008 VL 49 IS 5 BP 1946 EP 1956 DI 10.1167/iovs.07-0868 PG 11 WC Ophthalmology SC Ophthalmology GA 292UH UT WOS:000255291100028 PM 18436827 ER PT J AU Mattapallil, MJ Augello, A Cheadle, C Teichberg, D Becker, KG Chan, CC Mattapallil, JJ Pennesi, G Caspi, RR AF Mattapallil, Mary J. Augello, Andrea Cheadle, Chris Teichberg, Diane Becker, Kevin G. Chan, Chi-Chao Mattapallil, Joseph J. Pennesi, Giuseppina Caspi, Rachel R. TI Differentially expressed genes in MHC-compatible rat strains that are susceptible or resistant to experimental autoimmune uveitis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID PERIPHERAL-BLOOD LEUKOCYTES; SERUM LEPTIN CONCENTRATION; AGE-RELATED-CHANGES; NEUROPEPTIDE-Y; CHEMOTACTIC PROTEIN-1; RHEUMATOID-ARTHRITIS; NK CELLS; IN-VIVO; ENCEPHALOMYELITIS; IDENTIFICATION AB PURPOSE. Experimental autoimmune uveitis (EAU) is an established model for immune-mediated human uveitis. Although several genes from major histocompatibility complex (MHC) loci have been shown to play a role in uveitis, little is known about the role of non-MHC genes in the pathogenesis of EAU. Several non-MHC genes have been implicated in the pathogenesis of various autoimmune diseases. The primary objective of this study was to identify the non-MHC genes involved in the pathogenesis of EAU, to identify potential drug targets and possibly to target their protein products for immunotherapy. METHODS. EAU was induced in the susceptible (Lewis; LEW) or resistant (Fischer 344; F344) rats that have identical MHC class II haplotype. Draining lymph node cells were obtained during the innate and adaptive phase of the immune response, and the pattern of gene expression was evaluated using microarray technology. Differentially expressed genes were validated at mRNA and protein levels using various methods. RESULTS. Susceptibility to EAU was associated with an increased expression of numerous non-MHC genes such as Th1-type cytokines and chemokines, antiapoptotic factors, hormones, and neurotransmitters and a downregulation of selected adhesion molecules. In this study a combined genetic-genomic approach was used to identify different patterns of gene expression associated with the sensitization and effector phase of EAU pathogenesis. CONCLUSIONS. The data demonstrate that the differential expression of several non-MHC genes is associated with the mechanism of uveitis. C1 [Mattapallil, Mary J.; Chan, Chi-Chao; Caspi, Rachel R.] Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. [Mattapallil, Mary J.; Chan, Chi-Chao; Caspi, Rachel R.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Augello, Andrea; Pennesi, Giuseppina] Natl Inst Canc Res, Genoa, Italy. [Cheadle, Chris; Teichberg, Diane; Becker, Kevin G.] NIA, DNA Array Unit, NIH, Baltimore, MD 21224 USA. [Mattapallil, Joseph J.] Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. RP Pennesi, G (reprint author), Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. EM rcaspi@helix.nih.gov; rcaspi@helix.nih.gov RI Augello, Andrea/C-7321-2013; OI Augello, Andrea/0000-0001-5959-7989; Caspi, Rachel/0000-0002-7140-7671; Becker, Kevin/0000-0002-6794-6656 FU Intramural NIH HHS [Z99 EY999999, Z01 EY000184-25]; NIAID NIH HHS [K22 AI071812, K22 AI071812-01, K22 AI071812-02]; NIDCR NIH HHS [R21 DE018339, R21 DE018339-01, R21 DE018339-02, R21 DE018339-02S1] NR 46 TC 8 Z9 10 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2008 VL 49 IS 5 BP 1957 EP 1970 DI 10.1167/iovs.07-1295 PG 14 WC Ophthalmology SC Ophthalmology GA 292UH UT WOS:000255291100029 PM 18281616 ER PT J AU Kim, H Fariss, RN Zhang, C Robinson, SB Thill, M Csaky, KG AF Kim, Hyuncheol Fariss, Robert N. Zhang, Connie Robinson, Shaun B. Thill, Michelle Csaky, Karl G. TI Mapping of the neonatal Fc receptor in the rodent eye SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID BLOOD-BRAIN-BARRIER; IMMUNOGLOBULIN-G; MAMMARY-GLAND; IGG; TRANSPORT; RAT; EXPRESSION; CELLS; COMPLEX; LUNG AB PURPOSE. The neonatal Fc receptor (FcRn) has been known to modulate IgG transport and protect against IgG catabolism, resulting in extension of the serum half-life of IgG. The goal of this study was to localize FcRn receptor expression in the rat's eye. METHODS. The cornea, retina, conjunctiva, ciliary body and iris, retinal pigment epithelium and choroid, and lens were dissected from each rat's eye, and total RNA was purified. The first-strand cDNAs were synthesized and subjected to PCR reaction. For control samples, reverse transcriptase was omitted. A monoclonal antibody against the FcRn heavy chain was used to localize the distribution of the FcRn receptor in ocular tissues. Lymphatic vessels and blood vessels were stained with a rabbit anti-mouse lymphatic vessel endothelial receptor-1 polyclonal antibody and a rabbit anti-human von Willebrand factor polyclonal antibody, respectively. RESULTS. RT-PCR demonstrated expression of FcRn RNA in cornea, retina, conjunctiva, ciliary body and iris, and lens but absence of expression in the retinal pigment epithelium and choroid. Immunohistochemistry and double staining confirmed the expression of FcRn receptor to the conjunctival lymphatic vessels but not in the conjunctival blood vessels. In the ciliary body, the FcRn receptor was found to be expressed in both the nonpigmented ciliary epithelium and the ciliary blood vessels. The expression of FcRn receptor was confirmed in the retinal blood vessels, iris blood vessels, optic nerve vascular structures, corneal epithelium and endothelium, and lens epithelium. CONCLUSIONS. The FcRn receptor is expressed in multiple ocular tissues. The blood-ocular barrier showed FcRn receptor expression, indicating that IgG transport from ocular tissues to the blood system may use this receptor. The role of the FcRn receptor in the anterior segment and the conjunctiva remains unclear. C1 [Kim, Hyuncheol; Robinson, Shaun B.; Csaky, Karl G.] Duke Univ, Ctr Eye, Dept Ophthalmol, Durham, NC 27705 USA. [Fariss, Robert N.] NEI, NIH, Bethesda, MD 20892 USA. [Zhang, Connie; Thill, Michelle] NEI, Lab Retinal Dis & Therapeut, NIH, Bethesda, MD 20892 USA. RP Csaky, KG (reprint author), Duke Univ, Ctr Eye, Dept Ophthalmol, DUMC Box 3802,2530 Erwin, Durham, NC 27705 USA. EM karl.csaky@duke.edu FU Intramural NIH HHS [Z99 EY999999]; PHS HHS [VF/GK 018158] NR 27 TC 39 Z9 39 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAY PY 2008 VL 49 IS 5 BP 2025 EP 2029 DI 10.1167/iovs.07-0871 PG 5 WC Ophthalmology SC Ophthalmology GA 292UH UT WOS:000255291100038 PM 18436836 ER PT J AU Marsan, NA Arai, AE van Rossum, AC Zamorano, JL Bax, JJ AF Marsan, Nina Ajmone Arai, Andrew E. van Rossum, Albert C. Zamorano, Jose Luis Bax, Jeroen J. TI Imaging Highlights From the European Association of Echocardiography and the Society of Cardiovascular Magnetic Resonance SO JACC-CARDIOVASCULAR IMAGING LA English DT Article C1 [Bax, Jeroen J.] Leiden Univ, Med Ctr, Dept Cardiol, NL-2333 ZA Leiden, Netherlands. [Arai, Andrew E.] NHLBI, Bethesda, MD 20892 USA. [van Rossum, Albert C.] Free Univ Amsterdam, Amsterdam, Netherlands. [Zamorano, Jose Luis] Hosp Clin San Carlos, Madrid, Spain. RP Bax, JJ (reprint author), Leiden Univ, Med Ctr, Dept Cardiol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands. EM j.j.bax@lumc.nl FU European Society of Cardiology; Medtronic; BMS Medical Imaging; Boston Scientific FX Dr. Marsan is financially supported by the Research Fellowship of the European Society of Cardiology. Dr. Bax has received research grants from Medtronic, Boston Scientific, and BMS Medical Imaging. NR 28 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD MAY PY 2008 VL 1 IS 3 BP 380 EP 389 DI 10.1016/j.jcmg.2008.03.008 PG 10 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA V13EJ UT WOS:000207649800017 PM 19356453 ER PT J AU Bingham, RJ AF Bingham, Raymond J. TI Annotated bibliography of NINR findings on women's health in pregnancy and childbirth: 2008 update SO JOGNN-JOURNAL OF OBSTETRIC GYNECOLOGIC AND NEONATAL NURSING LA English DT Article C1 NINR, Off Sci Policy & Publ Liaison, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Bingham, RJ (reprint author), NINR, Off Sci Policy & Publ Liaison, NIH, US Dept HHS, 31 Ctr Dr,MSC-2178,Bldg 31,Room 5B-10, Bethesda, MD 20892 USA. EM binghamr@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0884-2175 J9 JOGNN-J OBST GYN NEO JI JOGNN PD MAY-JUN PY 2008 VL 37 IS 3 BP 350 EP 352 DI 10.1111/j.1552-6909.2008.00244.x PG 3 WC Nursing; Obstetrics & Gynecology SC Nursing; Obstetrics & Gynecology GA 306ID UT WOS:000256240600014 PM 18507605 ER PT J AU Thato, R Jenkins, RA Dusitsin, N AF Thato, R. Jenkins, R. A. Dusitsin, N. TI Effects of the culturally-sensitive comprehensive sex education programme among Thai secondary school students SO JOURNAL OF ADVANCED NURSING LA English DT Article DE abstinence; cognitive social learning theory; comprehensive sex education; culture; premarital sex; programme evaluation; school nurses; sexual intercourse ID SEXUALLY-TRANSMITTED DISEASES; HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; RISK-REDUCTION INTERVENTIONS; HIV PREVENTION INTERVENTION; CONDOM USE; VOCATIONAL STUDENTS; NORTHERN THAILAND; AFRICAN-AMERICAN; YOUNG MEN AB Aim. This paper reports on a study to evaluate the effectiveness of a culturally-sensitive comprehensive sex education programme among Thai secondary school students. Background. Increasing number of adolescents in Thailand have been engaging in premarital sex. No theory-based, abstinence-oriented models of sex education have been evaluated in this population. Method. A quasi-experimental study was conducted in 2006-2007. Outcome measures included sexual behaviour, condom use, intention to refuse sex, intention to use condoms, and knowledge regarding sexually transmitted infections/human immunodeficiency virus/acquired immunodeficiency syndrome and pregnancy. Findings. Students in the experimental group had lower levels of reported sexual intercourse at 3- and 6-month follow-ups, compared with those in control group (P < 0.01). Students participating in the programme had significantly greater intention to refuse sex in the future across time than controls (P < 0.05). Sexually active adolescents participating in the programme reported significantly lower frequencies of sexual intercourse across time than controls (P < 0.01). However, the programme did not influence consistent condom use (P > 0.05), although the intervention was associated with increased intention to use condoms (P < 0.01). Knowledge about sexually transmitted infections/human immunodeficiency virus/acquired immunodeficiency syndrome and pregnancy among students in the intervention group was significantly greater than that of the controls (P < 0.05). Conclusion. School nurses can play a major role by applying this kind of sex education programme. For nurse researchers, it would be useful to extend this research by considering alternative ways to foster condom use in the non-commercial partnerships that have become common among adolescents. C1 [Thato, R.] Chulalongkorn Univ, Fac Nursing, Bangkok, Thailand. [Dusitsin, N.] Chulalongkorn Univ, Inst Hlth Res, Ctr Res & Dev Sexual Educ, Bangkok, Thailand. [Jenkins, R. A.] Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD USA. RP Thato, R (reprint author), Chulalongkorn Univ, Fac Nursing, Bangkok, Thailand. EM ratsiri99@gmail.com NR 61 TC 17 Z9 18 U1 4 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0309-2402 J9 J ADV NURS JI J. Adv. Nurs. PD MAY PY 2008 VL 62 IS 4 BP 457 EP 469 DI 10.1111/j.1365-2648.2008.04609.x PG 13 WC Nursing SC Nursing GA 298VG UT WOS:000255714600006 PM 18476946 ER PT J AU O'Connor, GT Neas, L Vaughn, B Kattan, M Mitchell, H Crain, EF Evans, R Gruchalla, R Morgan, W Stout, J Adams, GK Lippmann, M AF O'Connor, George T. Neas, Lucas Vaughn, Benjamin Kattan, Meyer Mitchell, Herman Crain, Ellen F. Evans, Richard, III Gruchalla, Rebecca Morgan, Wayne Stout, James Adams, G. Kenneth Lippmann, Morton TI Acute respiratory health effects of air pollution on children with asthma in US inner cities SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE nitrogen dioxide; ozone; sulfur dioxide; carbon monoxide; fine particle emissions; asthma in children ID PEAK EXPIRATORY FLOW; FINE PARTICLES; DAILY MORTALITY; ENVIRONMENTAL INTERVENTION; HOSPITAL ADMISSIONS; CHILDHOOD ASTHMA; SYMPTOM SEVERITY; MEDICATION USE; MEXICO-CITY; URBAN AIR AB Background: Children with asthma in inner-city communities may be particularly vulnerable to adverse effects of air pollution because of their airways disease and exposure to relatively high levels of motor vehicle emissions. Objective: To investigate the association between fluctuations in outdoor air pollution and asthma morbidity among inner-city children with asthma. Methods: We analyzed data from 861 children with persistent asthma in 7 US urban communities who performed 2-week periods of twice-daily pulmonary function testing every 6 months for 2 years. Asthma symptom data were collected every 2 months. Daily pollution measurements were obtained from the Aerometric Information Retrieval System. The relationship of lung function and symptoms to fluctuations in pollutant concentrations was examined by using mixed models. Results: Almost all pollutant concentrations measured were below the National Ambient Air Quality Standards. In single-pollutant models, higher 5-day average concentrations of NO(2), sulfur dioxide, and particles smaller than 2.5 mu m were associated with significantly lower pulmonary function. Higher pollutant levels were independently associated with reduced lung function in a 3-pollutant model. Higher concentrations of NO(2) and particles smaller than 2.5 mu m were associated with asthma-related missed school days, and higher NO(2) concentrations were associated with asthma symptoms. Conclusion: Among inner-city children with asthma, short-term increases in air pollutant concentrations below the National Ambient Air Quality Standards were associated with adverse respiratory health effects. The associations with NO(2) suggest that motor vehicle emissions may be causing excess morbidity in this population. C1 [O'Connor, George T.] Boston Univ, Sch Med, Ctr Pulm, Dept Med, Boston, MA 02118 USA. [Neas, Lucas; Mitchell, Herman] US EPA, Res Triangle Pk, NC 27711 USA. [Vaughn, Benjamin] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Kattan, Meyer] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. [Crain, Ellen F.] Albert Einstein Coll Med, Dept Pediat Emergency Med, Jacobi Med Ctr, Bronx, NY 10467 USA. [Evans, Richard, III] Northwestern Univ, Sch Med, Dept Pediat & Med, Chicago, IL 60611 USA. [Gruchalla, Rebecca] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Gruchalla, Rebecca] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Morgan, Wayne] Univ Arizona, Coll Med, Resp Sci Ctr, Tucson, AZ 85721 USA. [Stout, James] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. [Adams, G. Kenneth] Natl Inst Allergy & Infect Dis, Bethesda, MD USA. [Lippmann, Morton] NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY USA. RP O'Connor, GT (reprint author), Boston Univ, Sch Med, Ctr Pulm, Dept Med, 715 Albany St,Room 304, Boston, MA 02118 USA. EM goconnor@bu.edu RI Neas, Lucas/J-9378-2012; Osborne, Nicholas/N-4915-2015; OI Osborne, Nicholas/0000-0002-6700-2284; O'Connor, George/0000-0002-6476-3926 FU NCRR NIH HHS [M01RR00533]; NIAID NIH HHS [AI-39901, AI-39761, AI-39769, AI-39776, AI-39785, AI-39789, AI-39900, AI-39902] NR 44 TC 87 Z9 95 U1 5 U2 23 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2008 VL 121 IS 5 BP 1133 EP 1139 DI 10.1016/j.jaci.2008.02.020 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 302IJ UT WOS:000255961700009 PM 18405952 ER PT J AU Lee, JH Kim, JW Ko, NY Mun, SH Her, E Kim, BK Han, JW Lee, HY Beaven, MA Kim, YM Choi, WS AF Lee, Jun Ho Kim, Jie Wan Ko, Na Young Mun, Se Hwan Her, Erk Kim, Bo Kyung Han, Jeung Whan Lee, Hoi Young Beaven, Michael A. Kim, Young Mi Choi, Wahn Soo TI Curcumin, a constituent of curry, suppresses IgE-mediated allergic response and mast cell activation at the level of Syk SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE curry spice; curcumin; allergy; passive cutaneous anaphylaxis; inast cells; IgE; Syk kinase ID AIRWAY HYPERRESPONSIVENESS; KINASE INHIBITOR; RBL-2H3 CELLS; 2 PARTS; RECEPTOR; DISEASES; INFLAMMATION; IMMUNOLOGY; SYMPTOMS; RHINITIS AB Background Activation of mast cells through the high-affinity receptor for IgE (Fc epsilon RI) underlies atopic allergic reactions. Curcumin can block this activation, but the mechanism and the effects of curcumin on IgE-mediated allergic reactions are unknown. Objectives: We sought to determine the antiallergic activity of curcumin in vivo and its mechanism of action in mast cells. Methods: The antiallergic activity of curcumin was evaluated in mast cell cultures and the passive cutaneous anaphylaxis model. The effects of curcumin on mast cell signaling events were examined by using immunoblotting, immunoprecipitation, RT-PCR, and other molecular biologic approaches. Results: Curcumin inhibited antigen-mediated activation of mast cells and passive cutaneous anaphylaxis in mice. Suppression of degranulation and secretion of TNF-alpha and IL-4 was apparent at concentrations as low as 3 mu mol/L curcumin in activated mast cells. Similar concentrations of curcumin suppressed Syk-dependent phosphorylations of the adaptor proteins linker of activated T cells and Grb2-associated binder 2, which are critical for mast cell activation. Although curcumin did not inhibit the phosphorylation of Syk itself, it directly inhibited Syk kinase activity in vitro. Further downstream, activating phosphorylations of Akt and the mitogen-activated protein kinases p38, p44/42 (extracellular signal-regulated kinase 1/2), and c-Jun N-terminal kinase, which are critical for the production of inflammatory cytokines, were also inhibited. Conclusions: Curcumin inhibits Syk kinase-dependent signaling events in mast cells and might thus contribute to its antiallergic activity. Therefore curcumin might be useful for the treatment of mast cell-related immediate and delayed allergic diseases. C1 [Lee, Jun Ho; Kim, Jie Wan; Ko, Na Young; Mun, Se Hwan; Her, Erk; Kim, Bo Kyung; Choi, Wahn Soo] Konkuk Univ, Coll Med, Dept Immunol & Physiol, Chungju, South Korea. [Han, Jeung Whan] Sungkyunkwan Univ, Suwon, South Korea. [Lee, Hoi Young] Konyang Univ, Coll Med, Nonsan, South Korea. [Beaven, Michael A.] Lung & Blood Inst, Immunol Lab, Natl Inst Hlth, Bethesda, MD USA. [Kim, Young Mi] Duksung Womens Univ, Coll Pharm, Seoul, South Korea. RP Choi, WS (reprint author), Konkuk Univ, Coll Med, Dept Immunol, Chungju 380701, South Korea. EM wahnchoi@kku.ac.kr FU Intramural NIH HHS NR 44 TC 50 Z9 50 U1 1 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2008 VL 121 IS 5 BP 1225 EP 1231 DI 10.1016/j.jaci.2007.12.1160 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 302IJ UT WOS:000255961700023 PM 18394691 ER PT J AU Gergen, PJ Arbes, SJ Vaughn, B Zeldin, DC AF Gergen, Peter J. Arbes, Samuel J., Jr. Ben Vaughn Zeldin, Dorryl C. TI Self-reported, doctor-diagnosed "asthma" is not necessarily asthma: 78.9% of these "asthma" cases were atopic - Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID CHILDHOOD; DISEASE; ADULTS C1 [Gergen, Peter J.] NIAID, NIH, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Arbes, Samuel J., Jr.; Ben Vaughn] Rho Inc, Chapel Hill, NC USA. [Zeldin, Dorryl C.] Natl Inst Environm Hlth Sci, NIH, Lab Resp Biol, Res Triangle Pk, NC USA. RP Gergen, PJ (reprint author), NIAID, NIH, Div Allergy Immunol & Transplantat, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM zeldin@niebs.nih.gov NR 8 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAY PY 2008 VL 121 IS 5 BP 1291 EP 1292 DI 10.1016/j.jaci.2008.02.022 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 302IJ UT WOS:000255961700035 ER PT J AU da Silva, APG Unks, D Lyu, SC Ma, J Zbozien-Pacamaj, R Chen, X Krensky, AM Clayberger, C AF Galvao da Silva, Ana Paula Unks, Donovan Lyu, Shu-chen Ma, Jeffrey Zbozien-Pacamaj, Renata Chen, Xi Krensky, Alan M. Clayberger, Carol TI In vitro and in vivo antimicrobial activity of granulysin-derived peptides against Vibrio cholerae SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE V. cholerae; antimicrobial peptides; cholera ID FATTY-ACIDS; T-CELLS; ANTIBACTERIAL; LIPOPOLYSACCHARIDE; BACTERIA; DIASTEREOMERS; COLONIZATION; CONJUGATION; PEGYLATION; RESISTANCE AB Objectives: To determine the antibacterial activity of synthetic peptides derived from the cationic antimicrobial peptide granulysin against Vibrio cholerae. Methods: The antibacterial activity of granulysin-derived peptides was assessed in vitro by microtitre and cfu assays. Toxicity against human peripheral blood mononuclear cells (PBMCs) was measured by propidium iodide uptake and haemolysis by measuring the levels of haemoglobin released after incubation of red blood cells (RBCs) with granulysin peptides. The ability of granulysin peptides to control bacterial growth in vivo was tested by the treatment of suckling mice infected with V. cholerae with granulysin peptides, administered by gavage 1 h after infection and determining the number of bacteria in the small and large intestines 24 h after infection. Results: All peptides tested inhibited V. cholerae growth in vitro, and they were more effective against stationary phase cells. Two peptides, G12.21 and G14.15, effectively controlled bacterial growth in vivo. The peptides did not lyse RBCs and, with the exception of two peptides, exhibited very little toxicity against human PBMCs. Conclusions: These results suggest that granulysin-derived peptides are candidates for the development of new agents for the treatment of V. cholerae infection. C1 [Galvao da Silva, Ana Paula; Unks, Donovan; Lyu, Shu-chen; Ma, Jeffrey; Zbozien-Pacamaj, Renata; Chen, Xi; Krensky, Alan M.; Clayberger, Carol] Stanford Univ, Dept Pediat,Sch Med, Div Immunol & Transplantat Biol, CCSR 2105, Stanford, CA 94305 USA. RP Clayberger, C (reprint author), NCI, Cellular & Mol Biol Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM claybergerc@mail.nih.gov RI Galvao, Daniel/A-2744-2010 OI Galvao, Daniel/0000-0002-8209-2281 FU NIAID NIH HHS [R01 AI043348-07, T32 AI007290, U19 AI056548] NR 41 TC 8 Z9 8 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD MAY PY 2008 VL 61 IS 5 BP 1103 EP 1109 DI 10.1093/jac/dkn058 PG 7 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 287ZF UT WOS:000254955300024 PM 18310138 ER PT J AU Trucksess, MW Weaver, CM Oles, CJ Fry, FS Noonan, GO Betz, JM Pader, JI AF Trucksess, Mary W. Weaver, Carol M. Oles, Carolyn J. Fry, Frederick S., Jr. Noonan, Gregory O. Betz, Joseph M. Pader, Jeanne I. TI Determination of aflatoxins B(1), B(2), G(1), and G(2) and ochratoxin A in ginseng and ginger by multitoxin immunoaffinity column cleanup and liquid chromatographic quantitation: Collaborative study SO JOURNAL OF AOAC INTERNATIONAL LA English DT Article ID MEDICINAL-PLANTS; FUMONISINS B-1; PERFORMANCE; PRECISION; DIETARY; HERBS; TEA AB The accuracy, repeatability, and reproducibility characteristics of a method using multitoxin immunoaffinity column cleanup with liquid chromatography (LC) for determination of aflatoxins (AF; sum of aflatoxins B(1), B(2), G(1), and G(2)) and ochratoxin A (OTA) in powdered ginseng and ginger have been established in a collaborative study involving 13 laboratories from 7 countries. Blind duplicate samples of blank, spiked (AF and OTA added) at levels ranging from 0.25 to 16.0 mu g/kg for AF and 0.25 to 8.0 mu g/kg for OTA were analyzed. A naturally contaminated powdered ginger sample was also included. Test samples were extracted with methanol and 0.5% aqueous sodium hydrogen carbonate solution (700 + 300, v/v). The extract was centrifuged, diluted with phosphate buffer (PB), filtered, and applied to an immunoaffinity column containing antibodies specific for AF and OTA. After washing the column with water, the toxins were eluted from the column with methanol, and quantified by high-performance LC with fluorescence detection. Average recoveries of AF from ginseng and ginger ranged from 70 to 87% (at spiking levels ranging from 2 to 16 mu g/kg), and of OTA, from 86 to 113% (at spiking levels ranging from 1 to 8 mu g/kg). Relative standard deviations for with in-laboratory repeatability (RSD(r)) ranged from 2.6 to 8.3% for AF, and from 2.5 to 10.7% for OTA. Relative standard deviations for between-laboratory reproducibility (RSD(R)) ranged from 5.7 to 28.6% for AF, and from 5.5 to 10.7% for OTA. HorRat values were <= 2 for the multi-analytes in the 2 matrixes. C1 [Trucksess, Mary W.; Weaver, Carol M.; Oles, Carolyn J.; Fry, Frederick S., Jr.; Noonan, Gregory O.; Pader, Jeanne I.] US FDA, College Pk, MD 20740 USA. [Betz, Joseph M.] NIH, Bethesda, MD 20892 USA. RP Trucksess, MW (reprint author), US FDA, 5100 Paint Branch Pkwy, College Pk, MD 20740 USA. EM mary.trucksess@fda.hhs.gov FU None [223-01-2464]; PHS HHS [223-01-2464] NR 15 TC 41 Z9 44 U1 2 U2 10 PU AOAC INT PI GAITHERSBURG PA 481 N FREDRICK AVE, STE 500, GAITHERSBURG, MD 20877-2504 USA SN 1060-3271 J9 J AOAC INT JI J. AOAC Int. PD MAY-JUN PY 2008 VL 91 IS 3 BP 511 EP 523 PG 13 WC Chemistry, Analytical; Food Science & Technology SC Chemistry; Food Science & Technology GA 310BU UT WOS:000256504700005 PM 18567295 ER PT J AU Hediger, ML England, LJ Molloy, CA Yu, KF Manning-Courtney, P Mills, JL AF Hediger, Mary L. England, Lucinda J. Molloy, Cynthia A. Yu, Kai F. Manning-Courtney, Patricia Mills, James L. TI Reduced bone cortical thickness in boys with autism or autism spectrum disorder SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE autism; autism spectrum disorder; boys; bone growth; calcium intake; dietary intake ID RETT-SYNDROME; GASTROINTESTINAL SYMPTOMS; DIETARY INTERVENTION; METACARPAL INDEX; HEALTHY-CHILDREN; MINERAL DENSITY; ABNORMALITIES; ASSOCIATION; PREVALENCE; ADRENARCHE AB Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4-8 years. Second metacarpal bone cortical thickness (BCT), measured on hand-wrist radiographs, and % deviations in BCT from reference medians were derived. BCT increased with age, but % deviations evidenced a progressive fall-off (p = .02): +3.1 +/- 4.7%, -6.5 +/- 4.0%, -16.6 +/- 3.4%, -19.4 +/- 3.7%, -24.1 +/- 4.4%, at ages 4-8, respectively, adjusting for height. The 12% of the boys on casein-free diets had an overall % deviation of -18.9 +/- 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (-10.5 +/- 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001). Our data suggest that the bone development of autistic boys should be monitored as part of routine care, especially if they are on casein-free diets. C1 [Hediger, Mary L.; Yu, Kai F.; Mills, James L.] NICHHD, NIH, DESPR, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [England, Lucinda J.] Natl Ctr Chron Dis Prevent & Hlth Promot, Ctr Dis Control & Prevent, Dept Hlth & Human Serv, Div Reprod Hlth, Atlanta, GA USA. [Molloy, Cynthia A.] Univ Cincinnati, Childrens Hosp, Coll Med, Med Ctr,Ctr Epidemiol & Biostat, Cincinnati, OH USA. [Manning-Courtney, Patricia] Cincinnati Childrens Hosp, Kelly O Leary Ctr Austin Spectrum Disorder, Div Dev Disablilities, Cincinnati, OH USA. RP Hediger, ML (reprint author), NICHHD, NIH, DESPR, Dept Hlth & Human Serv, Blbg 6100,Rm 7B03,MSC 7510,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hedigerm@exchange.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD008742] NR 48 TC 63 Z9 69 U1 1 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD MAY PY 2008 VL 38 IS 5 BP 848 EP 856 DI 10.1007/s10803-007-0453-6 PG 9 WC Psychology, Developmental SC Psychology GA 294NL UT WOS:000255412700006 PM 17879151 ER PT J AU Ornsland, A Cockrell, DC Fischer, ER Heinzen, RA AF Ornsland, Anders Cockrell, Diane C. Fischer, Elizabeth R. Heinzen, Robert A. TI Sustained axenic metabolic activity by the obligate intracellular bacterium Coxiella burnetii SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CHLAMYDIA-TRACHOMATIS; Q-FEVER; MYCOBACTERIUM-TUBERCULOSIS; PROTEIN-SYNTHESIS; GENOME SEQUENCE; HOST-CELLS; PH; EXPRESSION; INFECTION; GENE AB Growth of Coxiella burnetii, the agent of Q fever, is strictly limited to colonization of a viable eukaryotic host cell. Following infection, the pathogen replicates exclusively in an acidified (pH 4.5 to 5) phagolysosome-like parasitophorous vacuole. Axenic (host cell free) buffers have been described that activate C. burnetti metabolism in vitro, but metabolism is short-lived, with bacterial protein synthesis halting after a few hours. Here, we describe a complex axenic medium that supports sustained (>24 h) C burnetii metabolic activity. As an initial step in medium development, several biological buffers (pH 4.5) were screened for C burnetii metabolic permissiveness. Based on [S-35]Cys-Met incorporation, C. burnetii displayed optimal metabolic activity in citrate buffer. To compensate for C. burnetii auxotrophies and other potential metabolic deficiencies, we developed a citrate buffer-based medium termed complex Coxiella medium (CCM) that contains a mixture of three complex nutrient sources (neopeptone, fetal bovine serum, and RPMI cell culture medium). Optimal C. burnetii metabolism occurred in CCM with a high chloride concentration (140 mM) while the concentrations of sodium and potassium had little effect on metabolism. CCM supported prolonged de novo protein and ATP synthesis by C. burnetii (>24 h). Moreover, C. burnetii morphological differentiation was induced in CCM as determined by the transition from small-cell variant to large-cell variant. The sustained in vitro metabolic activity of C. burnetii in CCM provides an important tool to investigate the physiology of this organism including developmental transitions and responses to antimicrobial factors associated with the host cell. C1 [Ornsland, Anders; Cockrell, Diane C.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Fischer, Elizabeth R.] NIAID, Microscopy Unit, Res Technol Sect, Res Technol Branch,Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Rocky Mt Labs,NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov NR 43 TC 0 Z9 0 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2008 VL 190 IS 9 BP 3203 EP 3212 DI 10.1128/JB.01911-07 PG 10 WC Microbiology SC Microbiology GA 291MS UT WOS:000255202100014 ER PT J AU Thompson, J Jakubovics, N Abraham, B Hess, S Pikis, A AF Thompson, John Jakubovics, Nicholas Abraham, Bindu Hess, Sonja Pikis, Andreas TI The sim operon facilitates the transport and metabolism of sucrose isomers in Lactobacillus casei ATCC 334 SO JOURNAL OF BACTERIOLOGY LA English DT Article ID DEPENDENT PHOSPHOTRANSFERASE SYSTEM; FUSOBACTERIUM-MORTIFERUM ATCC-25557; SEQUENCE-BASED CLASSIFICATION; GLYCOSIDE HYDROLASE FAMILY-4; CARBON CATABOLITE REPRESSION; PHOSPHO-ALPHA-GLUCOSIDASE; GLUCOSYL-D-FRUCTOSES; THERMOTOGA-MARITIMA; KLEBSIELLA-PNEUMONIAE; BACILLUS-SUBTILIS AB Inspection of the genome sequence of Lactobacillus casei ATCC 334 revealed two operons that might dissimilate the five isomers of sucrose. To test this hypothesis, cells of L. casei ATCC 334 were grown in a defined medium supplemented with various sugars, including each of the five isomeric disaccharides. Extracts prepared from cells grown on the sucrose isomers contained high levels of two polypeptides with M(r)s of similar to 50,000 and similar to 17,500. Neither protein was present in cells grown on glucose, maltose or sucrose. Proteomic, enzymatic, and Western blot analyses identified the similar to 50-kDa protein as an NAD(+)- and metal ion-dependent phospho-a-glucosidase. The oligomeric enzyme was purified, and a catalytic mechanism is proposed. The smaller polypeptide represented an EIIA component of the phosphoenolpyruvate-dependent sugar phosphotransferase system. Phospho-alpha-glucosidase and EIIA are encoded by genes at the LSEI_0369 (simA) and LSEI_0374 (simF) loci, respectively, in a block of seven genes comprising the sucrose isomer metabolism (sim) operon. Northern blot analyses provided evidence that three mRNA transcripts were up-regulated during logarithmic growth of L. casei ATCC 334 on sucrose isomers. Internal simA and simF gene probes hybridized to similar to 1.5- and similar to 1.3-kb transcripts, respectively. A 6.8-kb mRNA transcript was detected by both probes, which was indicative of cotranscription of the entire sim operon. C1 [Jakubovics, Nicholas] NIDCR, NIH, Oral Bioflim Commun Unit, DHHS, Bethesda, MD 20892 USA. [Thompson, John; Pikis, Andreas] NIDCR, NIH, Microbiol Biochem & Genet unit, DHHS, Bethesda, MD 20892 USA. NIDCR, NIH, DHHS, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. NIDDK, NIH, DHHS, Mass Spectormetry Facil, Bethesda, MD 20892 USA. RP Thompson, J (reprint author), NIDCR, NIH, Microbiol Biochem & Genet unit, DHHS, 30,Rm 325,Convent Dr MSC-4350, Bethesda, MD 20892 USA. EM jthompson@dir.nidcr.nih.gov RI Jakubovics, Nicholas/B-1938-2010; Hess, Sonja/K-4842-2013 OI Jakubovics, Nicholas/0000-0001-6667-0515; Hess, Sonja/0000-0002-5904-9816 FU Intramural NIH HHS NR 51 TC 6 Z9 8 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2008 VL 190 IS 9 BP 3362 EP 3373 DI 10.1128/JB.02008-07 PG 12 WC Microbiology SC Microbiology GA 291MS UT WOS:000255202100030 PM 18310337 ER PT J AU Jakubovics, NS Gill, SR Iobst, SE Vickerman, MM Kolenbrander, PE AF Jakubovics, Nicholas S. Gill, Steven R. Iobst, Stacey E. Vickerman, M. M. Kolenbrander, Paul E. TI Regulation of gene expression in a mixed-genus community: Stabilized arginine biosynthesis in Streptococcus gordonii by coaggregation with Actinomyces naeslundii SO JOURNAL OF BACTERIOLOGY LA English DT Article ID AMINO-ACID REQUIREMENTS; HUMAN DENTAL PLAQUE; PYRUVATE OXIDASE; ORAL STREPTOCOCCI; INTERGENERIC COMMUNICATION; LACTOBACILLUS-PLANTARUM; VISCOSUS T14V; BIOFILMS; GROWTH; IDENTIFICATION AB Interactions involving genetically distinct bacteria, for example, between oral streptococci and actinomyces, are central to dental plaque development. A DNA microarray identified Streptococcus gordonii genes regulated in response to coaggregation with Actinomyces naeslundii. The expression of 23 genes changed >3-fold in coaggregates, including that of 9 genes involved in arginine biosynthesis and transport. The capacity of S. gordonii to synthesize arginine was assessed using a chemically defined growth medium. In monoculture, streptococcal arginine biosynthesis was inefficient and streptococci could not grow aerobically at low arginine concentrations. In dual-species cultures containing coaggregates, however, S. gordonii grew to high cell density at low arginine concentrations. Equivalent cocultures without coaggregates showed no growth until coaggregation was evident (9 h). An argH mutant was unable to grow at low arginine concentrations with or without A. naeslundii, indicating that arginine biosynthesis was essential for coaggregation-induced streptococcal growth. Using quantitative reverse transcriptase PCR, the expression of argC, argG, and pyrA(b) was strongly (10- to 100-fold) up-regulated in S. gordonii monocultures after 3 h of growth when exogenous arginine was depleted. Cocultures without induced coaggregation showed similar regulation. However, within 1 h after coaggregation with A. naeslundii, the expression of argC, argG, and pyrA(b) in S. gordonii was partially upregulated although arginine was plentiful, and mRNA levels did not increase further when arginine was diminished. Thus, A. naeslundii stabilizes S. gordonii expression of arginine biosynthesis genes in coaggregates but not cocultures and enables aerobic growth when exogenous arginine is limited. C1 [Jakubovics, Nicholas S.; Kolenbrander, Paul E.] NIDCR, NIH, Bethesda, MD 20892 USA. [Gill, Steven R.; Vickerman, M. M.] SUNY Buffalo, Sch Dent, Dept Oral Biol, Buffalo, NY 14260 USA. [Vickerman, M. M.] SUNY Buffalo, Sch Dent, Dept Periodont & Endodont, Buffalo, NY 14260 USA. [Gill, Steven R.; Iobst, Stacey E.] Inst Genom Res, Rockville, MD 20850 USA. RP Kolenbrander, PE (reprint author), NIDCR, NIH, Bldg 30,Room 310,Convent Dr,MSC 4350, Bethesda, MD 20892 USA. EM pkolenbrander@dir.nidcr.nih.gov RI Jakubovics, Nicholas/B-1938-2010 OI Jakubovics, Nicholas/0000-0001-6667-0515 FU Intramural NIH HHS; NIDCR NIH HHS [DE11090, R01 DE011090, R29 DE011090] NR 58 TC 53 Z9 55 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAY PY 2008 VL 190 IS 10 BP 3646 EP 3657 DI 10.1128/JB.00088-08 PG 12 WC Microbiology SC Microbiology GA 297ND UT WOS:000255622500025 PM 18359813 ER PT J AU Koushik, SV Vogel, SS AF Koushik, Srinagesh V. Vogel, Steven S. TI Energy migration alters the fluorescence lifetime of Cerulean: implications for fluorescence lifetime imaging Forster resonance energy transfer measurements SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE energy-migration resonance energy transfer; EM-RET; homo-fret; fluorescent proteins; Cerulean and Venus ID LIVING CELLS; REFRACTIVE-INDEX; MOLECULAR-INTERACTIONS; 2-PHOTON EXCITATION; TRANSFER MICROSCOPY; LIVE CELLS; PROTEIN; FRET; MEMBRANES; VARIANT AB Forster resonance energy transfer (FRET) is a physical phenomenon used to study molecular interactions in living cells. Changes in the fluorescence lifetime of proteins genetically tagged with a donor fluorophore, such as cyan fluorescent protein or Cerulean, are used to measure energy transfer to a protein tagged with an acceptor fluorophore (yellow fluorescent protein or Venus). Increased transfer efficiency is usually interpreted as closer proximity. Resonance energy transfer is also possible between identical fluorophores. This form of FRET is called energy migration resonance energy transfer (EM-RET). Theoretically, EM-RET should not alter the lifetime or emission spectrum measured from a population of fluorophores. We find a change in the fluorescent lifetime of Cerulean that correlates with energy migration and can result in significant errors when using Cerulean as a donor to measure fluorescence lifetime imaging (FLIM)-FRET efficiencies. (c) 2008 Society of Photo-Optical Instrumentation Engineers. C1 [Koushik, Srinagesh V.; Vogel, Steven S.] NIAAA, Lab Mol Physiol, Bethesda, MD 20852 USA. RP Koushik, SV (reprint author), NIAAA, NIH, DICBR, LMP, 5625 Fishers Lane, Rockville, MD 20872 USA. EM koushiks@mail.nih.gov RI Vogel, Steven/A-3585-2012; OI Vogel, Steven/0000-0002-3005-2667 FU Intramural NIH HHS [Z01 AA000452-05] NR 35 TC 31 Z9 31 U1 1 U2 8 PU SPIE-SOC PHOTOPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD MAY-JUN PY 2008 VL 13 IS 3 AR 031204 DI 10.1117/1.2940367 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 330NX UT WOS:000257951200011 PM 18601528 ER PT J AU Vogeli, B Yao, LS Bax, A AF Vogeli, Beat Yao, Lishan Bax, Ad TI Protein backbone motions viewed by intraresidue and sequential H(N)-H(alpha) residual dipolar couplings SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE (1)H-(1)H dipolar coupling; backbone dynamics; GB3; residual dipolar coupling; RDC ID MACROMOLECULAR STRUCTURE DETERMINATION; MODEL-FREE APPROACH; NMR-SPECTROSCOPY; BIOMOLECULAR NMR; SCALAR COUPLINGS; ORIENTED MEDIA; DYNAMICS; RELAXATION; ALIGNMENT; HOMONUCLEAR AB Triple resonance E.COSY-based techniques were used to measure intra-residue and sequential H(N)-H(alpha) stop residual dipolar couplings (RDCs) for the third IgG-binding domain of protein G (GB3), aligned in Pf1 medium. Measurements closely correlate with values predicted on the basis of an NMR structure, previously determined on the basis of a large number of one-bond backbone RDCs measured in five alignment media. However, in particular the sequential H(N)-H(alpha) RDCs are smaller than predicted for a static structure, suggesting a degree of motion for these internuclear vectors that exceeds that of the backbone amide N-H vectors. Of all experimentally determined GB3 structures available, the best correlation between experimental (1)H-(1)H couplings is observed for a GB3 ensemble, previously derived to generate a realistic picture of the conformational space sampled by GB3 (Clore and Schwieters, J Mol Biol 355:879-886, 2006). However, for both NMR and X-ray-derived structures the (1)H-(1)H couplings are found to be systematically smaller than expected on the basis of alignment tensors derived from (15)N-(1)H amide RDCs, assuming librationally corrected N-H bond lengths of 1.041 angstrom. C1 [Vogeli, Beat; Yao, Lishan; Bax, Ad] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Yao, Lishan /C-6961-2009; yao, lishan/H-3662-2012 OI yao, lishan/0000-0003-1797-922X FU Intramural NIH HHS [Z01 DK029020-23] NR 55 TC 24 Z9 24 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD MAY PY 2008 VL 41 IS 1 BP 17 EP 28 DI 10.1007/s10858-008-9237-3 PG 12 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 300YC UT WOS:000255860600004 PM 18458825 ER PT J AU Horvath, KA AF Horvath, Keith A. TI Transmyocardial laser revascularization SO JOURNAL OF CARDIAC SURGERY LA English DT Review ID CORONARY-ARTERY-DISEASE; REFRACTORY ANGINA-PECTORIS; PERCUTANEOUS MYOCARDIAL REVASCULARIZATION; NORWEGIAN RANDOMIZED-TRIAL; 5-YEAR FOLLOW-UP; GROWTH-FACTOR; HOLMIUM-YAG; CANINE MYOCARDIUM; MULTICENTER TRIAL; FUNCTIONAL STATUS AB It has been almost a decade since transmyocardial laser revascularization (TMR) was approved for clinical use in the United States. The safety of TMR was demonstrated initially with nonrandomized studies in which TMR was used as the only treatment for patients with severe angina. TMR efficacy was proven after multiple randomized controlled trials. These revealed significant angina relief compared to maximum medical therapy in patients with diffuse coronary disease not amenable to conventional revascularization. In light of these results, TMR has been used as an adjunct to coronary artery bypass grafting (CABG). By definition, patients treated with this combined therapy have more severe coronary disease and comorbidities that are associated with end-stage atherosclerosis. Combination CABG + TMR has resulted in symptomatic improvement without additional risk. The likely mechanism whereby TMR has provided benefit is the angiogenesis engendered by the laser-tissue interaction. Improved perfusion and concomitant improvement in myocardial function have been observed post-TMR. Additional therapies to enhance the angiogenic response include combining TMR with stem cell-based treatments, which appear to be promising future endeavors. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Horvath, KA (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC 1454,Bldg 10CRC,Room 6-5140, Bethesda, MD 20892 USA. EM khorvath@nih.gov FU Intramural NIH HHS [Z01 HL005071-03] NR 102 TC 15 Z9 19 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0886-0440 J9 J CARDIAC SURG JI J. Card. Surg. PD MAY-JUN PY 2008 VL 23 IS 3 BP 266 EP 276 DI 10.1111/j.1540-8191.2008.00579.x PG 11 WC Cardiac & Cardiovascular Systems; Surgery SC Cardiovascular System & Cardiology; Surgery GA 300PX UT WOS:000255838800021 PM 18435649 ER PT J AU Wesierska-Gadek, J Klima, A Ranftler, C Komina, O Hanover, J Invernizzi, P Penner, E AF Wesierska-Gadek, Jozefa Klima, Anna Ranftler, Carmen Komina, Oxana Hanover, John Invernizzi, Pietro Penner, Edward TI Characterization of the Antibodies to p62 Nucleoporin in Primary Biliary Cirrhosis Using Human Recombinant Antigen SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE ANA; autoimmunity; nuclear pore complexes; p62 nucleoporin; gp210 glycoprotein; nuclear envelope; human recombinant p62 nucleoporin ID NUCLEAR-PORE COMPLEX; ANTINUCLEAR ANTIBODIES; MAJOR GLYCOPROTEIN; LIVER-DISEASE; P53 PROTEIN; AUTOANTIBODIES; ENVELOPE; DOMAIN; POLYPEPTIDE; PHOSPHORYLATION AB Reactivity of sera from patients with primary biliary cirrhosis (PBC) with a 60 kDa component of nuclear Fore complexes (NPCs), purified by affinity chromatography on wheat-germ agglutinin (WGA)-Sepharose, was previously detected. Recently, clinical significance oft he anti-NPC antibodies in P BC became evident. In the light of recent resorts, indicating the correlation of the anti-NPC antibodies with severity and progression of the disease, the characterization of the reactive antigens is becoming essential in the clinical management of patients with PBC. Since accurate autoantibody detection represents one of the fundamental requirements for a reliable testing, we have generated a human recombinant p62 protein and validated an immunoprecipitation assay for the detection of anti-p62. We also demonstrated that the generated human recombinant p62 nucleoporin was modified by N-acetylglucosamine residues. More than 50% of tested PBC sera precipitated S-35-radioactively labeled p62 recombinant nucleoporin and 40% recognized this recombinant antigen by immunoblotting. We compared the reactivity of PBC sera with rat and human nucleoporin. The incidence of anti-p62 nucleoporin positive PBC sera increased by 15% when human recombinant antigen was used. The titer of autoantihodies in p62-positive PBC samples strongly varied. Preadsorption of the PBC sera with p62 recombinant protein completely abolished their reactivity with the antigen. In conclusion, this study unequivocally proves that autoantibodies reacting with the 60 kDa component of NPCs target p62 nucleoporin and, more importantly, Provide a better antigen source for future evaluations of the clinical role of anti-p62 in PBC.J.Cell.Biochem. 104:27-37, 2008. 2007 Wiley-Liss, Inc. C1 [Wesierska-Gadek, Jozefa; Klima, Anna; Ranftler, Carmen; Komina, Oxana] Med Univ Vienna, Dept Med 1, Div Inst Canc Res, Cell Cycle Regulat Grp, A-1090 Vienna, Austria. [Hanover, John] NIH, Bethesda, MD 20892 USA. [Penner, Edward] Med Univ Vienna, Dept Med 3, A-1090 Vienna, Austria. [Invernizzi, Pietro] Univ Milan, Sch Med, San Paolo Hosp, Div Internal Med, Milan, Italy. [Invernizzi, Pietro] Univ Milan, Sch Med, San Paolo Hosp, Liver Unit, Milan, Italy. RP Wesierska-Gadek, J (reprint author), Med Univ Vienna, Dept Med 1, Div Inst Canc Res, Cell Cycle Regulat Grp, Borschkegasse 8 A, A-1090 Vienna, Austria. EM jozefa.gadek-wesierski@meduniwien.ac.at OI Invernizzi, Pietro/0000-0003-3262-1998 NR 34 TC 6 Z9 6 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAY 1 PY 2008 VL 104 IS 1 BP 27 EP 37 DI 10.1002/jcb.21595 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 363OQ UT WOS:000260277000003 PM 17960595 ER PT J AU Wang, T Simbulan-Rosenthal, CM Smulson, ME Chock, PB Yang, DCH AF Wang, Tao Simbulan-Rosenthal, Cynthia M. Smulson, Mark E. Chock, P. Boon Yang, David C. H. TI Polyubiquitylation of PARP-1 Through Ubiquitin K48 Is Modulated by Activated DNA, NAD(+), and Dipeptides SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE poly(ADP-ribose) polymerase; protein degradation; ubiquitylation; poly(ADP-ribose); apoptosis ID DEPENDENT PROTEIN-KINASE; END RULE PATHWAY; POLY(ADP-RIBOSE) POLYMERASE; ADP-RIBOSYLATION; MULTIUBIQUITIN CHAIN; INDUCED APOPTOSIS; TRANSCRIPTION; CELLS; RADIATION; PROTEOLYSIS AB Poly(ADP-ribose) polymerase-1 (PARP-1) is the most abundant and the best-studied isoform of a family of enzymes that catalyze the polymerization of ADP-ribose from NAD(-) onto target proteins. PARP-1 is well known to involve in DNA repair, genomic stability maintenance, transcription regulation, apoptosis, and necrosis. Polyubiquitylation targets proteins towards degradation and regulates cell cycle progression, transcription, and apoptosis. Here we report polyubiquitylation of PARP-1 in mouse fibroblasts in the presence of proteasome inhibitor and in full-lenght recombinant PARP-1 in vitro under standard ubiquitylation assay conditions by immunoprecipitation and immunoblotting. Mutation of ubiquiting K48R but not ubiquitin K63R abolishes polyubiquitylation of PARP-1, indicating that K48 of ubiquitin was used in the formation of polyubiquitin chain and that ubiquitylated PARP-1, indicating that K48 of ubiquitin was used in the formation of polyubiquitin chainand that ubiquitylated PARP-1 is likely destined for degradation. Full-length PARP-1 was ubiquitylated most likely at the N-terminal 24 kDa domain of PARP-1 as suggested by the inhibition of ubiquitylation by activated DNA and the absence of polyubiquitin in the C-terminal 89 kDa PARP-1 derived from caspase-catalyzed cleavage. NAD(1) inhibited ubiquitylation of PARP-1, while dipeptides ArgAla and LeuAla enhanced ubiquitylation of PARP-1. ATP inhibited the synthesis of poly(ADP-ribose) by parp-1 and affinity purified polyubiquitylated PARP-1 was active in PAR synthesis. The results suggest polyubiquitylation of PARP-1 could reuglate poly(ADP-ribosyl)ation of nuclear proteins by PARP-1 and consequently apoptosis and PARP-1 regulated cellular processes through ubiquitin-dependent degradation pathways. I. Cell. Biochem. 104: 318-328, 2008. (C) 2007 Wiley-Liss. Inc. C1 [Wang, Tao; Yang, David C. H.] Georgetown Univ, Dept Chem, Washington, DC 20057 USA. [Simbulan-Rosenthal, Cynthia M.; Smulson, Mark E.] Georgetown Univ, Sch Med, Dept Biochem & Mol Biol, Washington, DC 20007 USA. [Chock, P. Boon] NHLBI, Biochem Lab, Bethesda, MD 20892 USA. RP Yang, DCH (reprint author), 37th & O St NW, Washington, DC 20057 USA. EM yangde@georgetown.edu RI Yang, David/A-7294-2009 FU National Cancer Institute [CA25344, IP01 CA74175] FX We thank Dr. H. Roder and Dr. S. Khorasanizadeh at Fox Chase for ubiquitin cDNA, Dr. Alexander Spoonde for the recombinant PARP1, and Dr. Hamid Boulares in Dr. Mark Smulson's lab for caspase-3. We also thank Dr. Zhao-Qi Wang at IARC in France for providing mouse immortalized PARP-1 +/+ fibroblasts. This work was in part supported by Grants CA25344 to M.E.S. and IP01 CA74175 from the National Cancer Institute. NR 42 TC 18 Z9 20 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-2312 EI 1097-4644 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAY 1 PY 2008 VL 104 IS 1 BP 318 EP 328 DI 10.1002/jcb.21624 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 363OQ UT WOS:000260277000028 PM 18041763 ER PT J AU Henning, EC Latour, LL Warach, S AF Henning, Erica C. Latour, Lawrence L. Warach, Steven TI Verification of enhancement of the CSF space, not parenchyma, in acute stroke patients with early blood-brain barrier disruption SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article; Proceedings Paper CT 15th Annual Meeting of the International-Society-of-Magnetic-Resonance-in-Medicine/European-Society -of-Magnetic-Resonance-in-Medicine-and-Biology CY MAY 12-18, 2007 CL Berlin, GERMANY SP Int Soc Magnet Resonance Med, European Soc Magnet Resonance Med & Biol DE ADC; blood-brain barrier; CSF; FLAIR; HARM; stroke ID MATRIX-METALLOPROTEINASE EXPRESSION; HEMORRHAGIC TRANSFORMATION; CEREBRAL INFARCTION; CONTRAST MATERIAL; ISCHEMIC-INJURY; FOCAL ISCHEMIA; RAT; MATRIX-METALLOPROTEINASE-9; VISUALIZATION; REPERFUSION AB Enhancement on post-contrast fluid-attenuated inversion recovery (FLAIR) images after acute stroke has been attributed to early blood-brain barrier disruption. Using an estimate of parenchymal volume fraction and the apparent diffusion coefficient (ADC), we investigated the relative contributions of cerebral spinal fluid (CSF) and parenchyma to enhancement seen on postcontrast FLAIR. Enhancing regions were found to have low parenchymal volume fractions and high ADC values, approaching that of pure CSF. These findings suggest that contrast enhancement on FLAIR occurs predominately in the CSF space, not parenchyma. C1 [Henning, Erica C.; Latour, Lawrence L.; Warach, Steven] Natl Inst Neurol Disorders & Stroke, NIH, Stroke Branch, Sect Stroke Diagnost & Therapeut, Bethesda, MD 20892 USA. RP Henning, EC (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Stroke Branch, Sect Stroke Diagnost & Therapeut, Bldg 10,Room B1D733,10 Ctr Dr,MSC 1063, Bethesda, MD 20892 USA. EM henninge@ninds.nih.gov RI Henning, Erica/E-8542-2010 FU Intramural NIH HHS [ZIA NS003043-07, ZIA NS003044-08, ZIA NS003120-07, ZIA NS003043-08, , ZIA NS003043-06, ZIA NS003044-07, ZIA NS003120-06] NR 21 TC 20 Z9 20 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAY PY 2008 VL 28 IS 5 BP 882 EP 886 DI 10.1038/sj.jcbfm.9600598 PG 5 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 292JC UT WOS:000255261300002 PM 18091756 ER PT J AU Stefanovic, B Hutchinson, E Yakovleva, V Schram, V Russell, JT Belluscio, L Koretsky, AP Silva, AC AF Stefanovic, Bojana Hutchinson, Elizabeth Yakovleva, Victoria Schram, Vincent Russell, James T. Belluscio, Leonardo Koretsky, Alan P. Silva, Afonso C. TI Functional reactivity of cerebral capillaries SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE brain; cerebral blood volume; functional activation; red blood cell flow; two-photon laser scanning microscopy ID RAT SOMATOSENSORY CORTEX; NITRIC-OXIDE SYNTHASE; BLOOD-FLOW; FOREPAW STIMULATION; MAGNETIC-RESONANCE; NEURONAL-ACTIVITY; ALPHA-CHLORALOSE; OLFACTORY-BULB; CONFOCAL LASER; BARREL CORTEX AB The spatiotemporal evolution of cerebral microcirculatory adjustments to functional brain stimulation is the fundamental determinant of the functional specificity of hemodynamically weighted neuroimaging signals. Very little data, however, exist on the functional reactivity of capillaries, the vessels most proximal to the activated neuronal population. Here, we used two-photon laser scanning microscopy, in combination with intracranial electrophysiology and intravital video microscopy, to explore the changes in cortical hemodynamics, at the level of individual capillaries, in response to steady-state forepaw stimulation in an anesthetized rodent model. Overall, the microcirculatory response to functional stimulation was characterized by a pronounced decrease in vascular transit times (20% +/- 8%), a dilatation of the capillary bed (10.9% +/- 1.2%), and significant increases in red blood cell speed (33.0% +/- 7.7%) and flux (19.5% +/- 6.2%). Capillaries dilated more than the medium-caliber vessels, indicating a decreased heterogeneity in vessel volumes and increased blood flow-carrying capacity during neuronal activation relative to baseline. Capillary dilatation accounted for an estimated similar to 18% of the total change in the focal cerebral blood volume. In support of a capacity for focal redistribution of microvascular flow and volume, significant, though less frequent, local stimulation-induced decreases in capillary volume and erythrocyte speed and flux also occurred. The present findings provide further evidence of a strong functional reactivity of cerebral capillaries and underscore the importance of changes in the capillary geometry in the hemodynamic response to neuronal activation. C1 [Stefanovic, Bojana; Hutchinson, Elizabeth; Yakovleva, Victoria; Belluscio, Leonardo; Koretsky, Alan P.; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Bethesda, MD USA. [Schram, Vincent; Russell, James T.] NICHHD, Bethesda, MD 20892 USA. RP Stefanovic, B (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Cerebral Microcirculat Unit, 10 Ctr Dr,Bldg 10,Room B1D109, Bethesda, MD 20892 USA. EM stefanovicb@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 42 TC 86 Z9 86 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD MAY PY 2008 VL 28 IS 5 BP 961 EP 972 DI 10.1038/sj.jcbfm.9600590 PG 12 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 292JC UT WOS:000255261300011 PM 18059431 ER PT J AU Nieman, LK Biller, BMK Findling, JW Newell-Price, J Savage, MO Stewart, PM Montori, VM AF Nieman, Lynnette K. Biller, Beverly M. K. Findling, James W. Newell-Price, John Savage, Martin O. Stewart, Paul M. Montori, Victor M. TI The diagnosis of Cushing's syndrome: An endocrine society clinical practice guideline SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID DEXAMETHASONE-SUPPRESSION TEST; CORTICOTROPIN-RELEASING HORMONE; URINARY FREE CORTISOL; MIDNIGHT SERUM CORTISOL; PITUITARY-ADRENAL AXIS; PERFORMANCE LIQUID-CHROMATOGRAPHY; NIGHTTIME SALIVARY CORTISOL; CHRONIC-RENAL-FAILURE; STIMULATION TEST; SUBCLINICAL HYPERCORTISOLISM AB Objective: The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome. Participants: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, membersresponding to awebposting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments. Conclusions: After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma. We recommend initial use of one test with high diagnostic accuracy (urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-h dexamethasone suppression test). We recommend that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test. Patients with concordant abnormal results should undergo testing for the cause of Cushing's syndrome. Patients with concordant normal results should not undergo further evaluation. We recommend additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time. C1 [Nieman, Lynnette K.] NIH, Program Reprod & Adult Endocrinol, NICHHD, Bethesda, MD 20892 USA. [Biller, Beverly M. K.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Findling, James W.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Newell-Price, John] Univ Sheffield, Sheffield S10 2JF, S Yorkshire, England. [Savage, Martin O.] Univ London, William Harvey Res Inst, London EC1M 6BQ, England. [Montori, Victor M.] Mayo Clin, Rochester, MN 55905 USA. [Stewart, Paul M.] Univ Birmingham, Birmingham B15 2TT, W Midlands, England. RP Nieman, LK (reprint author), Endocrine Soc, 8401 Connecticut Ave,Suite 900, Chevy Chase, MD 20815 USA. EM govt-prof@endo.society.org OI Montori, Victor/0000-0003-0595-2898 FU Intramural NIH HHS [Z01 HD008833-02] NR 109 TC 679 Z9 737 U1 1 U2 29 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2008 VL 93 IS 5 BP 1526 EP 1540 DI 10.1210/jc.2008-0125 PG 15 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 298CD UT WOS:000255663100002 PM 18334580 ER PT J AU Charmandari, E Kino, T Ichijo, T Chrousos, GP AF Charmandari, Evangelia Kino, Tomoshige Ichijo, Takamasa Chrousos, George P. TI Generalized glucocorticoid resistance: Clinical aspects, molecular mechanisms, and implications of a rare genetic disorder SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Review ID LIGAND-BINDING DOMAIN; PRIMARY CORTISOL RESISTANCE; NF-KAPPA-B; NUCLEAR RECEPTOR; DNA-BINDING; HORMONE-BINDING; POINT MUTATION; RESISTANCE/HYPERSENSITIVITY SYNDROMES; TRANSCRIPTIONAL COACTIVATOR; CUSHINGS-SYNDROME AB Context: Primary generalized glucocorticoid resistance is a rare genetic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. We review the clinical aspects, molecular mechanisms, and implications of this disorder. Evidence Acquisition: We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through February 2008) to identify original articles and reviews on this topic. Evidence Synthesis: We have relied on the experience of a number of experts in the field, including our extensive personal experience. Conclusions: The clinical spectrum of primary generalized glucocorticoid resistance is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue, and/or mineralocorticoid excess. The molecular basis of the condition has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and reduce tissue sensitivity to glucocorticoids. A consequent increase in the activity of the hypothalamic-pituitary-adrenal axis compensates for the reduced sensitivity of peripheral tissues to glucocorticoids at the expense of ACTH hypersecretion-related pathology. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology. C1 [Charmandari, Evangelia; Chrousos, George P.] Acad Athens, Biomed Res Fdn, Div Endocrinol & Metab, Clin Res Ctr, Athens 11527, Greece. [Charmandari, Evangelia; Kino, Tomoshige; Ichijo, Takamasa; Chrousos, George P.] NIH, Endocrinol Sect, Reprod Biol & Med Branch, NICHHD, Bethesda, MD 20892 USA. RP Charmandari, E (reprint author), Acad Athens, Biomed Res Fdn, Div Endocrinol & Metab, Clin Res Ctr, 4 Soranou Tou Efessiou St, Athens 11527, Greece. EM evangelia.charmandari@googlemail.com RI Charmandari, Evangelia/B-6701-2011 FU Intramural NIH HHS NR 71 TC 82 Z9 85 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2008 VL 93 IS 5 BP 1563 EP 1572 DI 10.1210/jc.2008-0040 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 298CD UT WOS:000255663100005 PM 18319312 ER PT J AU Berna, MJ Annibale, B Marignani, M Luong, TV Corleto, V Pace, A Ito, T Liewehr, D Venzon, DJ Delle Fave, G Bordi, C Jensen, RT AF Berna, Marc J. Annibale, Bruno Marignani, Massimo Luong, Tu Vinh Corleto, Vito Pace, Andrea Ito, Tetsuhide Liewehr, David Venzon, David J. Delle Fave, Gianfranco Bordi, Cesare Jensen, Robert T. TI A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: Identification of risk factors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INSTITUTES-OF-HEALTH; LONG-TERM; OXYNTIC MUCOSA; SERUM GASTRIN; HYPERGASTRINEMIA; MANAGEMENT; TUMORS; OMEPRAZOLE; GROWTH; PROLIFERATION AB Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (ZES). These patients can develop proliferative changes of gastric enterochromaffin-like (ECL) cells and gastric carcinoids (ECL-cell tumors). ECL-cell changes have been extensively studied in sporadic ZES patients and can be precursor lesions of gastric carcinoids, but little is known about factors influencing their severity or development of carcinoids in MEN1/ZES patients. Objectives: Our objective was to prospectively analyze ECL-cell changes and gastric carcinoids (ECL-cell tumors) in a large series of MEN1/ZES patients to detect risk factors and deduct clinical guidelines. Setting and Patients: Fifty-seven consecutive MEN1/ZES patients participated in this prospective study at two tertiary-care research centers. Interventions and Outcome Measures: Assessment of MEN1, gastric hypersecretion, and gastroscopy with multiple biopsies was done according to a fixed protocol and tumor status. ECL-cell changes and alpha-human chorionic gonadotropin staining were assessed in each biopsy and correlated with clinical, laboratory, and MEN1 features. Results: ECL-cell proliferative changes were universally present, advanced changes in 53% and carcinoids in 23%. Gastric nodules are common and are frequently associated with carcinoids. Patients with high fasting serum gastrin levels, long disease duration, or a strong alpha-human chorionic gonadotropin staining in a biopsy are at higher risk for an advanced ECL-cell lesion and/or gastric carcinoid. Conclusions: Gastric carcinoids and/or advanced ECL-cell changes are frequent in MEN1/ZES patients, and therefore, regular surveillance gastroscopy with multiple routine biopsies and biopsies of all mucosal lesions are essential. Clinical/laboratory data and biopsy results can be used to identify a subgroup of MEN1/ZES patients with a significantly increased risk for developing gastric carcinoids, allowing development of better surveillance strategies. C1 NIH, Digest Dis Branch, NIDDK, Bethesda, MD 20892 USA. NIH, Biostat & Data Management Sect, NCI, Bethesda, MD 20892 USA. [Annibale, Bruno; Marignani, Massimo; Corleto, Vito; Delle Fave, Gianfranco] Univ Roma La Sapienza, Div Digest & Liver Dis, I-00189 Rome, Italy. [Luong, Tu Vinh; Bordi, Cesare] Univ Parma, Dept Pathol & Lab Med, Sect Anat Pathol, I-43100 Parma, Italy. [Berna, Marc J.; Pace, Andrea] Univ Hamburg Hosp, Dept Internal Med, D-20245 Hamburg, Germany. [Ito, Tetsuhide] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 8128582, Japan. RP Jensen, RT (reprint author), Bldg 10,Room 9C-103,10 Ctr Dr, Bethesda, MD 20892 USA. EM RobertJ@bdg10.niddk.nih.gov FU Intramural NIH HHS NR 45 TC 54 Z9 56 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2008 VL 93 IS 5 BP 1582 EP 1591 DI 10.1210/jc.2007-2279 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 298CD UT WOS:000255663100009 PM 18270260 ER PT J AU Glassberg, MK Elliot, SJ Fritz, J Catanuto, P Potier, M Donahue, R Stetler-Stevenson, W Karl, M AF Glassberg, Marilyn K. Elliot, Sharon J. Fritz, Jason Catanuto, Paola Potier, Mylene Donahue, Roger Stetler-Stevenson, William Karl, Michael TI Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PROTEASOME-DEPENDENT DEGRADATION; STEROID-RECEPTORS; SURFACE BINDING; DISEASE; ALPHA; LAM; EXPRESSION; MODULATORS; PATHWAYS; TURNOVER AB Context: The role of estrogens in the pathogenesis of lymphangioleiomyomatosis (LAM), an aggressive and destructive, eventually fatal lung disease of women, is poorly understood. Objective: The study was conducted to test the hypothesis that the lung disease in LAM is estrogen mediated and to determine whether estrogens contribute to the invasiveness of LAM. Design: In vitro cell culture of spindle-shaped LAM cells(LAMD-SM) were isolated and propagated from affected lungs. Estrogen receptor (ER)-alpha and ER beta analyses were conducted by RT-PCR. ER alpha and ER beta, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinases (MMP)-2 had Western blot analysis for protein assessment. Activity assays were performed for MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2. Assessment of MMP-2 promoter function was done via transfection assays. Cell invasion chambers were used to determine and quantitate cell invasiveness. Setting: The study was conducted at an academic medical center. Patients: Tissue and cells were obtained from patients as outlined in approved institution review board protocol (97/007). Intervention: LAMD-SM cells were treated with a specific MMP-2 antibody or a nonspecific inhibitor, doxycycline. Main Outcome Measures: Activity of MMP-2 and invasiveness of LAMD-SM cells were measured. Results: LAMD-SM cells express functional ERs (ER alpha and ER beta), which undergo rapid intracellular turnover in their unbound state. 17 beta-Estradiol (E-2) enhances the transcriptional ER activity. E-2-induced ER activation increases synthesisandactivity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E-2/ER-mediated increase of MMP-2 promotes LAMD-SM invasiveness, in assays in vitro, which can be inhibited by specific antibodies against MMP-2 or doxycycline, an inhibitor of MMPs. Conclusion: The invasion and destruction of lung parenchyma in LAM is, at least partially, an estrogen-MMP-driven process, which has major implications for therapeutic interventions. C1 Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. Univ Miami, Miller Sch Med, Dept Surg, Miami, FL 33136 USA. [Stetler-Stevenson, William] NIH, NCI, Ctr Canc Res, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Potier, Mylene] CEN Bordeaux Gradignan, Unite Micronutriments Reprod Sanite ENITA Bordeau, F-33175 Gradignan, France. RP Glassberg, MK (reprint author), Univ Miami, Miller Sch Med, Dept Internal Med, Div Pulm & Crit Care Med, Room 1014,1600 NW 10th Ave, Miami, FL 33136 USA. EM mglassbe@med.miami.edu RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Fritz, Jason/0000-0002-0392-4562 NR 42 TC 36 Z9 39 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAY PY 2008 VL 93 IS 5 BP 1625 EP 1633 DI 10.1210/jc.2007-1283 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 298CD UT WOS:000255663100014 PM 18285421 ER PT J AU Milner, JD Fasth, A Etzioni, A AF Milner, Joshua D. Fasth, Anders Etzioni, Amos TI Autoimmunity in severe combined immunodeficiency (SCID): Lessons from patients and experimental models SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE autoimmunity immunodeficiency; Omenn syndrome; tolerance; AIRE; foxP3 ID OMENN-SYNDROME; T-CELLS; DEFICIENCY; INFECTION; MICE; AIRE AB Autoimmunity is observed in many inummodeficiencies and is thought to be mediated mainly by persistent infection. Severe combined immunodeficiency (SCID) is the most severe form of immunodeficiency and is also on occasion associated with autoimmune phenomena, usually in the form of the Omenn's Syndrome phenotype. Recent studies both in human and mice shed light into the pathogenesis of these two seemingly different conditions occurring together. Central tolerance, which is in charge of elimination of autoreactive T-cell clones, is defective in SCID because of markedly reduced expression of Aire, a transcriptional regulator for the expression of tissue-specific antigens in the thymus. Peripheral tolerance is also markedly decreased in SCID because of several factors including the expansion of T-cell clones as a consequence of the lymphopenia observed in these condition as well as a diminished number of T regulatory (FOXP3+)cells, allowing autoreactive T cells to proliferate and infiltrate various organs in the body of SCID. It is thus of no surprise when both central and peripheral tolerance arc! impaired that autoimmunity can be observed in SCID. C1 [Etzioni, Amos] Technion Israel Inst Technol, Meyer Childrens Hosp, Rappaport Sch Med, Haifa, Israel. [Milner, Joshua D.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Fasth, Anders] Gothenburg Univ, Dept Pediat, S-41124 Gothenburg, Sweden. [Fasth, Anders] Queen Silvia Childrens Hosp, Gothenburg, Sweden. RP Etzioni, A (reprint author), Technion Israel Inst Technol, Meyer Childrens Hosp, Rappaport Sch Med, Haifa, Israel. EM etzioni@rambam.health.gov.il OI Fasth, Anders/0000-0002-0033-740X FU Intramural NIH HHS NR 20 TC 17 Z9 17 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAY PY 2008 VL 28 SU 1 BP S29 EP S33 DI 10.1007/s10875-007-9159-y PG 5 WC Immunology SC Immunology GA 319WL UT WOS:000257195600005 PM 18193342 ER PT J AU Manolio, TA Brooks, LD Collins, FS AF Manolio, Teri A. Brooks, Lisa D. Collins, Francis S. TI A HapMap harvest of insights into the genetics of common disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Review ID GENOME-WIDE ASSOCIATION; AMYOTROPHIC-LATERAL-SCLEROSIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CORONARY-ARTERY-DISEASE; COPY-NUMBER VARIATION; MACULAR DEGENERATION; SEQUENCE VARIANTS; COLORECTAL-CANCER; BREAST-CANCER; SUSCEPTIBILITY VARIANTS AB The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that win be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new fight on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science. C1 [Manolio, Teri A.; Brooks, Lisa D.; Collins, Francis S.] NHGRI, Bethesda, MD 20892 USA. RP Manolio, TA (reprint author), NHGRI, 31 Ctr Dr,Room 4B-09, Bethesda, MD 20892 USA. EM manolio@nih.gov NR 137 TC 568 Z9 591 U1 3 U2 30 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2008 VL 118 IS 5 BP 1590 EP 1605 DI 10.1172/JCI34772 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 295QX UT WOS:000255490100002 PM 18451988 ER PT J AU Matsumoto, S Hyodo, F Subramanian, S Devasahayam, N Munasinghe, J Hyodo, E Gadisetti, C Cook, JA Mitchell, JB Krishna, MC AF Matsumoto, Shingo Hyodo, Fuminori Subramanian, Sankaran Devasahayam, Nallathamby Munasinghe, Jeeva Hyodo, Emi Gadisetti, Chandramouli Cook, John A. Mitchell, James B. Krishna, Murali C. TI Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID O2 TENSION MEASUREMENTS; IN-VIVO; UTERINE CERVIX; ADVANCED CANCER; ARTERIAL WATER; SOLID TUMORS; RAT-BRAIN; HYPOXIA; TIME; SPECTROSCOPY AB A priori knowledge of spatial and temporal changes in partial pressure of oxygen (oxygenation; PO2) in solid tumors, a key prognostic factor in cancer treatment outcome, could greatly improve treatment planning in radiotherapy and chemotherapy. Pulsed electron paramagnetic resonance imaging (EPRI) provides quantitative 3D maps of tissue PO2 in living objects. In this study, we implemented an EPRI set-up that could acquire PO2 maps in almost real time for 2D and in minutes for 3D. We also designed a combined EPRI and MRI system that enabled generation of pO(2) maps with anatomic guidance. Using EPRI and an air/carbogen (95% O-2 plus 5% CO2) breathing cycle, we visualized perfusion-limited hypoxia in murine tumors. The relationship between tumor blood perfusion and PO2 status was examined, and it was found that significant hypoxia existed even in regions that exhibited blood flow. In addition, high levels of lactate were identified even in normoxic tumor regions, suggesting the predominance of aerobic glycolysis in murine tumors. This report presents a rapid, noninvasive method to obtain quantitative maps of PO2 in tumors, reported with anatomy, with precision. In addition, this method may also be useful for studying the relationship between PO2 status and tumor-specific phenotypes such as aerobic glycolysis. C1 [Matsumoto, Shingo; Hyodo, Fuminori; Subramanian, Sankaran; Devasahayam, Nallathamby; Hyodo, Emi; Cook, John A.; Mitchell, James B.; Krishna, Murali C.] Natl Canc Inst, Canc Res Ctr, Radiat Biol Branch, Bethesda, MD 20892 USA. [Munasinghe, Jeeva] Natl Canc Inst, NINDS, NIH, Bethesda, MD USA. [Gadisetti, Chandramouli] Natl Canc Inst, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. RP Matsumoto, S (reprint author), Natl Canc Inst, Canc Res Ctr, Radiat Biol Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 51 TC 64 Z9 64 U1 1 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD MAY PY 2008 VL 118 IS 5 BP 1965 EP 1973 DI 10.1172/JCI34928 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 295QX UT WOS:000255490100039 PM 18431513 ER PT J AU Haller, DG Cassidy, J Clarke, SJ Cunningham, D Van Cutsem, E Hoff, PM Rothenberg, ML Saltz, LB Schmoll, HJ Allegra, C Bertino, JR Douillard, JY Gustavsson, BG Milano, G O'Connell, M Rustum, Y Tabernero, J Gilberg, F Sirzen, F Twelves, C AF Haller, Daniel G. Cassidy, Jim Clarke, Stephen J. Cunningham, David Van Cutsem, Eric Hoff, Paulo M. Rothenberg, Mace L. Saltz, Leonard B. Schmoll, Hans-Joachim Allegra, Carmen Bertino, Joseph R. Douillard, Jean-Yves Gustavsson, Bengt G. Milano, Gerard O'Connell, Michael Rustum, Youcef Tabernero, Josep Gilberg, Frank Sirzen, Florin Twelves, Chris TI Potential regional differences for the tolerability profiles of fluoropyrimidines SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 8th World Congress on Gastrointestinal Cancer CY JUN, 2006 CL Barcelona, SPAIN ID METASTATIC COLORECTAL-CANCER; III COLON-CANCER; FLUOROURACIL PLUS LEUCOVORIN; PHASE-III; ORAL CAPECITABINE; CONTINUOUS-INFUSION; ADJUVANT TREATMENT; TOXICITY; TRIAL; 5-FLUOROURACIL AB Purpose We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials ( bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. Methods Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States ( US) was compared with non-US countries ( all three studies) and with the rest of the world and East Asia ( adjuvant study). Results In the MCRC studies ( n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions ( RR, 1.72), and discontinuations ( RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study ( n = 1,864), more grade 3/4 AEs ( RR, 1.47) and discontinuations ( RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. Conclusion Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR. C1 Univ Penn, Abraham Canc Ctr, Philadelphia, PA 19104 USA. NSABP Fdn, Philadelphia, PA USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NCI, Navy Med Oncol Branch, Bethesda, MD 20892 USA. Inst Canc Res, New Brunswick, NJ USA. Univ Glasgow, Glasgow, Lanark, Scotland. Royal Marsden Hosp, London SW3 6JJ, England. Univ Leeds, Bradford, W Yorkshire, England. Bradford NHS Trust, Bradford, W Yorkshire, England. Univ Sydney, Sydney, NSW 2006, Australia. Sydney Canc Ctr, Sydney, NSW, Australia. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. Univ Halle Wittenberg, Halle, Germany. Ctr Antoine Lacassagne, F-06054 Nice, France. Gothenburg Univ, Gothenburg, Sweden. Vall Hebron Univ Hosp, Barcelona, Spain. F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland. RP Twelves, C (reprint author), St James Univ Hosp, Canc Res UK clin Ctr, Beckett St, Leeds LS9 7TF, W Yorkshire, England. EM c.j.twelves@leeds.ac.uk OI Saltz, Leonard/0000-0001-8353-4670; Cunningham, David/0000-0001-5158-1069 NR 26 TC 123 Z9 124 U1 0 U2 6 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2008 VL 26 IS 13 BP 2118 EP 2123 DI 10.1200/JCO.2007.15.2090 PG 6 WC Oncology SC Oncology GA 294ZB UT WOS:000255443700012 PM 18445840 ER PT J AU Blumenthal, GM Dennis, PA AF Blumenthal, Gideon M. Dennis, Phillip A. TI Germline PTEN mutations as a cause of early-onset endometrial cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID SPECTRA C1 [Blumenthal, Gideon M.; Dennis, Phillip A.] NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. RP Blumenthal, GM (reprint author), NCI, Ctr Canc Res, Med Oncol Branch, Bethesda, MD 20892 USA. NR 6 TC 5 Z9 6 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 1 PY 2008 VL 26 IS 13 BP 2234 EP 2234 DI 10.1200/JCO.2007.15.8949 PG 1 WC Oncology SC Oncology GA 294ZB UT WOS:000255443700039 PM 18445858 ER PT J AU Sahota, PKC Knowler, WC Looker, HC AF Sahota, Puneet K. C. Knowler, William C. Looker, Helen C. TI Depression, diabetes, and glycemic control in an American Indian community SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; NATIVE-AMERICANS; DOUBLE-BLIND; COMORBID DEPRESSION; AFRICAN-AMERICANS; UNITED-STATES; PIMA-INDIANS; SELF-CARE; SYMPTOMS; MELLITUS AB Objective: American Indians have a high prevalence of diabetes and its complications, and so it may be clinically important to identify psychiatric risk factors for the development of diabetes and its complications in this population. The objectives of this cross-sectional study were (1) to determine whether depression and diabetes are associated in the Pima Indians and (2) to determine if depression is associated with variables indicating risk for development of diabetes or diabetic complications. Method: Adults (aged ! 18 years) who attended research examinations in the Gila River Indian Community in Arizona from July 2003 through January 2007 were included. A sample of 2902 individuals (1121 with diabetes, 1781 without diabetes) was evaluated with the depression module of the Patient Health Questionnaire (DSM-IV criteria), physical examination, and laboratory tests. Results: The prevalence of depression was slightly, but not significantly, higher among participants with diabetes than those without diabetes (12.8% vs. 9.4%, p = .053). Among participants with diabetes, mean glycosylated hemoglobin levels were significantly higher among depressed individuals than among those who were not depressed (9.0% vs. 8.4%, p = .02), even when controlling for age, sex, duration of diabetes, and body mass index (p = .03). In participants without diabetes, mean glycosylated hemoglobin levels were similar among depressed and nondepressed participants (5.4% vs. 5.4%, p = .24). Conclusion: Overall, participants with diabetes had a slightly, but not significantly, higher prevalence of depression than those without diabetes. Among those with diabetes, depression was associated with worse glycemic control. Treatment of depression in Pima Indians with diabetes may improve glycemic control and thereby reduce the risk of diabetic complications. C1 [Sahota, Puneet K. C.; Knowler, William C.; Looker, Helen C.] NIDDK, NIH, Phoenix, AZ 85014 USA. [Sahota, Puneet K. C.] Washington Univ, Sch Med, St Louis, MO USA. RP Sahota, PKC (reprint author), NIDDK, NIH, Phoenix, AZ 85014 USA. EM singhp@msnotes.wustl.edu FU Intramural NIH HHS [Z01 DK069015-25, Z99 DK999999] NR 57 TC 20 Z9 21 U1 1 U2 5 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2008 VL 69 IS 5 BP 800 EP 809 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 306WU UT WOS:000256279600013 PM 18370573 ER PT J AU Nowakowska, C Sachs, GS Zarate, CA Marangell, LB Calabrese, JR Goldberg, JF Ketter, TA AF Nowakowska, Cecylia Sachs, Gary S. Zarate, Carlos A., Jr. Marangell, Lauren B. Calabrese, Joseph R. Goldberg, Joseph F. Ketter, Terence A. TI Increased rate of non-right-handedness in patients with bipolar disorder SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Letter ID SCHIZOPHRENIA; LATERALIZATION; RELATIVES C1 [Nowakowska, Cecylia; Ketter, Terence A.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Sachs, Gary S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Zarate, Carlos A., Jr.] NIMH, Bethesda, MD 20892 USA. [Marangell, Lauren B.] Baylor Coll Med, Houston, TX 77030 USA. [Calabrese, Joseph R.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. [Goldberg, Joseph F.] Mt Sinai Sch Med, New York, NY USA. RP Nowakowska, C (reprint author), Stanford Univ, Sch Med, Stanford, CA 94305 USA. FU Intramural NIH HHS [Z99 MH999999] NR 15 TC 5 Z9 6 U1 0 U2 0 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD MAY PY 2008 VL 69 IS 5 BP 866 EP 867 PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 306WU UT WOS:000256279600028 PM 18681768 ER PT J AU Dimitrov, DS Feng, Y Prabakaran, P AF Dimitrov, Dimiter S. Feng, Yang Prabakaran, Ponraj TI Antibody-guided nanoparticles SO JOURNAL OF COMPUTATIONAL AND THEORETICAL NANOSCIENCE LA English DT Review DE nanoparticles; antibody; therapeutics; vaccines; cancer ID DRUG-DELIVERY; QUANTUM DOTS; GENE DELIVERY; TARGETED LIPOSOMES; GOLD NANOPARTICLES; CANCER-CELLS; SYSTEMS; MODEL; PERMEABILITY; DIAGNOSTICS AB Solid particles, liquid droplets, gas bubbles, and liquid films between them in colloid systems have been known for decades to possess size-dependent properties that differ from those of the same material in bulk when size is smaller than about 100 nm. Recent advances in physics, chemistry, materials sciences, engineering, and molecular biology, have allowed the development of nanoparticles (size 1 to 100 nm) by combining atoms or molecules one at a time in arrangements that do not occur in nature. Such particles have attracted much attention because of their unique mechanical, electrical and optical properties. This resulted in a renewed interest to various nanoparticles already known for many years, e.g., liposomes, and to the development of new ones, e.g., quantum dots and gold nanoshells. Such particles conjugated to antibodies can improve their binding or/and effector functions or confer new functions, e.g., cytotoxicity, size-dependent fluorescence and light scattering. Compared to engineered antibody based on fusion proteins or chemical conjugates made with other compounds, the nanoparticle-antibody conjugates have the fundamental capability of separating compounds loaded inside the particle, e.g., inside liposomes, from the environment thus avoiding possible toxicity and immunogenicity. In addition, high local concentrations of loaded active substances, e.g., imaging agents, can be achieved. Nanoparticles can also serve as skeletons for construction of multifunctional nanoparticle-antibody conjugates that combine targeting, imaging and therapeutic properties. Thus nanoparticle-antibody conjugates can complement existing diagnostic tools and treatment protocols and offer entirely new possibilities for the diagnosis and treatment of diseases. C1 [Dimitrov, Dimiter S.; Feng, Yang; Prabakaran, Ponraj] NCI, Prot Interact Grp, Ctr Canc Res & Nanobiol Program, CCR,NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, Ctr Canc Res & Nanobiol Program, CCR,NIH, Frederick, MD 21702 USA. RI Ponraj, Prabakaran/D-6325-2011 NR 46 TC 4 Z9 4 U1 3 U2 15 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1546-1955 J9 J COMPUT THEOR NANOS JI J. Comput. Theor. Nanosci. PD MAY PY 2008 VL 5 IS 5 BP 751 EP 759 PG 9 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 300BR UT WOS:000255799800001 ER PT J AU Yadav, H Jain, S Sinha, PR AF Yadav, Hariorn Jain, Shalini Sinha, Pushpalata Ravindra TI Oral administration of dahi containing probiotic Lactobacillus acidophilus and Lactobacillus casei delayed the progression of streptozotocin-induced diabetes in rats SO JOURNAL OF DAIRY RESEARCH LA English DT Article DE diabetes; dahi; probiotics; antihyperlipidemic; antioxidant; Lactobacillus; milk; rat ID SUPEROXIDE-DISMUTASE; ANIMAL-TISSUES; PLASMA; ASSAY; MICE; LIPIDS; MODEL; MILK AB In this study, the effect of dahi containing probiotic Lactobacillus acidophilus NCDC14 and Lactobacillus casei NCDC19 (similar to 73 x 10(8) cfu/g) on progression of streptozotocin (STZ)-induced diabetes in rats (15 g/day/rat) for 28 days was investigated. Feeding of probiotic dahi significantly suppressed the incremental peaks and area under the curve and delayed reduction of insulin secretion during oral glucose tolerance test more than skim milk or control dahi. The feeding of milk products reduced the total cholesterol, triglycerides, LDL and VLDL-cholesterol and increased HDL-cholesterol levels (P<0.05). Moreover, probiotic dahi significantly suppressed STZ-induced oxidative damage in pancreatic tissues by inhibiting the lipid peroxidation and formation of nitric oxide, and preserving antioxidant pool such as glutathione content and activities of superoxide dismutase, catalase and glutathione peroxidase. The results suggest that the supplementation of probiotic Lb. acidophilus and Lb. casei with dahi cultures increased the efficacy of dahi to suppress STZ-induced diabetes in rats by inhibiting depletion of insulin as well as preserving diabetic dyslipidemia, and inhibiting lipid peroxidation and nitrite formation. This may empower antioxidant system of P-cells and may slow down the reduction of insulin and elevation of blood glucose levels. C1 [Yadav, Hariorn; Jain, Shalini; Sinha, Pushpalata Ravindra] Natl Dairy Res Inst, Anim Biochem Div, Karnal 132001, Haryana, India. RP Yadav, H (reprint author), NIDDK, Regenerat Biol Sect, Diabet Branch, NIH,Clin Res Ctr,W Labs, Bldg 10,5-5872 S Dr & Old Georgetown Rd, Bethesda, MD 20892 USA. EM yadavh@mail.nih.gov OI Yadav, Hariom/0000-0003-4504-1597 NR 42 TC 55 Z9 56 U1 0 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0022-0299 EI 1469-7629 J9 J DAIRY RES JI J. Dairy Res. PD MAY PY 2008 VL 75 IS 2 BP 189 EP 195 DI 10.1017/S0022029908003129 PG 7 WC Agriculture, Dairy & Animal Science; Food Science & Technology SC Agriculture; Food Science & Technology GA 312BU UT WOS:000256644900009 PM 18474136 ER PT J AU Qvarnstrom, M Janket, S Jones, JA Nuutinen, P Baird, AE Nunn, ME Van Dyke, TE Meurman, JH AF Qvarnstrom, M. Janket, S. Jones, J. A. Nuutinen, P. Baird, A. E. Nunn, M. E. Van Dyke, T. E. Meurman, J. H. TI Salivary lysozyme and prevalent hypertension SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE salivary lysozyme; hypertension; cytokines; advanced glycation end-products; endothelial dysfunction ID CORONARY-HEART-DISEASE; ADVANCED GLYCATION ENDPRODUCTS; DEPENDENT DIABETES-MELLITUS; ORAL-HEALTH; ENDOTHELIAL DYSFUNCTION; CARDIOVASCULAR EVENTS; METABOLIC SYNDROME; BLOOD-PRESSURE; INFLAMMATION; RISK AB Although the etiology of essential hypertension is not clearly understood, endothelial dysfunction from chronic infection and/or impaired glucose metabolism may be involved. We hypothesized that salivary lysozyme, a marker for oral infection and hyperglycemia, might display a significant relationship with hypertension, an early stage of cardiovascular disease. Logistic regression analyses of the Kuopio Oral Health and Heart Study demonstrated that persons with higher lysozyme levels were more likely to have hypertension, after adjustment for age, gender, smoking, BMI, diabetes, the ratio of total cholesterol to HDL cholesterol, and C-reactive protein. The exposure to increasing quartiles of lysozyme was associated with adjusted Odds Ratios for the outcome, hypertension, 1.00 (referent), 1.25, 1.42, and 2.56 (linear trend p < 0.003). When we restricted the sample to the individuals without heart disease (N = 250), we observed a non-significant trend for increasing odds. Our hypothesis-"high salivary lysozyme levels are associated with the odds of hypertension"-was confirmed. C1 [Janket, S.; Jones, J. A.; Nunn, M. E.; Van Dyke, T. E.] Boston Univ, Sch Dent Med, Hlth Policy & Hlth Serv Res, Boston, MA 02118 USA. [Qvarnstrom, M.] Univ Kuopio, FIN-70211 Kuopio, Finland. [Nuutinen, P.] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Baird, A. E.] NIH, Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. Univ Helsinki, Inst Dent, Helsinki, Finland. Univ Helsinki, Cent Hosp, Helsinki, Finland. RP Janket, S (reprint author), Boston Univ, Sch Dent Med, Hlth Policy & Hlth Serv Res, 100 E Newton St,Rm G-619, Boston, MA 02118 USA. EM skjanket@bu.edu OI Meurman, Jukka/0000-0001-6702-6836 FU NIDCR NIH HHS [DE13191, K24 DE018211A, P01 DE013191, R01 DE015566, R01 DE015566-04] NR 37 TC 9 Z9 9 U1 0 U2 1 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD MAY PY 2008 VL 87 IS 5 BP 480 EP 484 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 292ZC UT WOS:000255303600013 PM 18434581 ER PT J AU Latimer, AE Rivers, SE Rench, TA Katulak, NA Hicks, A Hodorowski, JK Higgins, ET Salovey, P AF Latimer, Amy E. Rivers, Susan E. Rench, Tara A. Katulak, Nicole A. Hicks, Althea Hodorowski, Julie Keany Higgins, E. Tory Salovey, Peter TI A field experiment testing the utility of regulatory fit messages for promoting physical activity SO JOURNAL OF EXPERIMENTAL SOCIAL PSYCHOLOGY LA English DT Article DE physical activity; regulatory focus; message tailoring; persuasion; cancer information service ID PLANNED BEHAVIOR; HEALTH COMMUNICATIONS; RANDOMIZED-TRIAL; FOCUS; PERCEPTIONS; INTEGRATION; INCENTIVES; CONGRUENCY; INTENTIONS; PERSUASION AB Guided by regulatory focus theory, we examined whether messages tailored to individuals' promotion- or prevention-goal orientation (regulatory focus) elicit positive thoughts and feelings about physical activity and increase participation in physical activity. Inactive participants (N = 206) were assigned randomly to receive either promotion-focused or prevention-focused messages encouraging physical activity. Two weeks after message exposure, we assessed participants' thoughts and feelings about physical activity and physical activity behavior. Tailored messages that fit individuals' regulatory focus led to greater physical activity participation and more positive feelings than non-fit messages, particularly in the promotion-focused condition. Furthermore, positive retrospective feelings about physical activity mediated the effects of the tailored messages on behavior. These findings provide support for regulatory focus theory and direction for enhancing the effectiveness of messages encouraging physical activity and other health behaviors. (c) 2007 Elsevier Inc. All rights reserved. C1 [Latimer, Amy E.; Rivers, Susan E.; Rench, Tara A.; Katulak, Nicole A.; Salovey, Peter] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Hicks, Althea; Hodorowski, Julie Keany] Mem Sloan Kettering Canc Ctr, Natl Canc Inst, Canc Informat Serv, New York, NY 10021 USA. [Higgins, E. Tory] Columbia Univ, Dept Psychol, New York, NY 10027 USA. RP Latimer, AE (reprint author), Yale Univ, Dept Psychol, POB 208205, New Haven, CT 06520 USA. EM amy.latimer@queensu.ca; peter.salovey@yale.edu OI Hodorowski, Julie/0000-0003-3587-2135 FU NCI NIH HHS [R01 CA068427-10, N02CO51101, R01 CA068427] NR 34 TC 55 Z9 58 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-1031 J9 J EXP SOC PSYCHOL JI J. Exp. Soc. Psychol. PD MAY PY 2008 VL 44 IS 3 BP 826 EP 832 DI 10.1016/j.jesp.2007.07.013 PG 7 WC Psychology, Social SC Psychology GA 298ZJ UT WOS:000255725300039 PM 19543443 ER PT J AU Heidenreich, PA Davis, BR Cutler, JA Furberg, CD Lairson, DR Shlipak, MG Pressel, SL Nwachuku, C Goldman, L AF Heidenreich, Paul A. Davis, Barry R. Cutler, Jeffrey A. Furberg, Curt D. Lairson, David R. Shlipak, Michael G. Pressel, Sara L. Nwachuku, Chuke Goldman, Lee TI Cost-effectiveness of chlorthalidone, amlodipine, and lisinopril as first-step treatment for patients with hypertension: An analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE hypertension; cost-effectiveness; diuretic; angiotensin-converting enzyme inhibitors; calcium channel blockers ID HIGH BLOOD-PRESSURE; DIABETES-MELLITUS; DISEASE; MORTALITY; IMPACT; PREFERENCES; OUTCOMES; BURDEN; STATES; WOMEN AB OBJECTIVE: To evaluate the cost-effectiveness of first-line treatments for hypertension. BACKGROUND: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that first-line treatment with lisinopril or amlodipine was not significantly superior to chlorthalidone in terms of the primary endpoint, so differences in costs may be critical for optimizing decision-making. METHODS: Cost-effectiveness analysis was performed using bootstrap resampling to evaluate uncertainty. RESULTS: Over a patient's lifetime, chlorthalidone was always least expensive (mean $4,802 less than amlodipine, $3,700 less than lisinopril). Amlodipine provided more life-years (LYs) than chlorthalidone in 84% of bootstrap samples (mean 37 days) at an incremental cost-effectiveness ratio of $48,400 per LY gained. Lisinopril provided fewer LYs than chlorthalidone in 55% of bootstrap samples (mean 7-day loss) despite a higher cost. At a threshold of $50,000 per LY gained, amlodipine was preferred in 50%, chlorthalidone in 40%, and lisinopril in 10% of bootstrap samples, but these findings were highly sensitive to the cost of amlodipine and the cost-effectiveness threshold chosen. Incorporating quality of life did not appreciably alter the results. Overall, no reasonable combination of assumptions led to 1 treatment being preferred in over 90% of bootstrap samples. CONCLUSIONS: Initial treatment with chlorthalidone is less expensive than lisinopril or amlodipine, but amlodipine provided a nonsignificantly greater survival benefit and may be a cost-effective alternative. A randomized trial with power to exclude "clinically important" differences in survival will often have inadequate power to determine the most cost-effective treatment. C1 [Davis, Barry R.; Lairson, David R.; Pressel, Sara L.] Univ Texas Houston, Sch Publ Hlth, Coordinat Ctr Clin Trials, Houston, TX 77030 USA. [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Cutler, Jeffrey A.; Nwachuku, Chuke] NHLBI, Bethesda, MD 20892 USA. [Furberg, Curt D.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Goldman, Lee] Columbia Univ, Coll Phys & Surg, New York, NY USA. RP Pressel, SL (reprint author), Univ Texas Houston, Sch Publ Hlth, Coordinat Ctr Clin Trials, 1200 Herman Pressler St,Suite E801, Houston, TX 77030 USA. EM Sara.L.Pressel@uth.tmc.edu OI Heidenreich, Paul/0000-0001-7730-8490 FU NHLBI NIH HHS [N01-HC-35130, N01HC35130] NR 21 TC 16 Z9 17 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD MAY PY 2008 VL 23 IS 5 BP 509 EP 516 DI 10.1007/s11606-008-0515-2 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 291KG UT WOS:000255195300001 PM 18228109 ER PT J AU Biswas, S Yin, SR Blank, PS Zimmerberg, J AF Biswas, Subrata Yin, Shu-Rong Blank, Paul S. Zimmerberg, Joshua TI Cholesterol promotes hemifusion and pore widening in membrane fusion induced by influenza hemagglutinin SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEMLIKI-FOREST-VIRUS; LIPID RAFT MICRODOMAINS; TRANSMEMBRANE DOMAIN; BIOLOGICAL-MEMBRANES; MEDIATED FUSION; PLASMA-MEMBRANE; STALK MECHANISM; CELL-MEMBRANES; VIRAL FUSION AB Cholesterol-specific interactions that affect membrane fusion were tested for using insect cells; cells that have naturally low cholesterol levels (< 4 mol %). Sf9 cells were engineered (HAS cells) to express the hemagglutinin (HA) of the influenza virus X-31 strain. Enrichment of HAS cells with cholesterol reduced the delay between triggering and lipid dye transfer between HAS cells and human red blood cells (RBC), indicating that cholesterol facilitates membrane lipid mixing prior to fusion pore opening. Increased cholesterol also increased aqueous content transfer between HAS cells and RBC over a broad range of HA expression levels, suggesting that cholesterol also favors fusion pore expansion. This interpretation was tested using both trans-cell dye diffusion and fusion pore conductivity measurements in cholesterol-enriched cells. The results of this study support the hypothesis that host cell cholesterol acts at two stages in membrane fusion: (1) early, prior to fusion pore opening, and (2) late, during fusion pore expansion. C1 [Biswas, Subrata; Yin, Shu-Rong; Blank, Paul S.; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. EM Joshz@helix.nih.gov FU Intramural NIH HHS NR 73 TC 31 Z9 31 U1 0 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD MAY PY 2008 VL 131 IS 5 BP 503 EP 513 DI 10.1085/jgp.200709932 PG 11 WC Physiology SC Physiology GA 294RP UT WOS:000255423500013 PM 18443361 ER PT J AU Chalasani, N Wilson, L Kleiner, DE Cummings, OW Brunt, EM Unalp, A AF Chalasani, Naga Wilson, Laura Kleiner, David E. Cummings, Oscar W. Brunt, Elizabeth M. Unalp, Aynur CA NASH Clin Res Network TI Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease SO JOURNAL OF HEPATOLOGY LA English DT Article DE non-alcoholic fatty liver disease; NASH; NASH CRN; NAS; steatosis ID HEPATIC STEATOSIS; FIBROSIS; PREDICTORS; SPECTRUM AB Background/Aims: The relationship between severity and zonal location of steatosis and the presence of steatohepatitis and various histological features that define NASH has not been formally studied. Methods: We conducted a study to examine the relationship of severity and zonal location of steatosis to the presence of NASH and to other histological features that define NASH in adult patients with NAFLD. Steatosis was graded as mild, moderate or severe. We examined the relationship between severity and zonal location of steatosis and the following: lobular inflammation, presence of ballooning, Mallory bodies, fibrosis score, and definite steatohepatitis. Results: Mild, moderate and severe steatosis was present in 44%, 31% and 25% of biopsies, respectively. Definite steatohepatitis was present in 59% and advanced fibrosis in 29% of liver biopsies. Increasing levels of steatosis severity were positively associated with lobular inflammation (p < 0.0001), zone 3 fibrosis (p < 0.001), and definite steatoliepatitis (p = 0.02), but were unrelated to ballooning, Mallory bodies, or advanced fibrosis. As compared to zone 3 steatosis, pan-acinar steatosis was more often associated with ballooning, Mallory bodies, and advanced fibrosis. Conclusions: Patients with severe steatosis are more likely to have steatohepatitis. More studies are needed to confirm this observation and to explore its significance. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Chalasani, Naga; Cummings, Oscar W.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. [Wilson, Laura; Unalp, Aynur] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Kleiner, David E.] NCI, Bethesda, MD 20892 USA. [Brunt, Elizabeth M.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. RP Chalasani, N (reprint author), Indiana Univ, Sch Med, RG 4100,1050 Wishard Blvd, Indianapolis, IN 46202 USA. EM nchalasa@iupui.edu OI Kleiner, David/0000-0003-3442-4453 FU NIDDK NIH HHS [P30 DK056341, P30 DK056341-07, P30 DK056341-08, U01 DK 061713, U01 DK 061718, U01 DK 061728, U01 DK 061730, U01 DK 061731, U01 DK 061732, U01 DK 061734, U01 DK 061737, U01 DK 061738, U01 DK061713, U01 DK061718, U01 DK061728, U01 DK061730, U01 DK061731, U01 DK061732, U01 DK061734, U01 DK061737, U01 DK061737-04, U01 DK061738] NR 11 TC 69 Z9 70 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD MAY PY 2008 VL 48 IS 5 BP 829 EP 834 DI 10.1016/j.jhep.2008.01.016 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 294SF UT WOS:000255425100020 PM 18321606 ER PT J AU Nash, WG Menninger, JC Padilla-Nash, HM Stone, G Perelman, PL O'Brien, SJ AF Nash, William G. Menninger, Joan C. Padilla-Nash, Hesed M. Stone, Gary Perelman, Polina L. O'Brien, Stephen J. TI The ancestral carnivore karyotype (2n=38) lives today in ringtails SO JOURNAL OF HEREDITY LA English DT Article ID CHROMOSOME-BANDING PATTERNS; ORDER CARNIVORA; DOMESTIC CAT; PHYLOGENETIC-RELATIONSHIPS; AMERICAN MINK; ZOO-FISH; RED FOX; EVOLUTION; DOG; FELIDS AB Chromosome painting was used to investigate the conservation of high-resolution longitudinal 4',6-diamidino-2-phenylindole (DAPI)/G bands in Carnivore chromosomes. Cat (Felis catus) and raccoon dog (Nyctereutes procyonoides) painting probes were hybridized to the ringtail (Bassaricus astutus), dwarf mongoose (Helogale parvula), and Malagasy civet (Fossa fossa) to identify homologous chromosome elements. The patterns of chromosome segment homology among Carnivore species allowed us to reconstruct and propose the disposition of a high-resolution banded ancestral carnivore karyotype (ACK). Three bi-armed chromosomes consistently found among Caniformia species are represented as 6 homologous acrocentric chromosomes among Feliformia species of Carnivora. However, reexamination of the most basal of Feliformia species, the African palm civet Nandinia, revealed the presence of the 3 heretofore Caniformia bi-armed chromosomes. Because these 3 bi-armed chromosomes are found in both Caniformia and Feliformia lineages, they are presumed ancestral for all Carnivora, suggesting that the ACK chromosome number would be 38, rather than the previously supposed 42. Banded chromosomes of the ACK are used to evaluate the consistency between recently determined molecular phylogenetic relationships and postulated cytogenetic dynamics in the same Carnivore species. C1 [Nash, William G.; Perelman, Polina L.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Nash, William G.] H & W Cytogenet Serv Inc, Lovettsville, VA 20180 USA. [Menninger, Joan C.] SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. [Padilla-Nash, Hesed M.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Stone, Gary] NCI, Canc Genet Program, Frederick, MD 21702 USA. RP O'Brien, SJ (reprint author), NCI, Lab Genom Divers, Bldg 560,Room 21-105, Frederick, MD 21702 USA. EM Obrien@ncifcrf.gov RI Perelman, Polina/N-8088-2015 OI Perelman, Polina/0000-0002-0982-5100 NR 29 TC 8 Z9 8 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD MAY-JUN PY 2008 VL 99 IS 3 BP 241 EP 253 DI 10.1093/jhered/esm130 PG 13 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 290VT UT WOS:000255151500001 PM 18339652 ER PT J AU Chackerian, B Durfee, MR Schiller, JT AF Chackerian, Bryce Durfee, Marisa R. Schiller, John T. TI Virus-like display of a neo-self antigen reverses B cell anergy in a B cell receptor Transgenic mouse model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS SWITCH RECOMBINATION; AUTOANTIBODY PRODUCTION; INDUCTION; PARTICLES; IMMUNOGENICITY; REPERTOIRE; ACTIVATION; TOLERANCE; RESPONSES; VACCINE AB The ability to distinguish between self and foreign Ags is a central feature of immune recognition. For B cells, however, immune tolerance is not absolute, and factors that include Ag valency, the availability of T help, and polyclonal B cell stimuli can influence the induction of autoantibody responses. Here, we evaluated whether multivalent virus-like particle (VLP)-based immunogens could induce autoantibody responses in well-characterized transgenic (Tg) mice that express a soluble form of hen egg lysozyme (HEL) and in which B cell tolerance to HEL is maintained by anergy. Immunization with multivalent VLP-arrayed HEL, but not a trivalent form of HEL, induced high-titer Ab responses against HEL in both soluble HEL Tg mice and double Tg mice that also express a monoclonal HEL-specific BCR. Induction of autoantibodies against HEL was not dependent on coadministration of strong adjuvants, such as CFA. In contrast to previous data showing the T-independent induction of Abs to foreign epitopes on VLPs, the ability of HEL-conjugated VLPs to induce anti-HEL Abs in tolerant mice was dependent on the presence of CD4(+) Th cells, and could be enhanced by the presence of pre-existing cognate T cells. In in vitro studies, VLP-conjugated HEL was more potent than trivalent HEL in up-regulating surface activation markers on purified anergic B cells. Moreover, immunization with VLP-HEL reversed B cell anergy in vivo in an adoptive transfer model. Thus, Ag multivalency and T help cooperate to reverse B cell anergy, a major mechanism of B cell tolerance. C1 [Chackerian, Bryce; Durfee, Marisa R.] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Chackerian, B (reprint author), Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, MSC08-4660, Albuquerque, NM 87131 USA. EM bchackerian@salud.unm.edu RI durfee, marisa/J-4809-2012 FU Intramural NIH HHS [ZIA BC009052-21]; NIAID NIH HHS [AI 065240, R01 AI065240] NR 45 TC 33 Z9 33 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2008 VL 180 IS 9 BP 5816 EP 5825 PG 10 WC Immunology SC Immunology GA 324GV UT WOS:000257507000012 PM 18424700 ER PT J AU Lutsiak, MEC Tagaya, Y Adams, AJ Schlom, J Sabzevari, H AF Lutsiak, M. E. Christine Tagaya, Yutaka Adams, Anthony J. Schlom, Jeffrey Sabzevari, Helen TI Tumor-induced impairment of TCR signaling results in compromised functionality of tumor-infiltrating regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNOLOGICAL SELF-TOLERANCE; PERIPHERAL-BLOOD; INCREASED POPULATIONS; AUTOIMMUNE-DISEASES; OVARIAN-CARCINOMA; IMMUNE-RESPONSE; LUNG-CANCER; IN-VITRO; RECEPTOR; LYMPHOCYTES AB This study demonstrates, for the first time, that murine regulatory T (Treg) cells in the tumor microenvironment display both enhanced proliferation and reduced functionality. This enhanced proliferation, combined with decreased apoptosis, leads to an intratumoral accumulation of Treg cells with a unique phenotype: CD4(+)CD25(+)FoxP3(+)GITR(high)CD27(low)CD62L(-). The loss of functionality is associated with down-regulation of the TCR signaling complex, including IL-2-inducible T cell kinase. It is also demonstrated that tumor-infiltrating Treg cells have impaired TCR-mediated signaling and calcium influx. Based on these findings, this study supports the hypothesis that 1) tumor-infiltrating Treg cells lose functionality due to their diminished ability to become effectively activated and 2) intratumoral accumulation of Treg cells may compensate for the impaired functionality, thus maintaining immune tolerance to the tumor. C1 [Lutsiak, M. E. Christine; Schlom, Jeffrey; Sabzevari, Helen] NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Tagaya, Yutaka] NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Adams, Anthony J.] NCI, Expt Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bldg 10,Room 8B09, Bethesda, MD 20892 USA. EM js14lc@nih.gov FU Intramural NIH HHS [Z01 BC010944-01] NR 54 TC 18 Z9 18 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 MAY 1 PY 2008 VL 180 IS 9 BP 5871 EP 5881 PG 11 WC Immunology SC Immunology GA 324GV UT WOS:000257507000018 PM 18424706 ER PT J AU Abrahams, VM Aldo, PB Murphy, SP Visintin, I Koga, K Wilson, G Romero, R Sharma, S Mor, G AF Abrahams, Vikki M. Aldo, Paulomi B. Murphy, Shaun P. Visintin, Irene Koga, Kaori Wilson, Gabriella Romero, Roberto Sharma, Surendra Mor, Gil TI TLR6 modulates first trimester trophoblast responses to peptidoglycan SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR-2; INNATE-IMMUNE-SYSTEM; NF-KAPPA-B; INTRAUTERINE GROWTH RESTRICTION; NECROSIS-FACTOR-ALPHA; PRETERM DELIVERY; CUTTING EDGE; BACTERIAL LIPOPROTEINS; PLACENTAL APOPTOSIS; PATTERN-RECOGNITION AB Intrauterine bacterial infections are a well-established cause of pregnancy complications. One key observation in a number of abnormal pregnancies is that placental apoptosis is significantly elevated. First trimester trophoblast cells are known to express TLR1 and TLR2 and to undergo apoptosis following exposure to Gram-positive bacterial peptidoglycan (PDG). Thus, the objectives of this study were to determine whether PDG-induced pregnancy complications are associated with placental apoptosis and to characterize the cellular mechanisms involved. We have demonstrated, using an animal model, that delivery of PDG to pregnant mice early in gestation resulted in highly elevated placental apoptosis, evidenced by trophoblast M-30 and active caspase 3 immunostaining. Using an in vitro model of human first trimester trophoblasts, apoptosis induced by PDG was found to be mediated by both TLR1 and TLR2 and that this could be blocked by the presence of TLR6. Furthermore, in the presence of TLR6, exposure to PDG resulted in trophoblast NF-kappa B activation and triggered these cells to secrete IL-8 and IL-6. The findings of this study suggest that a Gram-positive bacterial infection, through TLR2 and TLR1, may directly promote the elevated trophoblast cell death and that this may be the underlying mechanism of pregnancy complications, such as preterm delivery. Furthermore, the expression of TLR6 may be a key factor in determining whether the response to PDG would be apoptosis or inflammation. C1 [Abrahams, Vikki M.; Aldo, Paulomi B.; Visintin, Irene; Koga, Kaori; Wilson, Gabriella; Mor, Gil] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06520 USA. [Murphy, Shaun P.; Sharma, Surendra] Brown Univ, Rhode Isl Hosp, Women & Infants Hosp, Dept Pediat, Providence, RI 02903 USA. [Romero, Roberto] Brown Univ, Rhode Isl Hosp, Women & Infants Hosp, Dept Pathol, Providence, RI 02903 USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, Detroit, MI 48201 USA. RP Abrahams, VM (reprint author), Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, 333 Cedar St, New Haven, CT 06520 USA. EM vikki.abrahams@yale.edu; gil.mor@yale.edu FU Intramural NIH HHS; NCRR NIH HHS [P20 RR 018728, P20 RR018728]; NICHD NIH HHS [R01 HD049446, R01 HD 049446-01, P01 HD054713-01A2, P01 HD054713]; NIEHS NIH HHS [P42 ES013660, P42 ES 013660] NR 68 TC 49 Z9 52 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2008 VL 180 IS 9 BP 6035 EP 6043 PG 9 WC Immunology SC Immunology GA 324GV UT WOS:000257507000036 PM 18424724 ER PT J AU Liu, XB Lee, YS Yu, CR Egwuagu, CE AF Liu, Xuebin Lee, Yun Sang Yu, Cheng-Rong Egwuagu, Charles E. TI Loss of STAT3 in CD4(+) T cells prevents development of experimental autoimmune diseases SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T(H)17 CELLS; UVEITIS; TH1; UVEORETINITIS; SUPPRESSORS; ENCEPHALOMYELITIS; LYMPHOCYTES; MECHANISMS; GENERATION; INDUCTION AB Th17 cells are implicated in CNS autoimmune diseases. We show that mice with targeted-deletion of Stat3 in CD4(+) T cells (CD4(Stat3-/-)) do not develop experimental autoimmune uveoretinitis (EAU) or experimental autoinumme encephalomyelitis. Defective Th17 differentiation noted in CD4(Stat3-/-) mice is compensated by exaggerated increases in Foxp3-, IL-10-, IL-4-, and IFN-gamma-expressing T cells, suggesting critical roles of STAT3 in shaping Ag-specific CD4(+) T cell repertoire. In mice with EAU, a high percentage of IL-17-expressing T cells in their peripheral lymphoid organs also secrete IFN-gamma while these double-expressors are absent in CD4(Stat3-/-) and wild-type mice without EAU, raising the intriguing possibility that uveitis maybe mediated by Th17 and IL-17-expressing Th1 cells. Resistance of Stat3-deficient mice to EAU derives in part from an inability of uveitogenic Th17 and Thl cells to enter eyes or brain of the CD4(Stat3-/-) mouse because of the reduction in the expression of activated alpha 4/beta 1 integrins on CD4(Stat3-/-) T cells. Adoptive transfer of activated interphotoreceptor retinoid-binding protein-specific uveitogenic T cells induced in CD4(Stat3-/-) mice a severe EAU characterized by development of retinal folds, infiltration of inflammatory cells into the retina, and destruction of retinal architecture, underscoring our contention that the loss of STAT3 in CD4+ T cells results in an intrinsic developmental defect that renders CD4(Stat3-/-) resistant to CNS inflammatory diseases. STAT3 requirement for IL-17 production by Th17, generation of double positive T cells expressing IL-17 and IFN-gamma, and for T cell trafficking into CNS tissues suggests that STAT3 may be a therapeutic target for modulating uveitis, sceritis, or multiple sclerosis. C1 [Liu, Xuebin; Lee, Yun Sang; Yu, Cheng-Rong; Egwuagu, Charles E.] NEI, Sect Mol Immunol, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, Sect Mol Immunol, Immunol Lab, NIH, Bldg 10,Room 10N116,10 Ctr Dr, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000315-16] NR 27 TC 123 Z9 128 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 MAY 1 PY 2008 VL 180 IS 9 BP 6070 EP 6076 PG 7 WC Immunology SC Immunology GA 324GV UT WOS:000257507000040 PM 18424728 ER PT J AU Robbins, PF Li, YF El-Gamil, M Zhao, YB Wargo, JA Zheng, ZL Xu, H Morgan, RA Feldman, SA Johnson, LA Bennett, AD Dunn, SM Mahon, TM Jakobsen, BK Rosenberg, SA AF Robbins, Paul F. Li, Yong F. El-Gamil, Mona Zhao, Yangbing Wargo, Jennifer A. Zheng, Zhili Xu, Hui Morgan, Richard A. Feldman, Steven A. Johnson, Laura A. Bennett, Alan D. Dunn, Steven M. Mahon, Tara M. Jakobsen, Bent K. Rosenberg, Steven A. TI Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; HIGH-AFFINITY; PHAGE DISPLAY; DIRECTED EVOLUTION; CANCER REGRESSION; CUTTING EDGE; HIGH AVIDITY; IN-VITRO; RECEPTOR; RECOGNITION AB Single and dual amino acid substitution variants were generated in the TCR CDRs of three TCRs that recognize tumor-associated Ags. Substitutions that enhance the reactivity of TCR gene-modified T cells to the cognate Ag complex were identified using a rapid RNA-based transfection system. The screening of a panel of variants of the 1G4 TCR, that recognizes a peptide corresponding to amino acid residues 157-165 of the human cancer testis Ag NY-ESO-1 (SLLMWITQC) in the context of the HLA-A*02 class I allele, resulted in the identification of single and dual CDR3 alpha and CDR2 beta amino acid substitutions that dramatically enhanced the specific recognition of NY-ESO-1(+)/HLA-A*02(+) tumor cell lines by TCR gene-modified CD4(+) T cells. Within this group of improved TCRs, a dual substitution in the 1G4 TCR CDR3a chain was identified that enhanced Ag-specific reactivity in gene-modified CD4(+) and CD8(+) T cells. Separate experiments on two distinct TCRs that recognize the MART-1 27-35 (AAGIGILTV) peptide/HLA-A*02 Ag complex characterized single amino acid substitutions in both TCRs that enhanced CD4(+) T cell Ag-specific reactivity. These results indicate that simple TCR substitution variants that enhance T cell function can be identified by rapid transfection and assay techniques, providing the means for generating potent Ag complex-specific TCR genes for use in the study of T cell interactions and in T cell adoptive immunotherapy. C1 [Robbins, Paul F.; Li, Yong F.; El-Gamil, Mona; Zhao, Yangbing; Wargo, Jennifer A.; Zheng, Zhili; Xu, Hui; Morgan, Richard A.; Feldman, Steven A.; Johnson, Laura A.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Bennett, Alan D.; Dunn, Steven M.; Mahon, Tara M.; Jakobsen, Bent K.] MediGene Ltd, Abingdon, Oxon, England. RP Robbins, PF (reprint author), NCI, Surg Branch, NIH, 10 Ctr Dr,CRC 3-5744, Bethesda, MD 20892 USA. EM Paul_Robbins@nih.gov RI Johnson, Laura/H-4861-2013 FU Intramural NIH HHS [Z01 SC003811-33] NR 48 TC 117 Z9 118 U1 0 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2008 VL 180 IS 9 BP 6116 EP 6131 PG 16 WC Immunology SC Immunology GA 324GV UT WOS:000257507000045 PM 18424733 ER PT J AU Pepper, M Dzierszinski, F Wilson, E Tait, E Fang, Q Yarovinsky, F Laufer, TM Roos, D Hunter, CA AF Pepper, Marion Dzierszinski, Florence Wilson, Emma Tait, Elia Fang, Qun Yarovinsky, Felix Laufer, Terri M. Roos, David Hunter, Christopher A. TI Plasmacytoid dendritic cells are activated by Toxoplasma gondii to present antigen and produce cytokines SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERFERON-PRODUCING CELLS; T-CELLS; HOST-RESISTANCE; CUTTING EDGE; INTRACELLULAR PARASITE; VIRAL RECOGNITION; IL-12 PRODUCTION; BONE-MARROW; INFECTION; MACROPHAGES AB Infection with the parasite Toxoplasma gondii leads to the induction of a Th1-type response dominated by IFN-gamma production and control of this pathogen. Cells of the innate immune system are essential in initiating this response both through the production of IL-12 as well as the presentation of parasite-derived Ags to MHC-restricted T cells. Although dendritic cells (DCs) have been implicated in these events, the contribution of individual DC populations remains unclear. Therefore, multiparameter flow cytometry was used to identify and characterize subsets of murine DCs during acute toxoplasmosis. This approach confirmed that infection leads to the expansion and activation of conventional DC (cDC) subsets. Unexpectedly, however, this analysis further revealed that plasmacytoid DCs are also expanded and that these cells up-regulate MHC class II and costimulatory molecules associated with their acquired ability to prime naive CD4(+) T cells. Furthermore, T. gondii-activated plasmacytoid DCs produce high levels of IL-12 and both plasmacytoid DC maturation and cytokine production are dependent on TLR11. Together these studies suggest that pDCs are a prominent DC subset involved in the initial stages of T. gondii infection, presenting parasite Ags and producing cytokines that are important for controlling infection. C1 [Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Dzierszinski, Florence; Roos, David] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Laufer, Terri M.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Yarovinsky, Felix] NIAID, Immunobiol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Hunter, CA (reprint author), Univ Penn, Sch Vet Med, Dept Pathobiol, Room 313,Hill Pavillion,380 S Univ Ave, Philadelphia, PA 19104 USA. EM chunter@phl.vet.upenn.edu RI Hunter, Christopher/H-1970-2011 FU NIAID NIH HHS [AI 071302, AI 42334] NR 45 TC 55 Z9 58 U1 0 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2008 VL 180 IS 9 BP 6229 EP 6236 PG 8 WC Immunology SC Immunology GA 324GV UT WOS:000257507000057 PM 18424745 ER PT J AU Nakao, I Kanaji, S Ohta, S Matsushita, H Arima, K Yuyama, N Yamaya, M Nakayama, K Kubo, H Watanabe, M Sagara, H Sugiyama, K Tanaka, H Toda, S Hayashi, H Inoue, H Hoshino, T Shiraki, A Inoue, M Suzuki, K Aizawa, H Okinami, S Nagai, H Hasegawa, M Fukuda, T Green, ED Izuhara, K AF Nakao, Isao Kanaji, Sachiko Ohta, Shoichiro Matsushita, Hidetomo Arima, Kazuhiko Yuyama, Noriko Yamaya, Mutsuo Nakayama, Katsutoshi Kubo, Hiroshi Watanabe, Mika Sagara, Hironori Sugiyama, Kumiya Tanaka, Hiroyuki Toda, Shuji Hayashi, Hiroaki Inoue, Hiromasa Hoshino, Tomoaki Shiraki, Aya Inoue, Makoto Suzuki, Koichi Aizawa, Hisamichi Okinami, Satoshi Nagai, Hiroichi Hasegawa, Mamoru Fukuda, Takeshi Green, Eric D. Izuhara, Kenji TI Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EFFICIENT GENE-TRANSFER; SENDAI-VIRUS; EPITHELIAL-CELLS; GOBLET CELL; TRACHEAL EPITHELIUM; ALLERGIC-ASTHMA; APICAL PORTER; MUCIN GENES; INNER-EAR; PDS AB Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPI), in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with nentrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD. C1 [Nakao, Isao; Kanaji, Sachiko; Ohta, Shoichiro; Matsushita, Hidetomo; Arima, Kazuhiko; Hayashi, Hiroaki; Shiraki, Aya; Izuhara, Kenji] Saga Med Sch, Dept Biomol Sci, Saga 8498501, Japan. [Toda, Shuji] Saga Med Sch, Dept Pathol & Biodef, Saga 8498501, Japan. [Okinami, Satoshi] Saga Med Sch, Dept Ophthalmol, Saga 8498501, Japan. [Yuyama, Noriko] Genox Res Inc, Tokyo, Japan. [Yamaya, Mutsuo; Nakayama, Katsutoshi; Kubo, Hiroshi] Tohoku Univ Hosp, Dept Geriatr & Gerontol, Sendai, Miyagi, Japan. [Watanabe, Mika] Tohoku Univ Hosp, Dept Pathol, Sendai, Miyagi, Japan. [Sagara, Hironori; Sugiyama, Kumiya; Fukuda, Takeshi] Dokkyo Med Univ, Sch Med, Dept Pulm & Clin Immunol, Mibu, Tochigi, Japan. [Tanaka, Hiroyuki; Nagai, Hiroichi] Gifu Pharmaceut Univ, Dept Pharmacol, Gifu, Japan. [Inoue, Hiromasa] Kyushu Univ, Grad Sch Med Sci, Res Inst Dis Chest, Fukuoka 812, Japan. [Hoshino, Tomoaki; Aizawa, Hisamichi] Kurume Univ, Sch Med, Dept Med, Div Respirol Neurol & Rheumatol, Kurume, Fukuoka 830, Japan. [Inoue, Makoto; Hasegawa, Mamoru] DNAVEC Corp, Tsukuba, Ibaraki, Japan. [Suzuki, Koichi] Natl Inst Infect Dis, Leprosy Res Ctr, Dept Bioregulat, Higashimurayama, Japan. [Green, Eric D.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Izuhara, K (reprint author), Saga Med Sch, Dept Biomol Sci, Saga 8498501, Japan. EM kizuhara@cc.saga-u.ac.jp RI Kubo, Hiroshi/B-2760-2009; Arima, Kazuhiko/I-8962-2014 OI Kubo, Hiroshi/0000-0001-6097-4542; Arima, Kazuhiko/0000-0002-0607-8787 NR 42 TC 69 Z9 71 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD MAY 1 PY 2008 VL 180 IS 9 BP 6262 EP 6269 PG 8 WC Immunology SC Immunology GA 324GV UT WOS:000257507000061 PM 18424749 ER PT J AU Wang, L Li, M Dong, D Bach, THL Sturdevant, DE Vuong, C Otto, M Gao, Q AF Wang, Li Li, Min Dong, Dandan Bach, Thanh-Huy L. Sturdevant, Daniel E. Vuong, Cuong Otto, Michael Gao, Qian TI SarZ is a key regulator of Biofilm formation and virulence in Staphylococcus epidermidis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID POLYSACCHARIDE INTERCELLULAR ADHESIN; COAGULASE-NEGATIVE STAPHYLOCOCCI; QUORUM-SENSING SYSTEM; GENE-EXPRESSION; BINDING PROTEIN; AUREUS; INFECTIONS; RESISTANCE; SIGMA(B); MUTANTS AB Biofilm-associated infection due to Staphylococcus epidermidis, the leading nosocomial pathogen, is a major problem for the public health system, but the regulation of this important phenotype is not completely understood. Using a highly discriminatory screening procedure for genes that influence biofilm formation, we identified the transcriptional regulator SarZ as a novel important determinant of biofilm formation and biofilm-associated infection, on the basis of the significant impact of sarZ on the transcription of the biosynthetic operon for biofilm exopolysaccharide. In addition, sarZ influenced the expression of a series of virulence genes, including genes that influence the expression of lipases and proteases, resistance to an important human antimicrobial peptide, and hemolysis. Our study indicates that the SarZ regulator has a key role in maintaining the typical S. epidermidis phenotype, which is characterized by pronounced biofilm formation and immune evasion, a likely reason for the success of S. epidermidis as a colonizing organism and pathogen in chronic, biofilm-associated infection. C1 [Li, Min; Bach, Thanh-Huy L.; Vuong, Cuong; Otto, Michael] NIAID, Rocky Mt Lab, Natl Inst Hlth, Lab Human Bacterial Pathogenesis,Genom Unit, Hamilton, MT 59840 USA. [Wang, Li; Dong, Dandan; Gao, Qian] Fudan Univ, Shanghai Med Coll, Key Lab Med Mol Virol, Shanghai, Peoples R China. [Wang, Li; Dong, Dandan; Gao, Qian] Fudan Univ, Shanghai Med Coll, Inst Med Microbiol & Biomed Sci, Shanghai, Peoples R China. [Sturdevant, Daniel E.] NIAID, Rocky Mt Lab, Natl Inst Hlth, Res Technol Sect,Genom Unit, Hamilton, MT 59840 USA. RP Otto, M (reprint author), NIAID, Rocky Mt Lab, Natl Inst Hlth, Lab Human Bacterial Pathogenesis,Genom Unit, 903 S 4th St, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov; qiangao@shmu.edu.cn OI Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS [Z01 AI000904-06] NR 50 TC 23 Z9 28 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 MAY 1 PY 2008 VL 197 IS 9 BP 1254 EP 1262 DI 10.1086/586714 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 290KC UT WOS:000255120700007 PM 18422437 ER PT J AU Cooper, PJ Mitre, E Moncayo, AL Chico, ME Vaca, MG Nutman, TB AF Cooper, Philip J. Mitre, Edward Moncayo, Ana Lucia Chico, Martha E. Vaca, Maritza G. Nutman, Thomas B. TI Ascaris lumbricoides-induced interleukin-10 is not associated with atopy in schoolchildren in a rural area of the tropics SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID REGULATORY T-CELLS; GEOHELMINTH INFECTIONS; ALLERGIC DISEASE; SKIN-TEST; RESPONSES; CHILDREN; CYTOKINE; ASTHMA; IL-10; IGE AB Background. In areas where intestinal helminth infections are endemic, infections by these parasites may protect against skin test-measured reactivity to allergens, and it has been suggested that interleukin (IL)-10 may mediate this effect. This study investigated whether IL-10 and populations of IL-10(+) T cells may modulate atopy in children living in an area where intestinal helminth infections are endemic. Methods. Ecuadorian schoolchildren from rural communities were assessed for skin test-measured reactivity to Periplaneta americana allergen and Dermatophagoides pteronyssinus allergen. Blood samples were collected from 39 skin test-positive and 41 skin test-negative children, and peripheral-blood leukocytes were cultured in the presence of Ascaris lumbricoides antigen, to measure IL-10 protein and the frequency of T cell populations expressing intracellular IL-10. We also investigated whether these immunological factors affected the association between allergen-specific IgE and skin test-measured reactivity to aeroallergens. Results. There was no evidence of association between the level of A. lumbricoides-induced IL-10 protein or IL-10(+) T cells and skin test-measured reactivity to allergens. The association between allergen-specific IgE and skin test-measured reactivity was not affected by the level of IL-10 protein or the frequency of IL-10(+) T cells. Conclusions. The results of this study do not support the notion that IL-10 plays a role in modulating atopy in children living in a tropical area where intestinal helminth infections are endemic. C1 [Cooper, Philip J.; Moncayo, Ana Lucia; Chico, Martha E.; Vaca, Maritza G.] Hosp Pedro Vicente Maldonado, Lab Investigac, Quito, Pichincha Prov, Ecuador. [Cooper, Philip J.] Univ San Francisco Quito, Inst Microbiol, Quito, Ecuador. [Cooper, Philip J.] Univ London St Georges Hosp, Sch Med, Ctr Infect, London SW17 0RE, England. [Mitre, Edward] Uniformed Serv Univ Hlth Sci, Dept Microbiol, Bethesda, MD 20814 USA. [Nutman, Thomas B.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Cooper, PJ (reprint author), Casilla 17-14-39, Quito, Ecuador. EM pcooper@ecnet.ec FU Wellcome Trust [074679, 060120/Z/99/C] NR 25 TC 18 Z9 18 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 1 PY 2008 VL 197 IS 9 BP 1333 EP 1340 DI 10.1086/586904 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 290KC UT WOS:000255120700016 PM 18422446 ER PT J AU Scharschmidt, TC Segre, JA AF Scharschmidt, Tiffany C. Segre, Julia A. TI Modeling atopic dermatitis with increasingly complex mouse models SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Editorial Material ID ICHTHYOSIS VULGARIS; SKIN; FILAGGRIN; MICE; INFLAMMATION; BARRIER AB Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disorder that affects approximately 15% of children in the United States. A complex disorder, AD is characterized by both skin barrier impairment and immunologic abnormalities, including decreased innate immune function and a polarized adaptive immune response. Mouse models have demonstrated the complex interdependence of immune cell-keratinocyte interactions and teased apart gene-environment relationships in a controlled setting. In this issue, Nagelkerken et al. present a mouse model with transgenic expression of apolipoprotein C1 that disrupts the skin lipid barrier and manifests many hallmark features of AD. C1 [Segre, Julia A.] NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Scharschmidt, Tiffany C.] Univ Calif San Francisco, Sch Med, San Francisco, CA USA. RP Segre, JA (reprint author), NHGRI, NIH, Genet & Mol Biol Branch, 49 Convent Dr,Room 4A26, Bethesda, MD 20892 USA. EM jsegre@nhgri.nih.gov OI Scharschmidt, Tiffany/0000-0001-5517-089X FU Intramural NIH HHS [Z01 HG000180-08] NR 12 TC 15 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 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2008 VL 128 IS 5 BP 1061 EP 1064 DI 10.1038/sj.jid.5701201 PG 4 WC Dermatology SC Dermatology GA 292EX UT WOS:000255250400002 PM 18408744 ER PT J AU Terunuma, A Cross, JW Dyke, M Kapoor, V Telford, WG Vogel, JC AF Terunuma, Atsushi Cross, Justin W. Dyke, Michelle Kapoor, Veena Telford, William G. Vogel, Jonathan C. TI Behavior of human foreskin keratinocytes expressing a hair follicle stem cell marker CD200 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Letter ID SURFACE PHENOTYPE; SIDE POPULATION; MURINE; IDENTIFICATION; EPIDERMIS; SKIN C1 [Terunuma, Atsushi; Cross, Justin W.; Dyke, Michelle; Vogel, Jonathan C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kapoor, Veena; Telford, William G.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Terunuma, A (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jonvogel@mail.nih.gov FU Intramural NIH HHS NR 17 TC 10 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD MAY PY 2008 VL 128 IS 5 BP 1332 EP 1334 DI 10.1038/sj.jid.5701154 PG 3 WC Dermatology SC Dermatology GA 292EX UT WOS:000255250400039 PM 17989725 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI RNase A ribonucleases and host defense: an evolving story SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Review DE leukocyte; cationic; eosinophil; evolution; bactericidal; virus ID EOSINOPHIL CATIONIC PROTEIN; RESPIRATORY SYNCYTIAL VIRUS; AMINO-ACID-SEQUENCE; MAJOR BASIC-PROTEIN; ANTIMICROBIAL PROTEIN; GENE FAMILY; ANTITUMOR RIBONUCLEASE; COMPARATIVE TOXICITY; SUPERFAMILY MEMBERS; SCHISTOSOMA-MANSONI AB RNase A ( bovine pancreatic RNase) is the founding member an extensive family of divergent proteins that share specific elements of sequence homology, a unique disulfide-bonded tertiary structure, and the ability to hydrolyze polymeric RNA. Among the more intriguing and perhaps counterintuitive findings, at the current state of the art, the connection between RNase activity and characterized host defense functions is quite weak; whether this is a scientific reality or more a reflection of what has been chosen for study remains to be determined. Several of the RNase A family RNases are highly cationic and have cytotoxic and bactericidal properties that are clearly ( eosinophil cationic protein, leukocyte RNase A-2) or are probably ( RNase 7) unrelated to their enzymatic activity. Interestingly, peptides derived from the leukocyte RNase A-2 sequence are nearly as bactericidal as the entire protein, suggesting that among other functions, the RNase A superfamily may be serving as a source of gene scaffolds for the generation of novel cytotoxic peptides. Other RNase A ribonucleases are somewhat less cationic ( mouse angiogenin 4, zebrafish RNases) and have moderate bactericidal activities that have not yet been explored mechanistically. Additional host defense functions characterized specifically for the RNase eosinophil-derived neurotoxin include reducing infectivity of RNA viruses for target cells in culture, which does require RNase activity, chemoattraction of immature human dendritic cells via a G-protein-coupled receptor-dependent mechanism, and activation of TLR2. The properties of individual RNase A ribonucleases, recent experimental findings, and important questions for the near and distant future will be reviewed. C1 NIAID, Lab Allerg Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, Natl Inst Hlth, Bldg 10,Room 11C215,9000 Rockville Pike, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000942-04, Z01 AI000941-04, Z01 AI000943-04] NR 77 TC 83 Z9 93 U1 2 U2 12 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 MAY 1 PY 2008 VL 83 IS 5 BP 1079 EP 1087 DI 10.1189/jlb.1107725 PG 9 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 331NS UT WOS:000258019500002 PM 18211964 ER PT J AU van der Hilst, JCH Kluve-Beckerman, B Bodar, EJ van der Meer, JWM Drenth, JPH Simon, A AF van der Hilst, J. C. H. Kluve-Beckerman, B. Bodar, E. J. van der Meer, J. W. M. Drenth, J. P. H. Simon, A. TI Lovastatin inhibits formation of AA amyloid SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE amyloidosis; SAA; hyper IgD syndrome; monocyte; isoprenoid ID PERIODIC FEVER SYNDROME; CATHEPSIN-B; HYPERIMMUNOGLOBULINEMIA-D; PERITONEAL-MACROPHAGES; MOLECULAR-MECHANISMS; PROTEIN PRENYLATION; ALZHEIMERS-DISEASE; MONOCYTOID CELLS; SERUM; SAA AB Amyloid A (AA) amyloidosis is a severe complication of many chronic inflammatory disorders, including the hereditary periodic fever syndromes. However, in one of these periodic fever syndromes, the hyper IgD and periodic fever syndrome, amyloidosis is rare despite vigorous, recurring inflammation. This hereditary syndrome is caused by mutations in the gene coding for mevalonate kinase, an enzyme of the isoprenoid pathway. In this study, we used a cell culture system with human monocytes to show that inhibition of the isoprenoid pathway inhibits amyloidogenesis. Inhibition of the isoprenoid pathway by lovastatin resulted in a dose- dependent reduction of amyloid formed [53% at 10 mu M (P = 0.01)] compared with mononuclear cells that are exposed only to serum AA. The inhibitory effects of lovastatin are reversible by addition of farnesol but not geranylgeraniol. Farnesyl transferase inhibition also inhibited amyloidogenesis. These results implicate that the isoprenoid metabolism could be a potential target for prevention and treatment of AA amyloidosis. C1 [van der Hilst, J. C. H.; Bodar, E. J.; van der Meer, J. W. M.; Simon, A.] Radboud Univ Nijmegen, Med Ctr, Dept Gen Internal Med, NL-6500 HB Nijmegen, Netherlands. [Drenth, J. P. H.] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6500 HB Nijmegen, Netherlands. [Kluve-Beckerman, B.] Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46204 USA. [Simon, A.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP van der Hilst, JCH (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Gen Internal Med 463, Geert Grooteplein 8,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM j.vanderhilst@aig.umcn.nl RI Simon, Anna/D-3757-2009; Drenth, J.P.H./H-8025-2014; van der Meer, Jos/C-8521-2013 OI Simon, Anna/0000-0002-6141-7921; van der Meer, Jos/0000-0001-5120-3690 NR 50 TC 11 Z9 12 U1 1 U2 2 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 MAY 1 PY 2008 VL 83 IS 5 BP 1295 EP 1299 DI 10.1189/jlb.1107723 PG 5 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 331NS UT WOS:000258019500025 PM 18285405 ER PT J AU Paiva, FF Tannus, A Talagala, SL Silva, AC AF Paiva, Fernando F. Tannus, Alberto Talagala, S. Lalith Silva, Afonso C. TI Arterial spin labeling of cerebral perfusion territories using a seperate labeling coil SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE brain; cerebral blood flow; cerebrovascular diseases; magnetic resonance imaging; vascular territory ID BRAIN PERFUSION; BLOOD-FLOW; IMAGING TECHNIQUES; VERTEBRAL ARTERY; FEEDING ARTERIES; MRI; MULTISLICE; INVERSION; HUMANS; WATER AB Purpose: To obtain cerebral perfusion territories of the left, the right. and the posterior circulation in humans with high signal-to-noise ratio (SNR) and robust delineation. Materials and Methods: Continuous arterial spin labeling (CASL) was implemented using a dedicated radio frequency (RF) coil. positioned over the neck, to label the major cerebral feeding arteries in humans. Selective labeling was achieved by flow-driven adiabatic fast passage and by tilting the longitudinal labeling gradient about the Y-axis by theta = +/- 60 degrees. Results: Mean cerebral blood flow (CBF) values in gray matter (GM) and white matter (WM) were 74 +/- 13 mL center dot 100 g(-1) center dot minute(-1) and 14 +/- 13 mL center dot 100 g(-1) center dot minute(-1), respectively (N = 14). There were no signal differences between left and right hemispheres when theta = 0 degrees (P > 0.19), indicating efficient labeling of both hemispheres. When theta = +60 degrees, the signal in GM on the left hemisphere, 0.07 +/- 0.06%, was 92% lower than on the right hemisphere. 0.85 +/- 0.30% (P < 1 x 10(-9)). while for theta = -60 degrees, the signal in the right hemisphere. 0.16 +/- 0.13%, was 82% lower than on the contralateral side. 0.89 +/- 0.22% (P < 1 x 10(-10)). Similar attenuations were obtained in WM. Conclusion: Clear delineation of the left and right cerebral perfusion territories was obtained, allowing discrimination of the anterior and posterior circulation in each hemisphere. C1 [Paiva, Fernando F.; Silva, Afonso C.] NINDS, NIH, Lab Funct & Mol Imaging, Cerebral Microcirculat Unit, Bethesda, MD 20892 USA. [Paiva, Fernando F.; Tannus, Alberto] Univ Sao Paulo, Inst Phys Sao Carlos, Lab Magnet Resonance Imaging, Sao Carlos, SP, Brazil. [Talagala, S. Lalith] NINDS, NIH, MRI Res Facil, Bethesda, MD USA. RP Silva, AC (reprint author), NINDS, NIH, Lab Funct & Mol Imaging, Cerebral Microcirculat Unit, 10 Ctr Dr MSC 1065,Bldg 10 Room B1D106, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Paiva, Fernando/C-1429-2012; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; Tannus, Alberto/B-9821-2012 OI Paiva, Fernando/0000-0002-8989-9707; Tannus, Alberto/0000-0002-1675-1971 FU Intramural NIH HHS [Z01 NS003012-04] NR 40 TC 5 Z9 5 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD MAY PY 2008 VL 27 IS 5 BP 970 EP 977 DI 10.1002/jmri.21320 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 297NF UT WOS:000255622700004 PM 18425844 ER PT J AU Goldstein, AM Stacey, SN Olafsson, JH Jonsson, GF Helgason, A Sulem, P Sigurgeirsson, B Benediktsdottir, KR Thorisdottir, K Ragnarsson, R Kjartansson, J Kostic, J Masson, G Kristjansson, K Gulcher, JR Kong, A Thorsteinsdottir, U Rafnar, T Tucker, MA Stefansson, K AF Goldstein, A. M. Stacey, S. N. Olafsson, J. H. Jonsson, G. F. Helgason, A. Sulem, P. Sigurgeirsson, B. Benediktsdottir, K. R. Thorisdottir, K. Ragnarsson, R. Kjartansson, J. Kostic, J. Masson, G. Kristjansson, K. Gulcher, J. R. Kong, A. Thorsteinsdottir, U. Rafnar, T. Tucker, M. A. Stefansson, K. TI CDKN2A mutations and melanoma risk in the Icelandic population SO JOURNAL OF MEDICAL GENETICS LA English DT Article ID GERMLINE MUTATIONS; BREAST-CANCER; MALIGNANT-MELANOMA; PRONE FAMILIES; P16; DISEASE; P53; INHIBITION; FREQUENCY; VARIANTS AB Background: Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls. Methods: We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly. Results: We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma. Conclusions: This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available. C1 [Goldstein, A. M.] NCI, NIH, DHHS, Genet Epidemiol Branch, Bethesda, MD 20892 USA. [Goldstein, A. M.] NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Stacey, S. N.; Jonsson, G. F.; Helgason, A.; Sulem, P.; Kostic, J.; Masson, G.; Kristjansson, K.; Gulcher, J. R.; Kong, A.; Thorsteinsdottir, U.; Rafnar, T.; Stefansson, K.] deCODE Genet, Reykjavik, Iceland. [Olafsson, J. H.; Sigurgeirsson, B.; Thorisdottir, K.] Landspitali Univ Hosp, Dept Dermatol, Reykjavik, Iceland. [Benediktsdottir, K. R.] Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland. [Thorisdottir, K.; Ragnarsson, R.; Kjartansson, J.] Landspitali Univ Hosp, Dept Plast Surg, Reykjavik, Iceland. RP Goldstein, AM (reprint author), NCI, NIH, DHHS, Genet Epidemiol Branch, Execut Plaza S,Room 7004,6120 Execut Blvd MSC 723, Bethesda, MD 20892 USA. EM goldstea@exchange.nih.gov RI Tucker, Margaret/B-4297-2015; Helgason, Agnar/K-1522-2015; OI Sigurgeirsson, Bardur/0000-0002-9733-9742 FU Intramural NIH HHS [Z01 CP004410-31] NR 33 TC 16 Z9 16 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD MAY PY 2008 VL 45 IS 5 BP 284 EP 289 DI 10.1136/jmg.2007.055376 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 293YN UT WOS:000255371400004 PM 18178632 ER PT J AU Ferre, S AF Ferre, Sergi TI An update on the mechanisms of the psychostimulant effects of caffeine SO JOURNAL OF NEUROCHEMISTRY LA English DT Review DE adenosine receptors; caffeine; dopamine receptors; local modules; psychostimulants; receptor heteromers ID ADENOSINE A(2A) RECEPTORS; MEDIUM SPINY NEURONS; DOPAMINE-DENERVATED STRIATUM; IN-VIVO MICRODIALYSIS; HAMSTER OVARY CELLS; NUCLEUS-ACCUMBENS; 6-HYDROXYDOPAMINE-LESIONED RATS; MEDIATED MODULATION; TURNING BEHAVIOR; A(1) RECEPTORS AB There has been a long debate about the predominant involvement of the different adenosine receptor subtypes and the preferential role of pre- versus post-synaptic mechanisms in the psychostimulant effects of the adenosine receptor antagonist caffeine. Both striatal A(1) and A(2A) receptors are involved in the motor-activating and probably reinforcing effects of caffeine, although they play a different role under conditions of acute or chronic caffeine administration. The present review emphasizes the key integrative role of adenosine and adenosine receptor heteromers in the computation of information at the level of the striatal spine module (SSM). This local module is mostly represented by the dendritic spine of the medium spiny neuron with its glutamatergic and dopaminergic synapses and astroglial processes that wrap the glutamatergic synapse. In the SSM, adenosine acts both pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A(1) and A(2A) receptors among themselves and with D-1 and D-2 receptors, respectively. A critical aspect of the mechanisms of the psychostimulant effects of caffeine is its ability to release the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission by acting on different adenosine receptor heteromers localized in different elements of the SSM. C1 NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Ferre, S (reprint author), NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014 OI Ferre, Sergi/0000-0002-1747-1779 FU Intramural NIH HHS NR 127 TC 157 Z9 160 U1 9 U2 47 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2008 VL 105 IS 4 BP 1067 EP 1079 DI 10.1111/j.1471-4159.2007.05196.x PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 292SO UT WOS:000255286600001 PM 18088379 ER PT J AU Yamada, Y Tian, J Yang, Y Cutler, RG Wu, T Telljohann, RS Mattson, MP Handa, JT AF Yamada, Yuko Tian, Jane Yang, Yanqin Cutler, Roy G. Wu, Tinghuai Telljohann, Richard S. Mattson, Mark P. Handa, James T. TI Oxidized low density lipoproteins induce a pathologic response by retinal pigmented epithelial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE age-related macular degeneration; apoptosis; ceramides; cholesterol; oxidized low density lipoproteins; retinal pigmented epithelium ID RECOGNITION RECEPTOR PTX3; AGE-RELATED MACULOPATHY; HUMAN BRUCHS MEMBRANE; SMOOTH-MUSCLE-CELLS; MACULAR DEGENERATION; CHOLESTEROL ACYLTRANSFERASE; DENDRITIC CELLS; BASAL DEPOSITS; ACYL-COENZYME; ACCUMULATION AB The accumulation of apolipoprotein B100 lipoproteins in Bruch membrane is an early event thought to promote age-related macular degeneration (AMD). Immunohistochemistry using an anti-oxidized low density lipoprotein antibody on 10 AMD specimens showed staining in Bruch membrane including basal deposits, a marker of AMD. To determine whether retinal pigmented epithelial cells develop a pathologic phenotype after interaction with lipoproteins, ARPE-19 cells were exposed to low density lipoproteins (LDL) or oxidized LDLs (oxLDL). Analysis using the Affymetrix U133 Plus 2.0 (Affymetrix, Inc., Santa Clara, CA, USA) gene chip showed physiological and pathological transcriptional responses after LDL and oxLDL treatment, respectively. LDL induced a down-regulation of cholesterol biosynthesis genes while oxLDL induced transcriptional alterations in genes related to lipid metabolism, oxidative stress, inflammation and apoptosis. Electrospray mass spectrometry showed that oxLDL, but not LDL induced large cellular increases of sphingomyelin, ceramides, and cholesteryl esters. With TUNEL labeling, oxLDL caused 14.6% apoptosis compared to < 1% after LDL. Addition of an inhibitor of sphingomyelin synthase inhibited this apoptosis by 41%. These data support the hypothesis that oxidized lipoproteins are one trigger for initiating early events in the pathogenesis of AMD. C1 [Yamada, Yuko; Tian, Jane; Yang, Yanqin; Wu, Tinghuai; Handa, James T.] Johns Hopkins Med Inst, Wilmer Eye Inst, Baltimore, MD 21287 USA. [Cutler, Roy G.; Telljohann, Richard S.; Mattson, Mark P.] NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. RP Handa, JT (reprint author), Johns Hopkins Med Inst, Wilmer Eye Inst, 1550 Orleans St,Room 144, Baltimore, MD 21287 USA. EM jthanda@jhmi.edu RI Mattson, Mark/F-6038-2012 FU NEI NIH HHS [5P30EY001765, EY 14055, R01 EY014005] NR 47 TC 47 Z9 47 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2008 VL 105 IS 4 BP 1187 EP 1197 DI 10.1111/j.1471-4159.2008.05211.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 292SO UT WOS:000255286600011 PM 18182060 ER PT J AU Butt, C Alptekin, A Shippenberg, T Oz, M AF Butt, Christopher Alptekin, Alp Shippenberg, Toni Oz, Murat TI Endogenous cannabinoid anandamide inhibits nicotinic acetylcholine receptor function in mouse thalamic synaptosomes SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE anandamide; cannabinoids; nicotinic receptor; thalamic synaptosomes ID BOVINE SERUM-ALBUMIN; T-TUBULE MEMBRANES; MEDIATED RESPONSES; XENOPUS OOCYTES; SYNTHETIC CANNABINOIDS; RUBIDIUM EFFLUX; NERVOUS-SYSTEM; K+ CHANNELS; BRAIN; NEURONS AB The effects of the endogenous cannabinoid anandamide [arachidonylethanolamide (AEA)] on the function of nicotinic acetylcholine receptor (nAChR) were investigated using the Rb-86(+) efflux assay in thalamic synaptosomes. AEA reversibly inhibited Rb-86(+) efflux induced by 300 mu M ACh with an IC50 value of 0.9 +/- 2 mu M. Pre-treatment with the cannabinoid (CB1) receptor antagonist SR141716A (1 mu M), the CB2 receptor antagonist SR144528 (1 mu M), or pertussis toxin (0.2 mg/mL) did not alter the inhibitory effects of AEA, suggesting that known CB receptors are not involved in AEA inhibition of nAChRs. AEA inhibition of Rb-86(+) efflux was not reversed by increasing acetylcholine (ACh) concentrations. In radioligand binding studies, the specific binding of [H-3]-nicotine was not altered in the presence of AEA, indicating that AEA inhibits the function of nAChR in a non-competitive manner. Neither the amidohydrolase inhibitor phenylmethylsulfonyl fluoride (0.2 mM) nor the cyclooxygenase inhibitor, indomethacin, (5 mu M) affected AEA inhibition of nAChRs, suggesting that the effect of AEA is not mediated by its metabolic products. Importantly, the extent of AEA inhibition of Rb-86(+) efflux was significantly attenuated by the absence of 1% fatty acid free bovine serum albumin pre-treatment, supporting previous findings that fatty acid-like compounds modulate the activity of nAChRs. Collectively, the results indicate that AEA inhibits the function of nAChRs in thalamic synaptosomes via a CB-independent mechanism and that the background activity of these receptors is affected by fatty acids and AEA. C1 [Butt, Christopher] Martek Biosci, Neurosci Discovery, Boulder, CO USA. [Alptekin, Alp] Sami Ulus Taining & Res Hosp, Dept Anesthesiol, Ankara, Turkey. [Shippenberg, Toni; Oz, Murat] NIDA, IRP, Integrat Neurosci Sect, NIH,DHHS, Baltimore, MD 21224 USA. RP Oz, M (reprint author), NIDA, IRP, Integrat Neurosci Sect, NIH,DHHS, 333 Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 FU Intramural NIH HHS; NIAAA NIH HHS [5T32AA07464] NR 46 TC 13 Z9 13 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD MAY PY 2008 VL 105 IS 4 BP 1235 EP 1243 DI 10.1111/j.1471-4159.2008.05225.x PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 292SO UT WOS:000255286600015 PM 18194436 ER PT J AU Stewart, LQ Roper, JA Young, WS O'Carroll, AM Lolait, SJ AF Stewart, L. Q. Roper, J. A. Young, W. S., III O'Carroll, A. -M. Lolait, S. J. TI Pituitary-adrenal response to acute and repeated mild restraint, forced swim and change in environment stress in arginine vasopressin receptor 1b knockout mice SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE vasopressin; Avp1b receptor; ACTH; corticosterone; stress ID CORTICOTROPIN-RELEASING HORMONE; CHRONIC ACTIVE IMMUNIZATION; DEFICIENT BRATTLEBORO RATS; V1B RECEPTOR; PARAVENTRICULAR NUCLEUS; ADRENOCORTICAL FUNCTION; INDUCED SECRETION; BODY-TEMPERATURE; BETA-ENDORPHIN; FOS EXPRESSION AB Arginine vasopressin and corticotrophin-releasing hormone synthesised and released from the hypothalamic paraventricular nucleus are the prime mediators of the hypothalamic-pituitary-adrenal (HPA) axis response to stress. These neurohormones act synergistically to stimulate adrenocorticotophin (ACTH) secretion from the anterior pituitary, culminating in an increase in circulating glucocorticoids. Arginine vasopressin mediates this action at the arginine vasopressin 1b receptor (Avpr1b) located on pituitary corticotrophs. Arginine vasopressin is regarded as a minor ACTH secretagogue in rodents but evidence suggests that it has a role in mediating the neuroendocrine response to some acute and chronic stressors. To investigate the role of the Avpr1b in the HPA axis response to an acute and chronic (repeated) stress, we measured the plasma ACTH and corticosterone concentrations in three stress paradigms in both Avpr1b knockout and wild-type mice. Single acute exposure to restraint, forced swim and change in environment stressors elevated both plasma ACTH and corticosterone concentrations in wild-type animals. Conversely, the ACTH response to the acute stressors was significantly attenuated in Avpr1b knockout mice compared to their wild-type counterparts. Plasma corticosterone concentrations were reduced in Avpr1b knockout mice in response to change in environment but not to mild restraint or forced swim stress. Irrespective of genotype, there was no difference in the plasma ACTH or corticosterone concentrations in response to acute and repeated stressors. The data show that a functional Avpr1b is required for an intact pituitary ACTH response to the acute and chronic stressors used in this study. Furthermore, the normal corticosterone response to repeated exposure to change in environment stress also requires the Avpr1b to drive HPA axis responsiveness. C1 [Stewart, L. Q.; Roper, J. A.; O'Carroll, A. -M.; Lolait, S. J.] Univ Bristol, Henry Wellcome Labs Intergrat Neurosci & Endocrin, Bristol BS1 3NY, Avon, England. [Young, W. S., III] NIMH, Sect Neural Gene Express, NIH, Bethesda, MD 20892 USA. RP Lolait, SJ (reprint author), Univ Bristol, Henry Wellcome Labs Intergrat Neurosci & Endocrin, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM s.j.lolait@bristol.ac.uk RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU Intramural NIH HHS; Wellcome Trust NR 66 TC 32 Z9 33 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD MAY PY 2008 VL 20 IS 5 BP 597 EP 605 DI 10.1111/j.1365-2826.2008.01704.x PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 289FR UT WOS:000255040900007 PM 18363802 ER PT J AU Erten-Lyons, D Oken, B Woltjer, RL Quinn, J AF Erten-Lyons, D. Oken, B. Woltjer, R. L. Quinn, J. TI Relapsing polychondritis: an uncommon cause of dementia SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Letter ID LIMBIC ENCEPHALITIS C1 [Erten-Lyons, D.; Oken, B.; Quinn, J.] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR 97201 USA. [Erten-Lyons, D.; Quinn, J.] Oregon Hlth & Sci Univ, Vet Affairs Med Ctr, Portland, OR 97201 USA. [Woltjer, R. L.] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA. RP Erten-Lyons, D (reprint author), NIA, Layton Alzheimers Dis Ctr, 3181 SW Sam Jackson Pk Rd,CR 131, Portland, OR 97239 USA. EM ertenlyo@ohsu.edu FU NCRR NIH HHS [M01 RR000334, M01 RR000334-33]; NIA NIH HHS [AG08017, P30 AG008017-11, P30 AG008017-13, P30 AG008017-15, P30 AG008017-17, P30 AG008017-19, P30 AG008017-20, P30 AG008017-22, P30 AG008017-23, P30 AG008017, P30 AG008017-10, P30 AG008017-12, P30 AG008017-14, P30 AG008017-16, P30 AG008017-18, P30 AG008017-21] NR 5 TC 11 Z9 12 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD MAY PY 2008 VL 79 IS 5 BP 609 EP + DI 10.1136/jnnp.2007.131425 PG 2 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 287LK UT WOS:000254918400029 PM 18208859 ER PT J AU Hattab, EM Cheng, L Al-Khatib, SM Steeg, PS AF Hattab, Eyas M. Cheng, Liang Al-Khatib, Sohaib M. Steeg, Patricia S. TI Metastasizing breast carcinoma to the brain: a clinicopathologic and immunohistochemical study of 14 matched pairs SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Neuropathologists CY APR 04-07, 2008 CL San Diego, CA SP Amer Assoc Neuropathologists C1 [Hattab, Eyas M.; Cheng, Liang; Al-Khatib, Sohaib M.] Indiana Univ, Pathol & Lab Med, Indianapolis, IN 46204 USA. [Steeg, Patricia S.] Natl Canc Inst, Mol Pharmacol Lab, Bethesda, MD USA. RP Hattab, EM (reprint author), Indiana Univ, Pathol & Lab Med, Indianapolis, IN 46204 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2008 VL 67 IS 5 BP 506 EP 506 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 294YN UT WOS:000255442300099 ER PT J AU Iacono, D O'Brien, R Resnick, SM Zonderman, A Pletnikova, O Rudow, G Yang, A West, MJ Crain, B Troncoso, JC AF Iacono, Diego O'Brien, Richard Resnick, Susan M. Zonderman, Alan Pletnikova, Olga Rudow, Gay Yang, An West, Mark J. Crain, Barbara Troncoso, Juan C. TI Neuronal hypertrophy in asymptomatic Alzheimer's disease in the BLSA SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Neuropathologists CY APR 04-07, 2008 CL San Diego, CA SP Amer Assoc Neuropathologists C1 [Iacono, Diego; Pletnikova, Olga; Rudow, Gay; Crain, Barbara; Troncoso, Juan C.] Johns Hopkins Univ, Div Neuropathol, Baltimore, MD USA. [Resnick, Susan M.; Zonderman, Alan; Yang, An] NIA, Lab Personal & Cognit, Baltimore, MD 21224 USA. [West, Mark J.] Inst Anat, Aarhus 8000, Denmark. 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2008 VL 67 IS 5 BP 510 EP 511 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 294YN UT WOS:000255442300120 ER PT J AU Bornemann, A Mittelbronn, M Sullivan, T Stewart, CL AF Bornemann, Antje Mittelbronn, Michel Sullivan, Teresa Stewart, Colin L. TI Myonuclear degeneration in LMNA null mice SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 84th Annual Meeting of the American-Association-of-Neuropathologists CY APR 04-07, 2008 CL San Diego, CA SP Amer Assoc Neuropathologists C1 [Bornemann, Antje] Univ Tubingen, Inst Brain Res, D-7400 Tubingen, Germany. [Mittelbronn, Michel] Univ Zurich, Zurich, Switzerland. [Sullivan, Teresa; Stewart, Colin L.] NCI, Frederick Canc Res & Dev Ctr, Frederick, 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 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD MAY PY 2008 VL 67 IS 5 BP 521 EP 521 PG 1 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 294YN UT WOS:000255442300168 ER PT J AU Matteini, AM Walston, JD Fallin, MD Bandeen-Roche, K Kao, WHL Semba, RD Allen, RH Guralnik, J Fried, LP Stabler, SP AF Matteini, A. M. Walston, J. D. Fallin, M. D. Bandeen-Roche, K. Kao, W. H. L. Semba, R. D. Allen, R. H. Guralnik, J. Fried, L. P. Stabler, S. P. TI Markers of B-vitamin deficiency and frailty in older women SO JOURNAL OF NUTRITION HEALTH & AGING LA English DT Article DE frailty syndrome; vitamins B6, B12 and folate; older women ID BONE-MINERAL DENSITY; METHYLMALONIC ACID; COBALAMIN DEFICIENCY; PLASMA HOMOCYSTEINE; COGNITIVE FUNCTION; ELDERLY-WOMEN; SERUM; FOLATE; DISABILITY; ELEVATION AB Objective: To evaluate the association between markers of vitamins B12, B6 and folate deficiency and the geriatric syndrome of frailty. Design: Cross-sectional study of baseline measures from the combined Women's Health and Aging Studies. Setting: Baltimore, Maryland. Participants: Seven hundred three community-dwelling women, aged 70-79. Measurements: Frailty was defined by five-component screening criteria that include weight, grip strength, endurance, physical activity and walking speed measurements and modeled as binary and 3-level polytomous outcomes. Independent variables serum vitamin B6, vitamin B12, methylmalonic acid, total homocysteine, cystathionine and folate were modeled continuously and as abnormal versus normal. Results: Serum biomarker levels varied significantly by race. All analyses were race-stratified and results are reported only for Caucasian women due to small African American sample size. In polytomous logistic regression models of 3-level frailty, Caucasian women with increasing MMA, defined either continuously or using a predefined threshold, had 40-60% greater odds of being prefrail (p-values < 0.07) and 1.66-2.33 times greater odds of being frail (p-values < 0.02) compared to nonfrails after adjustment for age, education, low serum carotenoids, alcohol intake, cardiovascular disease and renal impairment. Both binary and polytomous frailty models evaluating vitamin B 12 as the main exposure estimated odds ratios that were similar in trend yet slightly less significant than the MMA results. Conclusions: These results suggest that vitamin B12 deficiency may contribute to the frailty syndrome in community-dwelling older women. Future studies are needed to explore these relationships longitudinally. C1 [Matteini, A. M.; Walston, J. D.; Fallin, M. D.; Bandeen-Roche, K.; Kao, W. H. L.; Semba, R. D.; Fried, L. P.] Johns Hopkins Univ, Johns Hopkins Inst, Baltimore, MD 21205 USA. [Allen, R. H.; Stabler, S. P.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Guralnik, J.] NIA, Bethesda, MD 20892 USA. RP Matteini, AM (reprint author), Johns Hopkins Univ, Johns Hopkins Inst, 2024 E Monument St,Suite 2-700, Baltimore, MD 21205 USA. EM amatteini@jhmi.edu; jwalston@jhmi.edu FU Intramural NIH HHS; NIA NIH HHS [R01 AG11703, AG09834, N01 AG12112, P30 AG021334, P30 AG021344, R01 AG 027012, R01 AG009834, R01 AG027012, R01 AG027236, R01 AG027236-04, R37 AG019905, T32 AG000247] NR 43 TC 27 Z9 28 U1 0 U2 12 PU SPRINGER FRANCE PI PARIS PA 22 RUE DE PALESTRO, PARIS, 75002, FRANCE SN 1279-7707 J9 J NUTR HEALTH AGING JI J. Nutr. Health Aging PD MAY PY 2008 VL 12 IS 5 BP 303 EP 308 DI 10.1007/BF02982659 PG 6 WC Geriatrics & Gerontology; Nutrition & Dietetics SC Geriatrics & Gerontology; Nutrition & Dietetics GA 307ZC UT WOS:000256357100003 PM 18443711 ER PT J AU Parashar, UD Glass, RI AF Parashar, Umesh D. Glass, Roger I. TI Rotavirus vaccination in Europe: The time has finally arrived SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE rotavirus; vaccination; immunization ID INTUSSUSCEPTION; EFFICACY; GASTROENTERITIS; DISEASE; SAFETY C1 [Parashar, Umesh D.] Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Div Viral Dis, Epidemiol Branch, Atlanta, GA USA. [Glass, Roger I.] Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. RP Parashar, UD (reprint author), CDC, Epidemiol Branch, Mailstop A47,1600 Clifton Rd, Atlanta, GA 30333 USA. EM uparashar@cdc.gov NR 12 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD MAY PY 2008 VL 46 SU 2 BP S21 EP S23 DI 10.1097/MPG.0b013e31816f77b9 PG 3 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 299TH UT WOS:000255777400003 PM 18460968 ER PT J AU Madigan, WP Raymond, WR Wroblewski, KJ Thebpatiphat, N Birdsong, RH Jaafar, MS AF Madigan, William P. Raymond, William R. Wroblewski, Keith J. Thebpatiphat, Nuthida Birdsong, Richard H. Jaafar, Mohamad S. TI A review of pediatric uveitis: Part I. Infectious causes and the masquerade syndromes SO JOURNAL OF PEDIATRIC OPHTHALMOLOGY & STRABISMUS LA English DT Review ID ACUTE RETINAL NECROSIS; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; NECROTIZING HERPETIC RETINOPATHY; SIMPLEX-VIRUS TYPE-2; OCULAR TOXOCARIASIS; CYTOMEGALOVIRUS RETINITIS; ANTERIOR UVEITIS; POSTSTREPTOCOCCAL UVEITIS; LYME-DISEASE AB Uveitis is a manifestation of complex processes that can represent an infectious or a purely immune system modulated condition and may have grave effects on the eye. Much of the morbidity in these conditions is the result of the immune response to these stimuli. These infectious diseases may be successfully treated by addressing the inciting organism with recognized interventions. Treatment of the immune response to the organism often must be pursued simultaneously to minimize long-term complications caused by structural changes within the eye. Assisting the individual's immune response to eliminate the organism while minimizing the immune response's damaging effects remains a unique challenge drawing on both the science and the art of medicine. Several non-infectious conditions that are not autoimmune diseases may commonly masquerade as uveitis, leading to delays in appropriate treatment. C1 [Madigan, William P.; Thebpatiphat, Nuthida; Jaafar, Mohamad S.] Childrens Natl Med Ctr, Washington, DC 20011 USA. [Raymond, William R.] Madigan Army Med Ctr, Tacoma, WA 98431 USA. [Wroblewski, Keith J.] NEI, NIH, Bethesda, MD 20892 USA. [Birdsong, Richard H.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Madigan, WP (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20011 USA. NR 117 TC 6 Z9 7 U1 0 U2 5 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0191-3913 J9 J PEDIAT OPHTH STRAB JI J. Pediatr. Ophthalmol. Strabismus. PD MAY-JUN PY 2008 VL 45 IS 3 BP 140 EP 149 PG 10 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 301RY UT WOS:000255914500003 PM 18524191 ER PT J AU Brown, RT Wiener, L Kupst, MJ Brennan, T Behrman, R Compas, BE Elkin, TD Fairclough, DL Friebert, S Katz, E Kazak, AE Madan-Swain, A Mansfield, N Mullins, LL Noll, R Patenaude, AF Phipps, S Sahler, OJ Sourkes, B Zeltzer, L AF Brown, Ronald T. Wiener, Lori Kupst, Mary Jo Brennan, Tara Behrman, Richard Compas, Bruce E. Elkin, T. David Fairclough, Diane L. Friebert, Sarah Katz, Ernest Kazak, Anne E. Madan-Swain, Avi Mansfield, Nancy Mullins, Larry L. Noll, Robert Patenaude, Andrea Farkas Phipps, Sean Sahler, O. J. Sourkes, Barbara Zeltzer, Lonnie TI Single parents of children with chronic illness: An understudied phenomenon SO JOURNAL OF PEDIATRIC PSYCHOLOGY LA English DT Article DE chronic illness; lone parenting; psychosocial functioning ID PSYCHOSOCIAL ADJUSTMENT; MATERNAL DISTRESS; FAMILY-STRUCTURE; CANCER; HEALTH; STRESS; ILL; ASSOCIATION; PREDICTORS; EXPERIENCE AB Objective To examine the chronic illness literature and evaluate the impact on single parenting and children and adolescents with chronic illness. Methods We conducted literature reviews of relevant research pertaining to single-parent families on PubMed, Medline, and PsychINFO and also surveyed pertinent book chapters and all of the articles from the Journal of Pediatric Psychology since 1987 for articles, specifically examining the potential associations of single (lone) parenting versus two-parent households on children's psychosocial functioning and the impact of the child's illness on caregiver functioning. Results While the literature has examined and discussed the stressors associated with parenting a child with an illness, including the impact of illness on finances, family roles, and caregiver burden, few studies have examined single parents of children and adolescents with chronic illnesses and related stressors stemming from being a lone caregiver. Conclusions There is a dearth of studies examining the association between lone parenting and psychosocial functioning among children and adolescents with chronic illnesses. Specific questions necessitating future investigation are summarized and recommendations are made for future research in this important area of inquiry. C1 [Brown, Ronald T.] Temple Univ, Coll Hlth Profess, Philadelphia, PA 19140 USA. [Wiener, Lori; Brennan, Tara] NCI, Bethesda, MD 20892 USA. [Kupst, Mary Jo] Med Coll Wisconsin, Milwaukee, WI USA. [Compas, Bruce E.] Vanderbilt Univ, Nashville, TN USA. [Elkin, T. David] Univ Mississippi, Med Ctr, University, MS 38677 USA. [Madan-Swain, Avi] Univ Alabama, Birmingham, AL USA. [Mullins, Larry L.] Univ Oklahoma, Hlth Sci Ctr, Norman, OK 73019 USA. [Noll, Robert] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Sahler, O. J.] Univ Rochester, Med Ctr, Rochester, NY 14627 USA. [Sourkes, Barbara] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Zeltzer, Lonnie] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Brown, RT (reprint author), Temple Univ, Coll Hlth Profess, 3307 N Broad St,300 Jones Hall, Philadelphia, PA 19140 USA. EM rtbrown@temple.edu FU Intramural NIH HHS [Z99 CA999999] NR 45 TC 50 Z9 50 U1 2 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0146-8693 J9 J PEDIATR PSYCHOL JI J. Pediatr. Psychol. PD MAY PY 2008 VL 33 IS 4 BP 408 EP 421 DI 10.1093/jpepsy/jsm079 PG 14 WC Psychology, Developmental SC Psychology GA 284NW UT WOS:000254714100010 PM 17906331 ER PT J AU Han, JC Rutledge, MS Kozlosky, M Salaita, CG Gustafson, JK Keil, MF Fleisch, AF Roberts, MD Ning, C Yanovski, JA AF Han, Joan C. Rutledge, Margaret S. Kozlosky, Merel Salaita, Christine G. Gustafson, Jennifer K. Keil, Margaret F. Fleisch, Abby F. Roberts, Mary D. Ning, Cong Yanovski, Jack A. TI Insulin resistance, hyperinsulinemia, and energy intake in overweight children SO JOURNAL OF PEDIATRICS LA English DT Article ID WEIGHT-GAIN; C-PEPTIDE; BODY-WEIGHT; INTRAVENOUS GLUCOSE; AFRICAN-AMERICAN; FASTING INSULIN; ZUCKER RATS; FOOD-INTAKE; SECRETION; OBESITY AB Objective To examine the relationship between energy intake during a buffet meal and indexes of insulin dynamics in overweight children. Study design Ninety-five nondiabetic, overweight (body mass index >= 95th percentile) children (age 10.3 +/- 1.4 years) selected lunch from a 9835-kcal buffet eaten ad libitum after an overnight fast. The associations between energy intake and measures of insulin dynamics, in the postabsorptive state and during a 2-hour hyperglycemic clamp, were determined. Covariates in the statistical model included race, sex, skeletal age, fat-free mass, fat mass, socioeconomic status, and number of foods in the buffet rated as acceptable. Results Energy intake was positively associated with the fasting homeostasis model assessment for insulin resistance index (beta = 0.24, P = .042), fasting insulin/glucose ratio (beta = 0.24, P = .044), first-phase insulin (beta = 0.23, P = .032), and first-phase C-peptide (beta = 0.21, P = .046); energy intake was negatively associated with clamp-derived insulin sensitivity (beta = -0.29, P = .042). Each 10% decrease in clamp-derived insulin sensitivity predicted a 27-kcal greater energy intake. Conclusions Insulin resistance and hyperinsulinemia are associated with greater energy intake after an overnight fast in overweight children. These associations suggest mechanisms whereby insulin resistance may contribute to excessive weight gain in children. C1 [Yanovski, Jack A.] NICHD, Unit Growth & Obesity, PDEGEN, NIH, Bethesda, MD 20892 USA. [Kozlosky, Merel; Salaita, Christine G.] NIH, Dept Nutr, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHD, Unit Growth & Obesity, PDEGEN, NIH, CRC Room IE-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM jyl5i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NICHD NIH HHS [Z01 HD000641] NR 41 TC 12 Z9 12 U1 3 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 J9 J PEDIATR JI J. Pediatr. PD MAY PY 2008 VL 152 IS 5 BP 612 EP 617 DI 10.1016/j.jpeds.2007.12.036 PG 6 WC Pediatrics SC Pediatrics GA 294AE UT WOS:000255375700006 PM 18410761 ER PT J AU Syed, SA Newman, AH Othman, AA Eddington, ND AF Syed, Shariq A. Newman, Amy H. Othman, Ahmed A. Eddington, Natalie D. TI Population pharmacokinetics, brain distribution, and pharmacodynamics of 2(nd) generation dopamine transporter selective benztropine analogs developed as potential substitute therapeutics for treatment of cocaine abuse SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Article DE pharmacokinetics; pharmacodynamics; dopamine; benztropine analogs; cocaine ID 3-ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS; UPTAKE INHIBITORS; RHESUS-MONKEYS; DRUG-ABUSE; IN-VITRO; RAT; HYPOTHESIS; OCCUPANCY; AHN-1055; LIGANDS AB A second generation of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M-1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (V-d = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t(1/2): 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (similar to 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association. C1 [Syed, Shariq A.; Othman, Ahmed A.; Eddington, Natalie D.] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Pharmacokinet & Biopharmaceut Lab, Baltimore, MD 21201 USA. [Newman, Amy H.] Natl Inst Drug Abuse, NIH, Med Chem Sect, Intramural Res Program, Baltimore, MD USA. RP Eddington, ND (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Pharmacokinet & Biopharmaceut Lab, Baltimore, MD 21201 USA. EM neddingt@rx.umaryland.edu FU NIDA NIH HHS [R01 DA16715-03] NR 32 TC 2 Z9 2 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3549 J9 J PHARM SCI-US JI J. Pharm. Sci. PD MAY PY 2008 VL 97 IS 5 BP 1993 EP 2007 DI 10.1002/jps.21123 PG 15 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 293AV UT WOS:000255308100022 PM 17879975 ER PT J AU Ahmet, I Krawczyk, M Zhu, WZ Woo, AYH Morrell, C Poosala, S Xiao, RP Lakatta, EG Talan, MI AF Ahmet, Ismayil Krawczyk, Melissa Zhu, Weizhong Woo, Anthony Yiu-Ho Morrell, Christopher Poosala, Suresh Xiao, Riu-Ping Lakatta, Edward G. Talan, Mark I. TI Cardioprotective and survival benefits of long-term combined therapy with beta(2) adrenoreceptor (AR) agonist and beta(1) AR blocker in dilated cardiomyopathy postmyocardial infarction SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID CHRONIC HEART-FAILURE; RAT VENTRICULAR MYOCYTES; CARDIAC MYOCYTES; ISCHEMIC CARDIOMYOPATHY; RECEPTOR SUBTYPES; APOPTOSIS; BETA(2)-ADRENOCEPTOR; CONTRACTILITY; STIMULATION; INHIBITION AB We have reported therapeutic effectiveness of pharmacological stimulation of beta(2) adrenoreceptors (ARs) to attenuate the cardiac remodeling and myocardial infarction (MI) expansion in a rat model of dilated cardiomyopathy (DCM) post-MI. Furthermore, the combination of beta(2) AR stimulation with beta(1) AR blockade exceeded the therapeutic effectiveness of beta(1) AR blockade. However, these studies were relatively short ( 6 weeks). In this study, in the same experimental model, we compared different effects, including survival benefit, of combined therapy with the beta(1) AR blocker, metoprolol, plus the beta(2) AR agonist, fenoterol (beta(-)(1)beta(+)(2)), and either therapy alone ( beta(-)(1) or beta(+)(2)) during the 1-year study. Therapy was started 2 weeks after permanent ligation of the left coronary artery. Cardiac remodeling, MI expansion, and left ventricular function were assessed by serial echocardiography and compared with untreated animals (nT). Sixty-seven percent mortality in nT was reduced to 33% in the beta(-)(1) beta(2)+ ( p < 0.01). Progressive cardiac remodeling observed in nT and beta(-)(1) was significantly attenuated in beta(-)(1) beta(+)(2) during the first 6 months of treatment. In beta(-)(1) beta(+)(2), MI expansion was completely prevented, and functional decline was significantly attenuated during the entire year. Myocardial apoptosis was significantly reduced in both beta(-)(1)beta(+)(2) and beta(-)(1). A reduction of cardiac beta(1) AR density and decreases in chronotropic and contractile responses to beta(2) AR-specific stimulation in the absence of a reduction of beta 2 AR density in nT were precluded in rats receiving combined therapy. The results demonstrate the cardioprotective and survival benefit of long-term combination therapy of beta(2) AR agonists and beta(1) AR blockers in a model of DCM. C1 [Ahmet, Ismayil; Krawczyk, Melissa; Zhu, Weizhong; Woo, Anthony Yiu-Ho; Morrell, Christopher; Poosala, Suresh; Xiao, Riu-Ping; Lakatta, Edward G.; Talan, Mark I.] NIA, Intramural Res Program, Gerontol Res Ctr, Cardiovasc Sci Lab,NIH, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Intramural Res Program, Gerontol Res Ctr, Cardiovasc Sci Lab,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov RI Woo, Anthony/D-4305-2014 OI Woo, Anthony/0000-0003-0662-698X FU Intramural NIH HHS NR 34 TC 40 Z9 42 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 MAY PY 2008 VL 325 IS 2 BP 491 EP 499 DI 10.1124/jpet.107.135335 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VL UT WOS:000255013800017 PM 18287209 ER PT J AU Fricks, IP Maddileti, S Carter, RL Lazarowski, ER Nicholas, RA Jacobson, KA Harden, TK AF Fricks, Ingrid P. Maddileti, Savitri Carter, Rhonda L. Lazarowski, Eduardo R. Nicholas, Robert A. Jacobson, Kenneth A. Harden, T. Kendall TI UDP is a competitive antagonist at the human P2Y(14) receptor SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-COUPLED RECEPTOR; HUMAN P2Y(6) RECEPTOR; PHOSPHOLIPASE-C; FUNCTIONAL EXPRESSION; URIDINE-DIPHOSPHATE; NUCLEOTIDE RECEPTOR; TISSUE DISTRIBUTION; ADENYLYL-CYCLASE; GPR105 KIAA0001; DENDRITIC CELLS AB G protein-coupled P2Y receptors (P2Y-R) are activated by adenine and uracil nucleotides. The P2Y(14) receptor (P2Y(14)-R) is activated by at least four naturally occurring UDP sugars, with UDP-glucose (UDP-Glc) being the most potent agonist. With the goal of identifying a competitive antagonist for the P2Y(14)-R, UDP was examined for antagonist activity in COS-7 cells transiently expressing the human P2Y(14)-R and a chimeric G alpha protein that couples Gi-coupled receptors to stimulation of phosphoinositide hydrolysis. UDP antagonized the agonist action of UDP-Glc, and Schild analysis confirmed that the antagonism was competitive (pK(B) = 7.28). Uridine 5'-O-thiodiphosphate also antagonized the human P2Y(14)-R (hP2Y(14)-R) with an apparent affinity similar to that of UDP. In contrast, no antagonist activity was observed with ADP, CDP, or GDP, and other uracil analogs also failed to exhibit antagonist activity. The antagonist activity of UDP was not observed at other hP2Y-R. In contrast to its antagonist action at the hP2Y(14)-R, UDP was a potent agonist (EC50 = 0.35 mu M) at the rat P2Y(14)-R. These results identify the first competitive antagonist of the P2Y(14)-R and demonstrate pharmacological differences between receptor orthologs. C1 [Fricks, Ingrid P.; Maddileti, Savitri; Carter, Rhonda L.; Lazarowski, Eduardo R.; Nicholas, Robert A.; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, Natl Inst Diabt, Bethesda, MD USA. RP Harden, TK (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol, CB 7365 Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. EM tkh@med.unc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS; NHLBI NIH HHS [P01 HL034322, P01 HL034322-220012, P01-HL034322, R01 HL071131]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 36 TC 32 Z9 33 U1 0 U2 2 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 MAY PY 2008 VL 325 IS 2 BP 588 EP 594 DI 10.1124/jpet.108.136309 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VL UT WOS:000255013800028 PM 18252808 ER PT J AU Meng, LH Meng, ZJ Miao, ZH Veenstra, TD Pommier, Y AF Meng, Ling-hua Meng, Zhaojing Miao, Ze-hong Veenstra, Timothy D. Pommier, Yves TI Cytokeratin-RNA cross-linking mediated by the antitumor aminoflavone, 5-amino-2,3-fluorophenyl-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID TUMOR-CELL-LINES; ANTICANCER AGENT; DNA-DAMAGE; ACTIVATION; LOCALIZATION; NSC-686288; CYTOSKELETON; DEGRADATION; INDUCTION; APOPTOSIS AB Aminoflavone (AF) is an anticancer drug in early clinical trials, and its antiproliferative activity involves the induction of DNA-protein cross-links. To identify the proteins cross-linked to nucleic acids, cesium chloride (CsCl) gradient centrifugation was used to isolate proteins tightly bound to nucleic acids in AF-treated human breast carcinoma MCF-7 cells. The identified proteins included structural proteins (several cytokeratins), transcription regulators, and stress response proteins. The identification of the cytokeratins was validated using direct immunoblotting of the high-density CsCl (nucleic acid) fractions isolated from AF-treated cells. Ribonuclease A pretreatment caused the cytokeratin signal in the heaviest CsCl fractions to disappear, suggesting that AF mediates RNA-cytokeratin cross-links. Additional experiments using radiolabeled AF showed that AF formed adducts with total RNA and mRNA with similar affinity to that of DNA. Moreover, 18S RNA was selectively pulled down using an anti-cytokeratin antibody after AF treatment. Consistent with the formation of these adducts, we found that AF inhibits RNA and protein synthesis in a dose-and time-dependent manner. This study provides evidence for the formation of AF-mediated cytokeratin-RNA cross-links and the presence of cytokeratin-RNA complexes. Thus, in addition to its anticancer activity, AF might be a useful molecular probe to study the potential role of cytokeratins in the subcellular localization and metabolism of RNA. C1 [Meng, Ling-hua; Meng, Zhaojing; Miao, Ze-hong] NIH, Mol Pharmacol Lab, Ctr Canc Res, Natl Canc Inst, Bethesda, MD 20892 USA. [Veenstra, Timothy D.; Pommier, Yves] NCI, Lab Proteom & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD USA. RP Pommier, Y (reprint author), NIH, Mol Pharmacol Lab, Ctr Canc Res, Natl Canc Inst, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NCI NIH HHS [N01-CO-12400] NR 20 TC 9 Z9 9 U1 1 U2 4 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 MAY PY 2008 VL 325 IS 2 BP 674 EP 680 DI 10.1124/jpet.108.137802 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VL UT WOS:000255013800038 PM 18287208 ER PT J AU Collins, GT Calinski, DM Newman, AH Grundt, P Woods, JH AF Collins, Gregory T. Calinski, Diane M. Newman, Amy Hauck Grundt, Peter Woods, James H. TI Food restriction alters N '-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole)-induced yawning, hypothermia, and locomotor activity in rats: Evidence for sensitization of dopamine D2 receptor-mediated effects SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID D3 RECEPTOR; FEEDING-BEHAVIOR; BODY-TEMPERATURE; AGONISTS; DEPRIVATION; D-3; AMPHETAMINE; SEROTONIN; TRANSMISSION; ANTAGONISTS AB Food restriction enhances sensitivity to the reinforcing effects of a variety of drugs of abuse including opiates, nicotine, and psychostimulants. Food restriction has also been shown to alter a variety of behavioral and pharmacological responses to dopaminergic agonists, including an increased sensitivity to the locomotor stimulatory effects of direct-and indirect-dopamine agonists, elevated extracellular dopamine levels in responses to psychostimulants, as well as suppression of agonist-induced yawning. Behavioral and molecular studies suggest that augmented dopaminergic responses observed in food-restricted animals result from a sensitization of the dopamine D2 receptor; however, little is known about how food restriction affects dopamine D3 receptor function. The current studies were aimed at better defining the effects of food restriction on D2 and D3 receptor function by assessing the capacity of N'-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (pramipexole) to induce yawning, penile erection (PE), hypothermia, and locomotor activity in free-fed and food-restricted rats. Food restriction resulted in a suppression of pramipexole-induced yawning, a sensitized hypothermic response, and an enhanced locomotor response to pramipexole, effects that are suggestive of an enhanced D2 receptor activity; no effect on pramipexole-induced PE was observed. Antagonist studies further supported a food restriction-induced enhancement of the D2 receptor activity because the D2 antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole (L741,626) recovered pramipexole-induced yawning to free-fed levels, whereas yawning and PE were suppressed following pretreatment with the D3 antagonist N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride (PG01037). The results of the current studies suggest that food restriction sensitized rats to the D2-mediated effects of pramipexole while having no effect on the D3-mediated effects of pramipexole. C1 [Collins, Gregory T.; Calinski, Diane M.; Woods, James H.] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Newman, Amy Hauck; Grundt, Peter] Natl Inst Drug Abuse, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Woods, JH (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 Med Sci Res Bldg 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM jhwoods@umich.edu RI Collins, Gregory/K-3125-2012 FU Intramural NIH HHS; NIDA NIH HHS [F31 DA019322-03, DA20669, F31 DA019322, R01 DA020669, R01 DA020669-02]; PHS HHS [F013771] NR 40 TC 33 Z9 33 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 MAY PY 2008 VL 325 IS 2 BP 691 EP 697 DI 10.1124/jpet.107.133181 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VL UT WOS:000255013800040 PM 18305018 ER PT J AU Srivastava, S AF Srivastava, Sudhir TI Move over proteomics, here comes glycomics SO JOURNAL OF PROTEOME RESEARCH LA English DT Editorial Material C1 US Natl Canc Inst, Canc Prevent Div, Bethesda, MD USA. RP Srivastava, S (reprint author), US Natl Canc Inst, Canc Prevent Div, Bethesda, MD USA. NR 0 TC 8 Z9 8 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAY PY 2008 VL 7 IS 5 BP 1799 EP 1799 DI 10.1021/pr083696k PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 296CD UT WOS:000255520200001 PM 18509903 ER PT J AU Baler, RD Volkow, ND Fowler, JS Benveniste, H AF Baler, Ruben D. Volkow, Nora D. Fowler, Joanna S. Benveniste, Helene TI Is fetal brain monoamine oxidase inhibition the missing link between maternal smoking and conduct disorders? SO JOURNAL OF PSYCHIATRY & NEUROSCIENCE LA English DT Review DE monoamine oxidase; smoking; maternal-fetal exchange; conduct disorder ID KNOCK-OUT MICE; PRENATAL NICOTINE EXPOSURE; DISRUPTIVE BEHAVIOR DISORDERS; MESSENGER-RNA EXPRESSION; LOW-BIRTH-WEIGHT; AGGRESSIVE-BEHAVIOR; ANTISOCIAL-BEHAVIOR; CIGARETTE-SMOKE; MAO-A; PEDUNCULOPONTINE NUCLEUS AB Smoking is the leading cause of preventable illness in the world today. Prenatal cigarette smoke exposure (PCSE) is a particularly insidious form because so many of its associated health effects befall the unborn child and produce behavioural outcomes that manifest themselves only years later. Among these are the associations between PCSE and conduct disorders, which have been mostly ascribed to the deleterious effects of nicotine on the fetal brain. Here we hypothesize that inhibition of brain monoamine oxidase (MAO) during fetal brain development, secondary to maternal cigarette smoking and in addition to nicotine, is a likely contributor to this association. MAOs play a central role in monoaminergic balance in the brain, and their inhibition during fetal development - but not during adult life - is known to result in an aggressive phenotype in laboratory animals. This paper provides theoretical and experimental support for the notion that cigarette smoke-induced inhibition of MAO in the fetal brain, particularly when it occurs in combination with polymorphisms in the MAOA gene that lead to lower enzyme concentration in the brain, may result in brain morphologic and functional changes that enhance the risk of irritability, poor self-control and aggression in the offspring. It also encourages research to evaluate whether the interaction of smoking exposure during fetal development and MAOA genotype increases the risk for conduct disorder over that incurred by mere fetal exposure to tobacco smoke. C1 [Baler, Ruben D.; Volkow, Nora D.] Natl Inst Drug Abuse, Off Sci Policy & Commun, NIH, Bethesda, MD 20892 USA. [Fowler, Joanna S.; Benveniste, Helene] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Fowler, Joanna S.; Benveniste, Helene] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. RP Baler, RD (reprint author), Natl Inst Drug Abuse, Off Sci Policy & Commun, NIH, 6001 Executive Blvd,Rm 5241,MSC 9591, Bethesda, MD 20892 USA. EM balerr@mail.nih.gov NR 121 TC 21 Z9 21 U1 5 U2 8 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 1180-4882 J9 J PSYCHIATR NEUROSCI JI J. Psychiatry Neurosci. PD MAY PY 2008 VL 33 IS 3 BP 187 EP 195 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 306HB UT WOS:000256237800002 PM 18592036 ER PT J AU Harrison, PJ Lyon, L Sartorius, LJ Burnet, PWJ Lane, TA AF Harrison, P. J. Lyon, L. Sartorius, L. J. Burnet, P. W. J. Lane, T. A. TI The group II metabotropic glutamate receptor 3 (mGluR3, mGlu3, GRM3): expression, function and involvement in schizophrenia SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Review DE glutamate; GRM3; metabotropic; mGlu3; mGluR3; schizophrenia ID GLUTAMATE-RECEPTOR AGONIST; CATECHOL-O-METHYLTRANSFERASE; DORSOLATERAL PREFRONTAL CORTEX; PROTEIN-COUPLED RECEPTORS; MESSENGER-RNA EXPRESSION; INDUCED DOPAMINE RELEASE; NUCLEUS-ACCUMBENS SHELL; TYPE-3 GENE GRM3; KNOCK-OUT MICE; N-ACETYLASPARTYLGLUTAMATE AB Group II metabotropic glutamate receptors (mGluRs) comprise mGluR2 (mGlu2; encoded by GRM2) and mGluR3 (mGlu3; encoded by GRM3) and modulate glutamate neurotransmission and synaptic plasticity. Here we review the expression and function of mGluR3 and its involvement in schizophrenia. mGluR3 is expressed by glia and neurons in many brain regions and has a predominantly presynaptic distribution, consistent with its role as an inhibitory autoreceptor and heteroceptor. mGluR3 splice variants exist in human brain but are of unknown function. Differentiation of mGluR3 from mGluR2 has been problematic because of the lack of selective ligands and antibodies; the available data suggest particular roles for mGluR3 in long-term depression, in glial function and in neuroprotection. Some but not all studies find genetic association of GRM3 polymorphisms with psychosis, with the risk alleles also being associated with schizophrenia-related endophenotypes such as impaired cognition, cortical activation and glutamate markers. The dimeric form of mGluR3 may be reduced in the brain in schizophrenia. Finally, preclinical findings have made mGluR3 a putative therapeutic target, and now direct evidence for antipsychotic efficacy of a group II mGluR agonist has emerged from a randomised clinical trial in schizophrenia. Together these data implicate mGluR3 in aetiological, pathophysiological and pharmacotherapeutic aspects of the disorder. C1 [Harrison, P. J.; Lyon, L.; Sartorius, L. J.; Burnet, P. W. J.; Lane, T. A.] Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. [Sartorius, L. J.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Harrison, PJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Neurosci Bldg, Oxford OX3 7JX, England. EM paul.harrison@psych.ox.ac.uk FU Medical Research Council [, G0801747] NR 156 TC 85 Z9 85 U1 1 U2 15 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD MAY PY 2008 VL 22 IS 3 BP 308 EP 322 DI 10.1177/0269881108089818 PG 15 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 320QN UT WOS:000257250200012 PM 18541626 ER PT J AU Abbott, E Veenstra, TD Issaq, HJ AF Abbott, Eric Veenstra, Timothy D. Issaq, Haleem J. TI Clinical and pharmaceutical applications of packed-column supercritical fluid chromatography SO JOURNAL OF SEPARATION SCIENCE LA English DT Review DE clinical analysis; drug analysis; pharmaceutical compounds; supercritical fluid chromatography ID TANDEM MASS-SPECTROMETRY; PERFORMANCE LIQUID-CHROMATOGRAPHY; URINARY METABOLITES; STATIONARY PHASES; BREAST-CANCER; HUMAN PLASMA; SEPARATION; BLOOD; SERUM; ENANTIOMERS AB Packed-column supercritical fluid chromatography (pSFC) is a fast separation technique that combines the properties of HPLC and GC. pSFC with carbon dioxide as the mobile phase and packed silica column as the stationary phase possesses the properties of normal phase mechanism; however, the addition of modifiers to the mobile phase allows the separation of relatively polar compounds. In spite of its many positive attributes, pSFC has not been widely used in areas such as proteomics, where methods such as HPLC dominate. Packed column SFC has been extensively used in clinical and pharmaceutical laboratories, especially for separation of nonpolar and chiral drugs. This review will discuss recently published applications of pSFC, with a specific focus on its advantages and limitations for the analysis of pharmaceuticals with varying chemical properties. C1 [Abbott, Eric; Veenstra, Timothy D.; Issaq, Haleem J.] NCI, Lab Proteom & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NCI, Lab Proteom & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, 1050 Boyles St,POB B, Frederick, MD 21702 USA. EM issaqh@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 39 TC 34 Z9 35 U1 1 U2 27 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD MAY PY 2008 VL 31 IS 8 BP 1223 EP 1230 DI 10.1002/jssc.200700579 PG 8 WC Chemistry, Analytical SC Chemistry GA 305EG UT WOS:000256160000002 PM 18366028 ER PT J AU Burroughs, AM Jaffee, M Iyer, LM Aravind, L AF Burroughs, A. Maxwell Jaffee, Marcie Iyer, Lakshminarayan M. Aravind, L. TI Anatomy of the E2 ligase fold: Implications for enzymology and evolution of ubiquitin/Ub-like protein conjugation SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE ubiquitin; ligation; trans-thiolation; E2; E1; active site; UBC; RWD; ubiquitin-conjugation; enzyme evolution; cataysis ID CRYSTAL-STRUCTURE; SEQUENCE ALIGNMENT; COMPARATIVE GENOMICS; SECONDARY STRUCTURE; STRUCTURAL BASIS; ENZYME; SYSTEM; PATHWAY; COMPLEX; FAMILY AB The configuration of the active site of E2 ligases, central enzymes in the ubiquitin/ubiquitin-like protein (Ub/Ub2) conjugation systems, has long puzzled researchers. Taking advantage of the wealth of newly available structures and sequences of E2s from diverse organisms, we performed a large-scale comparative analysis of these proteins. As a result we identified a previously under-appreciated diversity in the active site of these enzymes, in particular, the spatial location of the catalytic cysteine and a constellation of associated conserved residues that potentially contributes to catalysis. We observed structural innovations of differing magnitudes occurring in various families across the E2 fold that might correlate in part with differences in target interaction. A key finding was the independent emergence on multiple occasions of a polar residue, often a histidine, in the vicinity of the catalytic cysteine in different E2 families. We propose that these convergently emerging polar residues have a common function, such as in the stabilization of oxyanion holes during Ub/Ub1 transfer and spatial localization of the Ub/Ub1 tails in the active site. Thus, the E2 ligases represent a rare example in enzyme evolution of high structural diversity of the active site and position of the catalytic residue despite all characterized members catalyzing a similar reaction. Our studies also indicated certain evolutionarily conserved features in all active members of the E2 superfamily that stabilize the unusual flap-like structure in the fold. These features are likely to form a critical mechanical element of the fold required for catalysis. The results presented here could aid in new experiments to understand E2 catalysis. Published by Elsevier Inc. C1 [Burroughs, A. Maxwell; Jaffee, Marcie; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Burroughs, A. Maxwell] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Aravind, L (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM aravind@mail.nih.gov FU Intramural NIH HHS [Z99 LM999999, Z01 LM594244-01] NR 57 TC 58 Z9 59 U1 4 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAY PY 2008 VL 162 IS 2 BP 205 EP 218 DI 10.1016/j.jsb.2007.12.006 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 295YK UT WOS:000255510300002 PM 18276160 ER PT J AU Lee, J Kim, Y Kim, MJ Hong, SH AF Lee, Jae-il Kim, Young-suk Kim, Myung-Jin Hong, Sung-Hyeok TI Idiopathic new bone formation in the femoral shafts of a cynomolgus monkey (Macaca fascicularis) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID PATHOLOGICAL FRACTURE; INFANTS AB A 6.5-y-old cynomolgus monkey was referred to the Veterinary Medical Teaching Hospital at Chungnam National University for suspected bone fracture. The monkey had been reared singly in a cage at a laboratory facility: An animal caretaker incidentally found a bone fragment protruding through the skin of the right leg. Radiographic examination revealed 2 new bone fragments clearly distinguishable from the original femurs; the fragments seemed to be inserted into both femurs. One of the new bone fragments was easily separated surgically from the right femur. Although the bone fragment consisted of a medullary cavity and bone cortex, the periosteal structure was incomplete. New bone formation in nonhuman primates, as manifested in this case, has been reported previously. However, growth of an additional long bone from the original, penetrating the skin without motional disturbance, has not been reported previously. C1 [Lee, Jae-il] Seoul Natl Univ Hosp, Dept Expt Anim Res, Clin Res Inst, Seoul 110744, South Korea. [Kim, Young-suk; Kim, Myung-Jin] Chungnam Natl Univ, Lab Vet Surg, Coll Vet Med, Taejon, South Korea. [Hong, Sung-Hyeok] Natl Canc Inst, Tumor Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD USA. RP Lee, J (reprint author), Seoul Natl Univ Hosp, Dept Expt Anim Res, Clin Res Inst, Seoul 110744, South Korea. EM jaeil@snuh.org NR 18 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAY PY 2008 VL 47 IS 3 BP 68 EP 71 PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 302LC UT WOS:000255968800012 PM 18459717 ER PT J AU Bachman, JL Reedy, J Subar, AF Krebs-Smith, SM AF Bachman, Jessica L. Reedy, Jill Subar, Amy F. Krebs-Smith, Susan M. TI Sources of food group intakes among the US population, 2001-2002 SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID UNITED-STATES POPULATION; DIETARY SOURCES; WHOLE GRAINS; CONTINUING SURVEY; GUIDANCE-SYSTEM; MEAT INTAKE; NUTRIENTS; ADULTS; WOMEN; NUTRITION AB Background Food guides are typically built around a system of food groups. Accordingly, the US Department of Agriculture's MyPyramid includes both food groups and subgroups, as well as an allowance for discretionary calories, in its guidance. Objective To identify the major dietary contributors to food group intake in the US population. Methods This cross-sectional study used 2001-2002 National Health and Nutrition Examination Survey data to determine weighted population proportions for the contribution of each subgroup to its MyPyramid food group (ie, proportion), and the contribution of specific foods to the subgroups oils, solid fats, and added sugars (ie, major contributors). Food codes associated with each food were sorted into 96 categories, termed specific foods, and were linked to the MyPyramid Equivalents Database to obtain food group equivalents. Results In regard to proportion, dark green vegetables (6%), orange vegetables (5%), and legumes (6%) fell well short of recommended levels. Intake of whole grains (10% of total) was far below the recommendation that at least half of all grains be whole. In regard to major contributors, top sources of oils were potato chips, salad dressing, and nuts/seeds; major contributors of solid fats were grain-based desserts, cheese, and sausages. Sweetened carbonated beverages provided 37% of added sugars. Conclusions Americans do not, in general, consume the most nutrient-dense forms of basic food groups, instead consuming foods that are high in solid fats and added sugars. The main culprits-the foods that contribute most to discrepancies between recommendations and actual intake-are sweetened carbonated beverages and other sweetened beverages, grain-based desserts, nonskim dairy products, and fatty meats. C1 [Reedy, Jill; Subar, Amy F.; Krebs-Smith, Susan M.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. [Bachman, Jessica L.] Univ Tennessee, Dept Nutr, Knoxville, TN 37996 USA. RP Reedy, J (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM reedyj@mail.nih.gov NR 39 TC 103 Z9 104 U1 0 U2 16 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAY PY 2008 VL 108 IS 5 BP 804 EP 814 DI 10.1016/j.jada.2008.02.026 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 294PI UT WOS:000255417600016 PM 18442504 ER PT J AU Hicks, GE Shardell, M Miller, RR Bandinelli, S Guralnik, J Cherubini, A Lauretani, F Ferrucci, L AF Hicks, Gregory E. Shardell, Michelle Miller, Ram R. Bandinelli, Stefania Guralnik, Jack Cherubini, Antonio Lauretani, Fulvio Ferrucci, Luigi TI Associations between vitamin D status and pain in older adults: The Invecchiare in Chianti Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE vitamin D; pain; aging ID BONE-MINERAL DENSITY; LOW-BACK-PAIN; MUSCULOSKELETAL PAIN; D DEFICIENCY; HYPOVITAMINOSIS-D; SERUM-LEVELS; WOMEN; MEN; HYPERPARATHYROIDISM; OSTEOARTHRITIS AB OBJECTIVES: To examine cross-sectional associations between vitamin D status and musculoskeletal pain and whether they differ by sex. DESIGN: Population-based study of persons living in the Chianti geographic area (Tuscany, Italy). SETTING: Community. PARTICIPANTS: Nine hundred fifty-eight persons (aged >= 65) selected from city registries of Greve and Bagno a Ripoli. MEASUREMENTS: Pain was categorized as mild or no pain in the lower extremities and back; moderate to severe back pain, no lower extremity pain; moderate to severe lower extremity pain, no back pain; and moderate to severe lower extremity and back pain (dual region). Vitamin D was measured according to radioimmunoassay, and deficiency was defined as 25-hydroxyvitamin D (25(OH)D) less than 25 nmol/L. RESULTS: The mean age +/- standard deviation was 75.1 +/- 7.3 for women and 73.9 +/- 6.8 for men. Fifty-eight percent of women had at least moderate pain in some location, compared with 27% of men. After adjusting for potential confounders, vitamin D deficiency was not associated with lower extremity pain or dual-region pain, although it was associated with a significantly higher prevalence of at least moderate back pain without lower extremity pain in women (odds ratio=1.96, 95% confidence interval=1.01-3.59) but not in men. CONCLUSION: Lower concentrations of 25(OH)D are associated with significant back pain in older women but not men. Because vitamin D deficiency and chronic pain are fairly prevalent in older adults, these findings suggest it may be worthwhile to query older adults about their pain and screen older women with significant back pain for vitamin D deficiency. C1 [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Hicks, Gregory E.; Shardell, Michelle; Miller, Ram R.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Div Gerontol, Baltimore, MD 21201 USA. [Bandinelli, Stefania] INRCA Geriatr Dept, Lab Clin Epidemiol, Florence, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Cherubini, Antonio] Univ Perugia, Sch Med, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. [Lauretani, Fulvio] Tuscany Reg Hlth Agcy, Florence, Italy. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitud Studies Sect, Baltimore, MD 21224 USA. RP Hicks, GE (reprint author), Univ Delaware, Dept Phys Therapy, 303 McKinly Lab, Newark, DE 19716 USA. EM ghicks@udel.edu RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Cherubini, Antonio/0000-0003-0261-9897 FU Intramural NIH HHS [Z99 AG999999]; NICHD NIH HHS [K12 HD043489, K12 HD43489]; NIMHD NIH HHS [263 MD 821336, 263 MD 916413] NR 34 TC 31 Z9 34 U1 0 U2 3 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 MAY PY 2008 VL 56 IS 5 BP 785 EP 791 DI 10.1111/j.1532-5415.2008.01644.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 295PI UT WOS:000255486000001 PM 18331295 ER PT J AU Masys, DR Ellison, D Stead, WW AF Masys, Daniel R. Ellison, Donald Stead, William W. TI Presentation of the 2007 Morris F. Collen Award to William W. Stead, MD, including comments from recipient SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Biographical-Item C1 [Masys, Daniel R.; Stead, William W.] Vanderbilt Univ, Med Ctr, Dept Biomed Informat, McKesson Fdn Prof Biomed Informat, Nashville, TN 37232 USA. [Ellison, Donald] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Audiovisual Program Dev Branch, Bethesda, MD USA. RP Masys, DR (reprint author), Vanderbilt Univ, Med Ctr, Dept Biomed Informat, McKesson Fdn Prof Biomed Informat, Nashville, TN 37232 USA. EM dan.masys@vanderbilt.edu NR 1 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY-JUN PY 2008 VL 15 IS 3 BP 302 EP 306 DI 10.1197/jamia.M2739 PG 5 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 302JV UT WOS:000255965500008 PM 18308976 ER PT J AU Zeng-Treitler, Q Goryachev, S Tse, T Keselman, A Boxwala, A AF Zeng-Treitler, Qing Goryachev, Sergey Tse, Tony Keselman, Alla Boxwala, Aziz TI Estimating consumer familiarity with health terminology: A context-based approach SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID LATENT SEMANTIC ANALYSIS; COMMUNICATION AB Objectives: Effective health communication is often hindered by a "vocabulary gap" between language familiar to consumers and jargon used in medical practice and research. To present health information to consumers in a comprehensible fashion, we need to develop a mechanism to quantify health terms as being more likely or less likely to be understood by typical members of the lay public. Prior research has used approaches including syllable count, easy word list, and frequency count, all of which have significant limitations. Design: In this article, we present a new method that predicts consumer familiarity using contextual information. The method was applied to a large query log data set and validated using results from two previously conducted consumer surveys. Measurements: We measured the correlation between the survey result and the context-based prediction, syllable count, frequency count, and log normalized frequency count. Results: The correlation coefficient between the context-based prediction and the survey result was 0.773 (p < 0.001), which was higher than the correlation coefficients between the survey result and the syllable count, frequency count, and log normalized frequency count (p <= 0.012). Conclusions: The context-based approach provides a good alternative to the existing term familiarity assessment methods. C1 [Zeng-Treitler, Qing; Goryachev, Sergey; Boxwala, Aziz] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol,Decis Syst Grp, Boston, MA 02215 USA. [Tse, Tony; Keselman, Alla] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Keselman, Alla] Aquilent Inc, Laurel, MD USA. RP Zeng-Treitler, Q (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol,Decis Syst Grp, 900 Commonwealth Ave,3rd Floor, Boston, MA 02215 USA. EM qzeng@dsg.bwh.harvard.edu FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK75837, R01 DK075837]; NLM NIH HHS [R01 LM007222, R01 LM07222] NR 27 TC 9 Z9 9 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAY-JUN PY 2008 VL 15 IS 3 BP 349 EP 356 DI 10.1197/jamia.M2592 PG 8 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 302JV UT WOS:000255965500014 PM 18308983 ER PT J AU Miller, FG Kaptchuk, TJ AF Miller, Franklin G. Kaptchuk, Ted J. TI The power of context: reconceptualizing the placebo effect SO JOURNAL OF THE ROYAL SOCIETY OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; LOW-BACK-PAIN; ACUPUNCTURE AB The placebo effect has received increasing scientific attention in recent years. Progress in translating knowledge about this phenomenon into improved outcomes for patients, however, is hampered by conceptual confusion and misleading terminology. In this article we diagnose what is wrong with the placebo concept and suggest 'contextual healing' as a fruitful alternative way of conceiving the placebo effect. C1 [Miller, Franklin G.] NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Inst, Cambridge, MA 02138 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 18 TC 70 Z9 75 U1 0 U2 8 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0141-0768 J9 J ROY SOC MED JI J. R. Soc. Med. PD MAY PY 2008 VL 101 IS 5 BP 222 EP 225 DI 10.1258/jrsm.2008.070466 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 305KA UT WOS:000256176000010 PM 18463276 ER PT J AU Hamill, N Grant, JA Myers, SA AF Hamill, Neil Grant, John A. Myers, Stephen A. TI Congenital dermal sinus SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article ID MRI AB A congenital dermal sinus tract is an uncommon type of spinal dysraphism that results when a focal area of the ectoderm fails to separate from the underlying neuroectoderm, a process termed nondysjunction. Nondysjunction prevents the insertion and subsequent development of mesodermal tissue, which normally separates the spinal cord from the skin. Congenital dermal sinus tracts occur rarely and are usually located in the lumbar or lumbosacral regions. Skin findings include abnormal pigmentation, subcutaneous lipomas, skin tags, hypertrichosis, angiomas, infection, and sinus ostia with a cephalically oriented tract, which may prompt further investigation and subsequent diagnosis. Congenital dermal sinus tracts may also be seen with other pathologic inclusion tumors such as dermoids, epi-dermoids, and teratomas. Treatment is surgical excision, with successful results in more than 90% of patients. (1)To our knowledge, neither antenatal diagnoses nor cutaneous cystic findings have been reported for congenital dermal sinus tracts to date. We report a case of a dermal sinus incorrectly identified prenatally and postnatally as myelomeningocele. C1 [Hamill, Neil; Myers, Stephen A.] Univ Kansas, Med Ctr, Dept Obstet & Gynecol, Kansas City, KS 66103 USA. [Grant, John A.] Univ Kansas, Med Ctr, Dept Neurosurg, Kansas City, KS 66103 USA. RP Hamill, N (reprint author), Wayne State Univ, NICHHD, NIH,Dept Hlth & Human Serv, Hutzel Womens Hosp,Perinatol Res Branch, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM nhamill@med.wayne.edu NR 5 TC 1 Z9 1 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD MAY PY 2008 VL 27 IS 5 BP 799 EP 802 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 294YC UT WOS:000255441200017 PM 18424658 ER PT J AU Domi, A Weisberg, AS Moss, B AF Domi, Arban Weisberg, Andrea S. Moss, Bernard TI Vaccinia virus E2L null mutants exhibit a major reduction in extracellular virion formation and virus spread SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIN-CONTAINING MICROVILLI; BACTERIAL ARTIFICIAL CHROMOSOME; OUTER ENVELOPE PROTEIN; CELL-CELL FUSION; TAIL FORMATION; MEMBRANE-PROTEINS; ESCHERICHIA-COLI; MATURE VIRION; F12L PROTEIN; GENE AB The vaccinia virus E2L (VACWR058) gene is conserved in all sequenced chordopoxviruses and is predicted to encode an 86-kDa protein with no recognizable functional motifs or nonpoxvirus homologs. Although the region immediately upstream of the open reading frame lacked optimal consensus promoter motifs, expression of the E2 protein occurred after viral DNA replication. Transfection studies, however, indicated that the promoter was weak compared to well-characterized intermediate and late promoters. The E2 protein was present in mature virions purified from infected cells but was more abundant in extracellular enveloped forms. Despite the conservation of the E2L gene in chordopoxviruses, deletion mutants could be isolated from both the WR and IHD-J strains of vaccinia virus. These null mutants produced very small plaques in all cell lines tested, reduced amounts of mature infectious virions, and very low numbers of extracellular virions. Nevertheless, viral protein synthesis appeared qualitatively and quantitatively normal. The defect in extracellular virus formation was corroborated by electron microscopy, which also showed some aberration in the wrapping of virions by cisternal membranes. Extracellular virions that did form, however, were able to induce actin tail formation. C1 [Domi, Arban; Weisberg, Andrea S.; Moss, Bernard] NIAID, NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, NIH, Viral Dis Lab, Bldg 4,Rm 229, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS NR 45 TC 18 Z9 18 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 MAY PY 2008 VL 82 IS 9 BP 4215 EP 4226 DI 10.1128/JVI.00037-08 PG 12 WC Virology SC Virology GA 289WM UT WOS:000255084600003 PM 18287229 ER PT J AU Raviv, Y Blumenthal, R Tompkins, SM Humberd, J Hogan, RJ Viard, M AF Raviv, Yossef Blumenthal, Robert Tompkins, S. Mark Humberd, Jennifer Hogan, Robert J. Viard, Mathias TI Hydrophobic inactivation of influenza viruses confers preservation of viral structure with enhanced immunogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID MEMBRANE-FUSION; SELECTIVE INACTIVATION; CROSS-PROTECTION; PORE FORMATION; HEMAGGLUTININ; VACCINE; HEMIFUSION; INFECTION; CELLS; GAMMA AB The use of inactivated influenza virus for the development of vaccines with broad heterosubtypic protection requires selective inactivation techniques that eliminate viral infectivity while preserving structural integrity. Here we tested if a hydrophobic inactivation approach reported for retroviruses could be applied to the influenza virus. By this approach, the transmembrane domains of viral envelope proteins are selectively targeted by the hydrophobic photoactivatable compound 1,5-iodonaphthyl-azide (INA). This probe partitions into the lipid bilayer of the viral envelope and upon far UV irradiation reacts selectively with membrane-embedded domains of proteins and lipids while the protein domains that localize outside the bilayer remain unaffected. INA treatment of influenza virus blocked infection in a dose-dependent manner without disrupting the virion or affecting neuraminidase activity. Moreover, the virus maintained the full activity in inducing pH-dependent lipid mixing, but pH-dependent redistribution of viral envelope proteins into the target cell membrane was completely blocked. These results indicate that INA selectively blocks fusion of the virus with the target cell membrane at the pore formation and expansion step. Using a murine model of influenza virus infection, INA-inactivated influenza virus induced potent anti-influenza virus serum antibody and T-cell responses, similar to live virus immunization, and protected against heterosubtypic challenge. INA treatment of influenza A virus produced a virus that is noninfectious, intact, and fully maintains the functional activity associated with the ectodomains of its two major envelope proteins, neuraminidase and hemagglutinin. When used as a vaccine given intranasally (i.n.), INA-inactivated influenza virus induced immune responses similar to live virus infection. C1 [Raviv, Yossef; Viard, Mathias] NCI, SAIC Fredrick Inc, Basic Res Program, Frederick, MD 21701 USA. [Tompkins, S. Mark; Humberd, Jennifer] Univ Georgia, Dept Infect Dis, Athens, GA 30602 USA. [Hogan, Robert J.] Univ Georgia, Dept Anat & Radiol, Athens, GA 30602 USA. RP Raviv, Y (reprint author), NCI, Bldg 469 Room 215, Ft Detrick, MD 21702 USA. EM yraviv@ncifcrf.gov RI Tompkins, Stephen/A-3317-2008 OI Tompkins, Stephen/0000-0002-1523-5588 FU NCI NIH HHS [N01CO12400] NR 46 TC 15 Z9 15 U1 1 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 MAY PY 2008 VL 82 IS 9 BP 4612 EP 4619 DI 10.1128/JVI.02233-07 PG 8 WC Virology SC Virology GA 289WM UT WOS:000255084600041 PM 18305038 ER PT J AU Day, PM Garnbhira, R Roden, RBS Lowy, DR Schiller, JT AF Day, Patricia M. Garnbhira, Ratish Roden, Richard B. S. Lowy, Douglas R. Schiller, John T. TI Mechanisms of human papillomavirus type 16 neutralization by L2 cross-neutralizing and L1 type-specific antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; MINOR CAPSID PROTEIN; CELL-SURFACE; MONOCLONAL-ANTIBODIES; HEPARAN-SULFATE; INFECTION; INHIBITION; ANTIGEN; BINDING; FURIN AB Pseudovirions of human papillomavirus type 16 (HPV16), the principal etiologic agent in 50% of cervical cancers, were used as a model system to investigate the cell surface interactions involved in the exposure of the broadly cross-neutralizing papillomavirus L2 epitopes. These neutralizing epitopes were exposed only after cell surface binding and a subsequent change in capsid conformation that permitted cleavage by the cellular protease furin at a specific highly conserved site in L2 that is immediately upstream of the cross-neutralizing epitopes. Unexpectedly, binding of L2 antibodies led to the release of the capsid/antibody complexes from the cell surface and their accumulation on the extracellular matrix. Study of the dynamics of exposure of the L2 epitopes further revealed that representatives of the apparently dominant class of L1-specific neutralizing antibodies induced by virus-like particle vaccination prevent infection, not by preventing cell surface binding but rather by preventing the conformation change involved in exposure of the L2 neutralizing epitope. These findings suggest a dynamic model of virion-cell surface interactions that has implications for both evolution of viral serotypes and the efficacy of current and future HPV vaccines. C1 [Day, Patricia M.; Lowy, Douglas R.; Schiller, John T.] NIH, Cellular Oncol Lab, Natl Canc Inst, Bethesda, MD 20892 USA. [Garnbhira, Ratish; Roden, Richard B. S.] Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. RP Day, PM (reprint author), NIH, Cellular Oncol Lab, Natl Canc Inst, 37 Convent Dr,Room 4112 MSC 4263, Bethesda, MD 20892 USA. EM pmd@nih.gov FU Intramural NIH HHS; NCI NIH HHS [CA118790, P50 CA098252, R01 CA118790] NR 38 TC 102 Z9 105 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2008 VL 82 IS 9 BP 4638 EP 4646 DI 10.1128/JVI.00143-08 PG 9 WC Virology SC Virology GA 289WM UT WOS:000255084600044 PM 18305047 ER PT J AU Boni, MF Zhou, Y Taubenberger, JK Holmes, EC AF Boni, Maciei F. Zhou, Yang Taubenberger, Jeffery K. Holmes, Edward C. TI Homologous recombination is very rare or absent in human influenza A virus SO JOURNAL OF VIROLOGY LA English DT Article ID HEMAGGLUTININ GENE; EVOLUTION; SEQUENCE; RESISTANCE; PANDEMICS; H3N2 AB To determine the extent of homologous recombination in human influenza A virus, we assembled a data set of 13,852 sequences representing all eight segments and both major circulating subtypes, H3N2 and H1N1. Using an exhaustive search and a nonparametric test for mosaic structure, we identified 315 sequences (similar to 2%) in five different RNA segments that, after a multiple-comparison correction, had statistically significant mosaic signals compatible with homologous recombination. Of these, only two contained recombinant regions of sufficient length (> 100 nucleotides [nt]) that the occurrence of homologous recombination could be verified using phylogenetic methods, with the rest involving very short sequence regions (15 to 30 nt). Although this secondary analysis revealed patterns of phylogenetic incongruence compatible with the action of recombination, neither candidate recombinant was strongly supported. Given our inability to exclude the occurrence of mixed infection and template switching during amplification, laboratory artifacts provide an alternative and likely explanation for the occurrence of phylogenetic incongruence in these two cases. We therefore conclude that, if it occurs at all, homologous recombination plays only a very minor role in the evolution of human influenza A virus. C1 [Boni, Maciei F.] Res Future, Washington, DC 20036 USA. [Boni, Maciei F.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Zhou, Yang; Holmes, Edward C.] Penn State Univ, State Coll, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. [Taubenberger, Jeffery K.] NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Holmes, Edward C.] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. RP Boni, MF (reprint author), Res Future, 1616 P St NW, Washington, DC 20036 USA. EM boni@rff.org OI Holmes, Edward/0000-0001-9596-3552 FU Intramural NIH HHS; NIGMS NIH HHS [GM080533-01, GM28016, P50 GM071508, P50GM071508, R01 GM028016, R01 GM080533] NR 31 TC 57 Z9 59 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAY PY 2008 VL 82 IS 10 BP 4807 EP 4811 DI 10.1128/JVI.02683-07 PG 5 WC Virology SC Virology GA 297MA UT WOS:000255619600012 PM 18353939 ER PT J AU McWilliams, MJ Julias, JG Hughes, SH AF McWilliams, M. J. Julias, J. G. Hughes, S. H. TI Mutations in the human immunodeficiency virus type 1 polypurine tract (PPT) reduce the rate of PPT cleavage and plus-strand DNA synthesis SO JOURNAL OF VIROLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE AFFECT; REPLICATION; SPECIFICITY; TITER AB Previously, we analyzed the effects of point mutations in the human immunodeficiency virus type 1 (HIV-1) polypurine tract (PPT) and found that some mutations affected both titer and cleavage specificity. We used HIV-1 vectors containing two PPTs and the D116N integrase active-site mutation in a cell-based assay to measure differences in the relative rates of PPT processing and utilization. The relative rates were measured by determining which of the two PPTs in the vector is used to synthesize viral DNA. The results indicate that mutations that have subtle effects on titer and cleavage specificity can have dramatic effects on rates of PPT generation and utilization. C1 [McWilliams, M. J.; Hughes, S. H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Julias, J. G.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Rm 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01CO-12400] NR 7 TC 2 Z9 2 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 MAY PY 2008 VL 82 IS 10 BP 5104 EP 5108 DI 10.1128/JVI.01897-07 PG 5 WC Virology SC Virology GA 297MA UT WOS:000255619600042 PM 18321979 ER PT J AU Shiffman, M Rodriguez, AC AF Shiffman, Mark Rodriguez, Ana Cecilia TI Heterogeneity in CIN3 diagnosis SO LANCET ONCOLOGY LA English DT Editorial Material ID CERVICAL INTRAEPITHELIAL NEOPLASIA; HUMAN-PAPILLOMAVIRUS; LESIONS; INFECTION C1 [Shiffman, Mark] Natl Canc Inst, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS, Washington, DC USA. [Rodriguez, Ana Cecilia] Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. RP Shiffman, M (reprint author), Natl Canc Inst, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS, Washington, DC USA. EM schiffmm@mail.nih.gov NR 10 TC 3 Z9 4 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2008 VL 9 IS 5 BP 404 EP 406 PG 3 WC Oncology SC Oncology GA 300JC UT WOS:000255819100003 ER PT J AU Etzioni, R Feuer, E AF Etzioni, Ruth Feuer, Eric TI Studies of prostate-cancer mortality: caution advised SO LANCET ONCOLOGY LA English DT Editorial Material ID UNITED-STATES; TRENDS; KINGDOM C1 [Etzioni, Ruth] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Feuer, Eric] Natl Canc Inst, Bethesda, MD USA. RP Etzioni, R (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM retzioni@fhcrc.org FU NCI NIH HHS [U01-CA88160] NR 12 TC 18 Z9 18 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD MAY PY 2008 VL 9 IS 5 BP 407 EP 409 DI 10.1016/S1470-2045(08)70112-8 PG 3 WC Oncology SC Oncology GA 300JC UT WOS:000255819100005 PM 18452850 ER PT J AU Pike, BL Greiner, TC Wang, X Weisenburger, DD Hsu, YH Renaud, G Wolfsberg, TG Kim, M Weisenberger, DJ Siegmund, KD Ye, W Groshen, S Mehrian-Shai, R Delabie, J Chan, WC Laird, PW Hacia, JG AF Pike, B. L. Greiner, T. C. Wang, X. Weisenburger, D. D. Hsu, Y-H Renaud, G. Wolfsberg, T. G. Kim, M. Weisenberger, D. J. Siegmund, K. D. Ye, W. Groshen, S. Mehrian-Shai, R. Delabie, J. Chan, W. C. Laird, P. W. Hacia, J. G. TI DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status SO LEUKEMIA LA English DT Article DE epigenetics; genomics; CpG island; microarray; gene expression ID CPG ISLAND MICROARRAYS; NON-HODGKINS-LYMPHOMAS; HISTONE ACETYLATION; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; DISTINCT SUBGROUPS; TISSUE MICROARRAY; CANCER; HYPERMETHYLATION; SURVIVAL; INACTIVATION AB In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEUROD1, ONECUT2 and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of 67 genes proximal (within 500 bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted. C1 [Pike, B. L.; Wang, X.; Hsu, Y-H; Kim, M.; Weisenberger, D. J.; Mehrian-Shai, R.; Laird, P. W.; Hacia, J. G.] Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. [Greiner, T. C.; Weisenburger, D. D.; Chan, W. C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Renaud, G.; Wolfsberg, T. G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Kim, M.; Weisenberger, D. J.; Laird, P. W.] Univ So Calif, Dept Surg, Los Angeles, CA USA. [Siegmund, K. D.; Ye, W.; Groshen, S.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Delabie, J.] Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. RP Hacia, JG (reprint author), Univ So Calif, Dept Biochem & Mol Biol, 2250 Alcazar St,IGM 240, Los Angeles, CA 90089 USA. EM hacia@hsc.usc.edu RI Laird, Peter/G-8683-2012; OI Delabie, Jan/0000-0001-5023-0689 FU Intramural NIH HHS [Z01 HG000185-07, Z99 HG999999]; NCI NIH HHS [C06 CA062528, C06 CA62528-01, CA36727, CA84967, P30 CA014089, P30 CA014089-26, P30 CA014089-30, P30 CA036727, P30 CA036727-24, P30-CA014089, U01 CA084967, U01 CA084967-05]; NCRR NIH HHS [C06 RR10600-01, C06 RR014514, C06 RR14514-01]; NHGRI NIH HHS [P50 HG002790, P50 HG002790-01A1, P50 HG002790-02, P50 HG002790-03, P50 HG002790-04, P50-HG002790]; NIGMS NIH HHS [R01 GM072477, R01 GM072477-01A1, R01 GM072477-02, R01 GM072477-03, R01 GM072477-04, R01 GM072477-05] NR 38 TC 61 Z9 61 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD MAY PY 2008 VL 22 IS 5 BP 1035 EP 1043 DI 10.1038/leu.2008.18 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 300AV UT WOS:000255797600018 PM 18288132 ER PT J AU Kajiguchi, T Lee, S Lee, MJ Trepel, JB Neckers, L AF Kajiguchi, Tomohiro Lee, Sunmin Lee, Min-Jung Trepel, Jane B. Neckers, Len TI KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia SO LEUKEMIA RESEARCH LA English DT Article DE c-kit; mast cell; beta-catenin; tyrosine phosphorylation ID UBIQUITIN-PROTEASOME PATHWAY; PROTOONCOGENE C-KIT; WILD-TYPE; SIGNALING PATHWAY; MYELOID-LEUKEMIA; KINASE-ACTIVITY; CYCLIN D1; RECEPTOR; ACTIVATION; EXPRESSION AB Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and beta-catenin signaling in mast cell leukemia. beta-Catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. beta-Catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia. Published by Elsevier Ltd. C1 [Kajiguchi, Tomohiro; Neckers, Len] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. [Lee, Sunmin; Lee, Min-Jung; Trepel, Jane B.] NCI, NIH, Med Oncol Branch, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), Bldg 10-CRC,Room 1-5940,9000 Rockville Pike, Bethesda, MD 20892 USA. EM neckers@nih.gov FU Intramural NIH HHS [Z99 CA999999, Z01 SC010074-12] NR 43 TC 14 Z9 14 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD MAY PY 2008 VL 32 IS 5 BP 761 EP 770 DI 10.1016/j.leukres.2007.08.023 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 284FK UT WOS:000254692000011 PM 17949810 ER PT J AU Calzada, MJ Kuznetsova, SA Sipes, JM Rodrigues, RG Cashel, JA Annis, DS Mosher, DF Roberts, DD AF Calzada, Maria J. Kuznetsova, Svetlana A. Sipes, John M. Rodrigues, Rul G. Cashel, Jo Anne Annis, Douglas S. Mosher, Deane F. Roberts, David D. TI Calcium indirectly regulates immunochemical reactivity and functional activities of the N-domain of thrombospondin-1 SO MATRIX BIOLOGY LA English DT Article DE thrombospondin-1; integrin recognition; conformational epitopes; calcium binding; cell adhesion; extracellular matrix ID HUMAN-PLATELET THROMBOSPONDIN; C-TERMINAL REGION; MONOCLONAL-ANTIBODIES; CELL-ADHESION; ALPHA(3)BETA(1) INTEGRIN; HEPARIN-BINDING; DISULFIDE ISOMERIZATION; MYOCARDIAL-INFARCTION; ELECTRON-MICROSCOPY; AMINO-TERMINUS AB Conformational changes induced in thrombospondin-1 by removal of calcium regulate interactions with some ligands of its N-modules. Because calcium binds primarily to elements of the C-terminal signature domain of thrombospondin-1, which are distant from the N-modules, such regulation was unexpected. To clarify the mechanism for this regulation, we compared ligand binding to the N-modules of thrombospondin-1 in the full-length protein and recombinant trimeric thrombospondin-1 truncated prior to the signature domain. Three monoclonal antibodies were identified that recognize the N-modules, two of which exhibit calcium-dependent binding to native thrombospondin-l but not to the truncated trimeric protein. These antibodies or calcium selectively modulate interactions of fibronectin, heparin, sulfatide, alpha 3 beta 1 integrin, tumor necrosis factor-alpha-stimulated gene-6 protein, and, to a lesser extent, alpha 4 beta 1 integrin with native thrombospondin-1 but not with the truncated protein. These results indicate connectivity between calcium binding sites in the C-terminal signature domain and the N-modules of thrombospondin-1 that regulates ligand binding and functional activities of the N-modules. (c) Published by Elsevier B.V. C1 [Calzada, Maria J.; Kuznetsova, Svetlana A.; Sipes, John M.; Rodrigues, Rul G.; Cashel, Jo Anne; Roberts, David D.] NCI, Pathol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Annis, Douglas S.; Mosher, Deane F.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Natl Inst Hlth, Bldg 10 Room 2A33 10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS [Z01 SC009172-04]; NHLBI NIH HHS [HL54462, R01 HL054462] NR 61 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD MAY PY 2008 VL 27 IS 4 BP 339 EP 351 DI 10.1016/j.matbio.2007.12.002 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 307KS UT WOS:000256318400008 PM 18226512 ER PT J AU Landgren, O Goldin, LR Caporaso, NE Kyle, RA Rajkurnar, SV AF Landgren, Ola Goldin, Lynn R. Caporaso, Neil E. Kyle, Robert A. Rajkurnar, S. Vincent TI Genetic predisposition for monoclonal gammopathy of undetermined significance - In reply SO MAYO CLINIC PROCEEDINGS LA English DT Letter ID MULTIPLE-MYELOMA; EVENTS; MGUS C1 [Landgren, Ola; Goldin, Lynn R.; Caporaso, Neil E.] NCI, NIH, Bethesda, MD 20892 USA. [Kyle, Robert A.; Rajkurnar, S. Vincent] Mayo Clin, Rochester, MN USA. RP Landgren, O (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD MAY PY 2008 VL 83 IS 5 BP 602 EP 603 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 297EX UT WOS:000255601000020 ER PT J AU Liu, YP Li, HW Bubolz, AH Zhang, DX Gutterman, DD AF Liu, Yanping Li, Hongwei Bubolz, Aaron H. Zhang, David X. Gutterman, David D. TI Endothelial cytoskeletal elements are critical for flow-mediated dilation in human coronary arterioles SO MEDICAL & BIOLOGICAL ENGINEERING & COMPUTING LA English DT Article DE shear stress; cytoskeleton; coronary microcirculation; oxidative stress ID CA2+-ACTIVATED K+ CHANNELS; VASCULAR SMOOTH-MUSCLE; SHEAR-STRESS; NITRIC-OXIDE; HYDROGEN-PEROXIDE; ACTIN-FILAMENTS; DEPENDENT DILATION; PROTEIN-KINASES; LIVING CELLS; MECHANOTRANSDUCTION AB Mitochondrial H2O2 contributes to flow-mediated dilation (FMD) in human coronary arterioles (HCA). We examined the hypothesis that the endothelial cytoskeleton plays a critical role in transducing endothelial wall shear stress into a stimulus for releasing mitochondrial ROS. Phallacidin together with alpha-, beta-tubulin antibodies and Mito-Tracker Red showed the proximity of F-actin, microtubules and mitochondria in endothelial cells. Cytochalasin D (CytoD) and nocodazole (Noc) disrupted endothelial F-actin and microtubules in HCA, respectively, concurrent with a reduction in the generation of cytosolic O-2(center dot-) and H2O2 (hydroethidine and dichlorodihydrofluorescein fluorescence) and mitochondrial superoxide (mitoSox) during flow (control: 3.5 +/- 1.6, Cyto D: 0.51 +/- 0.2, Noc: 0.81 +/- 0.6). FMD, but not the dilation to bradykinin or papaverine, was reduced by Cyto D (26 +/- 10% vs. 56 +/- 3%) or Noc (26 +/- 11% vs. 58 +/- 7%). These results suggest that cytoskeletal elements are a critical component of the signaling mechanism linking endothelial shear stress and mitochondrial release of ROS in the human coronary microcirculation. C1 [Bubolz, Aaron H.; Zhang, David X.; Gutterman, David D.] Med Coll Wisconsin, Vet Adm Med Ctr, Milwaukee, WI 53226 USA. [Bubolz, Aaron H.; Zhang, David X.; Gutterman, David D.] Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. [Bubolz, Aaron H.; Zhang, David X.; Gutterman, David D.] Ctr Cardiovasc, Milwaukee, WI USA. [Liu, Yanping] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Li, Hongwei] Capital Univ Med Sci, Beijing Friendship Hosp, Beijing, Peoples R China. RP Gutterman, DD (reprint author), Med Coll Wisconsin, Vet Adm Med Ctr, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM dgutt@mcw.edu FU NHLBI NIH HHS [P01 HL068769, R01 HL067968, R01 HL080704, R01 HL080704-03] NR 45 TC 30 Z9 32 U1 2 U2 5 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0140-0118 J9 MED BIOL ENG COMPUT JI Med. Biol. Eng. Comput. PD MAY PY 2008 VL 46 IS 5 BP 469 EP 478 DI 10.1007/s11517-008-0331-1 PG 10 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology; Medical Informatics SC Computer Science; Engineering; Mathematical & Computational Biology; Medical Informatics GA 292GY UT WOS:000255255700008 PM 18340474 ER PT J AU Abraham, TL McClain, JJ Tudor-Locke, C AF Abraham, Teresa L. McClain, James J. Tudor-Locke, Catrine TI The Sex-Stratified Relationship Between Sitting and Walking SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Abraham, Teresa L.; McClain, James J.; Tudor-Locke, Catrine] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol,Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP 37 EP 37 DI 10.1249/01.mss.0000320836.00623.7b PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070900006 ER PT J AU Chantler, P Melensovsky, V Schulman, SP Gerstenblith, G Becker, L Ferrucci, L Fleg, JL Lakatta, EG Najjar, SS AF Chantler, Paul Melensovsky, Vojtech Schulman, Steven P. Gerstenblith, Gary Becker, Lewis Ferrucci, Luigi Fleg, Jerome L. Lakatta, Edward G. Najjar, Samer S. TI The Effects of Systolic Hypertension on Arterial-Ventricular Coupling at Rest & During Exercise In Men and Women SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. IKEM, Dept Cardiol, Inst Clin & Expt Med, Prague, Czech Republic. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. NIA, Lab Cardiovasc Sci, Baltimore, MD 21224 USA. 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP 49 EP 49 DI 10.1249/01.mss.0000321037.29444.a9 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070900008 ER PT J AU Arena, R Owens, DS Arevalo, J Smith, K Mohiddin, SA Mcareavey, D Ulisney, KL Tripodi, D Fananapazir, L Plehn, JF AF Arena, Ross Owens, David S. Arevalo, Josefino Smith, Kevin Mohiddin, Saidi A. Mcareavey, Dorothea Ulisney, Karen L. Tripodi, Dorothy Fananapazir, Lameh Plehn, Jonathan F. TI Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE exercise testing; diastolic function; expired gas analysis; heart failure ID CHRONIC HEART-FAILURE; EXERCISE CAPACITY; CARDIOPULMONARY EXERCISE; FUNCTIONAL-CAPACITY; VE/VCO2 SLOPE; PEAK VO2; DETERMINANTS; RESPONSES; PERFUSION AB Purpose: In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardionryopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardionryopathy NHCM. Methods: We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption (VO2) and minute ventilation/carbon dioxide ratio (V-E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). Results: Elevations in PCWP (>= 15 mm Hg), PASP (>= 30 and >= 40 mm Hg), PADP (> 15 mm Hg) and MPAP (>= 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V-E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V-E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP >= 40 mm Hg (77%/100%), 0.86 for MPAP > 20 into Hg (83%/79%), and 0.84 for PCWP : 15 mm Hg (80%/06%). Conclusions: CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted. C1 [Arena, Ross] Virginia Commonwealth Univ, Dept Physiol, Richmond, VA 23298 USA. [Arena, Ross] Virginia Commonwealth Univ, Dept Phys Therapy, Richmond, VA 23298 USA. [Owens, David S.; Smith, Kevin; Mohiddin, Saidi A.; Mcareavey, Dorothea; Ulisney, Karen L.; Tripodi, Dorothy; Fananapazir, Lameh; Plehn, Jonathan F.] NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. [Arevalo, Josefino; Plehn, Jonathan F.] George Washington Univ, Sch Med, Div Cardiol, Washington, DC USA. RP Arena, R (reprint author), Virginia Commonwealth Univ, Dept Phys Therapy, Box 980224,Hlth Sci Campus, Richmond, VA 23298 USA. EM raarena@vcu.edu RI Arena, Ross/A-3141-2008; OI Arena, Ross/0000-0002-6675-1996; Owens, David/0000-0002-7293-9688 NR 27 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 BP 799 EP 805 DI 10.1249/MSS.0b013e31816459a1 PG 7 WC Sport Sciences SC Sport Sciences GA 292AH UT WOS:000255238200003 PM 18408621 ER PT J AU Johnson, CC Murray, DM Elder, JP Jobe, JB Dunn, AL Kubik, M Voorhees, C Schachter, K AF Johnson, Carolyn C. Murray, David M. Elder, John P. Jobe, Jared B. Dunn, Andrea L. Kubik, Martha Voorhees, Carolyn Schachter, Kenneth TI Depressive symptoms and physical activity in adolescent girls SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE sixth graders; accelerometry; 3DPAR; sedentary behavior ID MENTAL-HEALTH; SELF-REPORT; VALIDATION; CHILDREN; SAMPLE; ACCELEROMETRY; POPULATION; INSTRUMENT; BEHAVIORS; EXERCISE AB Purpose: To evaluate the relationship between depressive symptoms and physical activity in a geographically and ethnically diverse sample of sixth-grade adolescent girls. Methods: The Trial of Activity for Adolescent Girls (TAAG) baseline measurement included a random sample (N = 1721) of sixth-grade girls in 36 schools at six field sites. Measurements were accelerometry and the 3-d Physical Activity Recall (3DPAR) for physical activity, and the Center for Epidemiological Studies-Depression scale (CES-D) for depressive symptoms. Results: Girls with complete data (N = 1397), mean age 12 yr, had an average CES-D score of 14.7 (SD = 9.25) and engaged in an average of about 460 min of sedentary activity, < 24 min of moderate to vigorous physical activity (MVPA), and < 6 min of vigorous physical activity (VPA) in an 18-h day. Thirty-minute segments of MVPA ranged in number from 3.9 to 1.2, and METS for these segments ranged from > 3.0 to > 6.5. Mixed-model regression indicated no relationship between depressive symptoms and physical activity; however, a significant but modest inverse relationship between sedentary activity and depressive symptoms was observed. Conclusion: A sufficient sample size, standardized procedures, and validated instruments characterized this study; however, a relationship between depressive symptoms and physical activity was not observed for sixth-grade girls from diverse geographic locations. The average CES-D score was lower than is considered clinically meaningful for either adolescents or adults, and MET-minutes of sedentary activity were high. This combination of data may be different from other studies and could have contributed to the unexpected finding. This unexpected finding is informative, however, because it shows the need for additional research that includes a wider range of possible combinations of data, especially with young adolescent girls. C1 [Johnson, Carolyn C.] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. [Murray, David M.] Ohio State Univ, Columbus, OH 43210 USA. [Elder, John P.] San Diego State Univ, San Diego, CA 92182 USA. [Jobe, Jared B.] NHLBI, Bethesda, MD 20892 USA. [Dunn, Andrea L.] Klein Buendel Inc, Golden, CO USA. [Kubik, Martha] Univ Minnesota, Minneapolis, MN USA. [Voorhees, Carolyn] Univ Maryland, College Pk, MD 20742 USA. [Schachter, Kenneth] Univ Arizona, Tucson, AZ USA. RP Johnson, CC (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, 1440 Canal St,Rm 2309, New Orleans, LA 70112 USA. EM cjohnso5@tulane.edu FU NHLBI NIH HHS [U01HL66845, U01HL66852, U01HL66856, U01HL66858, U01HL66853, U01HL66855, U01HL66857] NR 40 TC 35 Z9 35 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 BP 818 EP 826 DI 10.1249/MSS.0b013e3181632d49 PG 9 WC Sport Sciences SC Sport Sciences GA 292AH UT WOS:000255238200006 PM 18408618 ER PT J AU Abraham, TL McClain, JJ Getz, RS Tudor-Locke, C AF Abraham, Teresa L. McClain, James J. Getz, Renee S. Tudor-Locke, Catrine TI Comparison Of Low Cost Objective Physical Activity Assessment Instruments Versus The Actigraph Accelerometer SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Abraham, Teresa L.; Getz, Renee S.; Tudor-Locke, Catrine] Arizona State Univ, Mesa, AZ USA. [McClain, James J.] NCI, NIH, Bethesda, MD 20892 USA. EM teresa.abraham@asu.edu NR 0 TC 1 Z9 1 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S63 EP S63 DI 10.1249/01.mss.0000321721.52734.cd PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901243 ER PT J AU Arena, R Shizukuda, Y Bolan, CD Tripodi, DTJ Yau, YY Smith, KP Waclawiw, MA Leitman, SF Rosing, DR AF Arena, Ross Shizukuda, Yukitaka Bolan, Charles D. Tripodi, Dorothy J. Tripodi Yau, Yu-Ying Smith, Kevin P. Waclawiw, Myron A. Leitman, Susan F. Rosing, Douglas R. TI Phlebotomy Improves the Oxygen Uptake Efficiency Slope in Asymptomatic Hereditary Hemochromatosis Subjects SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Arena, Ross] Virginia Commonwealth Univ, Richmond, VA USA. [Shizukuda, Yukitaka] Univ Cincinnati, Cincinnati, OH USA. [Shizukuda, Yukitaka] NIH, Cincinnati, OH USA. [Bolan, Charles D.; Tripodi, Dorothy J. Tripodi; Yau, Yu-Ying; Smith, Kevin P.; Waclawiw, Myron A.; Leitman, Susan F.; Rosing, Douglas R.] NIH, Bethesda, MD 20892 USA. EM raarena@vcu.edu RI Arena, Ross/A-3141-2008 OI Arena, Ross/0000-0002-6675-1996 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S30 EP S31 DI 10.1249/01.mss.0000321579.74576.a1 PG 2 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901118 ER PT J AU Delmonico, MJ Zmuda, JM Taylor, BC Cauley, JA Harris, TB Manini, T Schwartz, A Li, RL Roth, SM Hurley, BF Ferrell, RE Newman, AB AF Delmonico, Matthew J. Zmuda, Joseph M. Taylor, Brent C. Cauley, Jane A. Harris, Tamara B. Manini, Todd Schwartz, Ann Li, Rongling Roth, Stephen M. Hurley, Ben F. Ferrell, Robert E. Newman, Anne B. TI Association of the ACTN3 Genotype and Physical Functioning with Age in Older Adults SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Delmonico, Matthew J.] Univ Rhode Isl, Kingston, RI 02881 USA. [Zmuda, Joseph M.; Cauley, Jane A.; Ferrell, Robert E.; Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Taylor, Brent C.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Manini, Todd] Univ Florida, Gainesville, FL USA. [Schwartz, Ann] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Li, Rongling] Univ Tennessee, Memphis, TN USA. [Roth, Stephen M.; Hurley, Ben F.] Univ Maryland, College Pk, MD 20742 USA. EM delmonico@uri.edu RI Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015 OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S44 EP S44 DI 10.1249/01.mss.0000321639.38724.34 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901171 ER PT J AU Fenty-Stewart, NM Park, JY Roth, SM Hagberg, JM Basu, S Ferrell, RE Brown, MD AF Fenty-Stewart, Nicola M. Park, Joon-Young Roth, Stephen M. Hagberg, James M. Basu, Samar Ferrell, Robert E. Brown, Michael D. TI Influence Of AGTR1 Gene Variants And Aerobic Exercise Training On Angiotensin II And Oxidative Stress SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Fenty-Stewart, Nicola M.; Brown, Michael D.] Temple Univ, Philadelphia, PA 19122 USA. [Park, Joon-Young] NHLBI, NIH, Bethesda, MD 20892 USA. [Roth, Stephen M.; Hagberg, James M.] Univ Maryland, College Pk, MD 20742 USA. [Basu, Samar] Uppsala Univ, Uppsala, Sweden. [Ferrell, Robert E.] Univ Pittsburgh, Pittsburgh, PA 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S44 EP S44 DI 10.1249/01.mss.0000321638.61595.c1 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901170 ER PT J AU Kostek, MC Gordish-Dressman, H Harris, TB Thompson, PD Clarkson, PM Angelopoulos, TJ Gordon, PM Moyna, N Pescatello, L Visich, P Zoeller, R Seip, R Garcia, M Li, RL Zmuda, J Delmonico, MJ Kanaya, A Hoffman, EP Devaney, JM AF Kostek, Matthew C. Gordish-Dressman, Heather Harris, Tamara B. Thompson, Paul D. Clarkson, Priscilla M. Angelopoulos, Theodore J. Gordon, Paul M. Moyna, Niall Pescatello, Linda Visich, Paul Zoeller, Robert Seip, Richard Garcia, Melissa Li, Rongling Zmuda, Joseph Delmonico, Matthew J. Kanaya, Alka Hoffman, Eric P. Devaney, Joseph M. TI An IGF1 Promoter Polymorphism is Associated with Muscle Function in the Health ABC and FMS cohorts SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Kostek, Matthew C.] Univ S Carolina, Columbia, SC 29208 USA. [Gordish-Dressman, Heather; Hoffman, Eric P.; Devaney, Joseph M.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Harris, Tamara B.] NIH, Washington, DC USA. [Thompson, Paul D.; Seip, Richard] Henry Low Heart Ctr, Hartford, CT USA. [Clarkson, Priscilla M.] Univ Massachusetts, Amherst, MA 01003 USA. [Angelopoulos, Theodore J.] Univ Cent Florida, Orlando, FL 32816 USA. [Gordon, Paul M.] W Virginia Univ, Morgantown, WV 26506 USA. [Moyna, Niall] Dublin City Univ, Dublin 9, Ireland. [Pescatello, Linda] Univ Connecticut, Storrs, CT USA. [Visich, Paul] Cent Michigan Univ, Mt Pleasant, MI 48859 USA. [Zoeller, Robert] Florida Atlantic Univ, Davie, FL USA. [Garcia, Melissa] NIH, Bethesda, MD 20892 USA. [Li, Rongling] Univ Tennessee, Memphis, TN USA. [Zmuda, Joseph] Univ Pittsburgh, Pittsburgh, PA USA. [Delmonico, Matthew J.] Univ Rhode Isl, Kingston, RI 02881 USA. [Kanaya, Alka] Univ Calif San Francisco, San Francisco, CA 94143 USA. EM mkostek@gwm.sc.edu NR 0 TC 0 Z9 0 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S183 EP S183 DI 10.1249/01.mss.0000322256.27464.b8 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070902059 ER PT J AU Ludlow, AT Metter, EJ Ferrucci, L Roth, SM AF Ludlow, Andrew T. Metter, E. Jeffrey Ferrucci, Luigi Roth, Stephen M. TI The Vitamin D Receptor (VDR) FokI Polymorphism is Associated with Muscle Mass and Strength in Men SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Ludlow, Andrew T.; Roth, Stephen M.] Univ Maryland, College Pk, MD 20742 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Harbor Hosp, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S44 EP S45 DI 10.1249/01.mss.0000321640.46348.32 PG 2 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901172 ER PT J AU Manini, T Everhart, J Anton, S Schoeller, D Cummings, S Simonsick, E Delmonico, M Colbert, L Tylavsky, F Newman, A Harris, T AF Manini, Todd Everhart, James Anton, Steve Schoeller, Dale Cummings, Steve Simonsick, Eleanore Delmonico, Matt Colbert, Lisa Tylavsky, Fran Newman, Anne Harris, Tamara TI Activity Energy Expenditure And The Change In Body Composition During Late Life SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Everhart, James] NIDDK, Bethesda, MD USA. [Manini, Todd; Anton, Steve] Univ Florida, Gainesville, FL USA. [Schoeller, Dale; Colbert, Lisa] Univ Wisconsin, Madison, WI USA. [Cummings, Steve] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Simonsick, Eleanore] NIA, Baltimore, MD 21224 USA. [Delmonico, Matt] Univ Rhode Isl, Kingston, RI 02881 USA. [Tylavsky, Fran] Univ Tennessee, Memphis, TN USA. [Newman, Anne] Univ Pittsburgh, Pittsburgh, PA USA. [Harris, Tamara] NIA, Bethesda, MD 20892 USA. EM tmanini@aging.ufl.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S486 EP S486 DI 10.1249/01.mss.0000323061.63373.e2 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070903640 ER PT J AU Roth, SM Walsh, S Metter, EJ Ferrucci, L AF Roth, Stephen M. Walsh, Sean Metter, E. Jeffrey Ferrucci, Luigi TI Genetic Analysis of Atrogin-1 (FBXO32) Polymorphisms with Muscle Mass and Strength in Men and Women SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Roth, Stephen M.; Walsh, Sean] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. EM sroth1@umd.edu 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S45 EP S45 DI 10.1249/01.mss.0000321641.84466.28 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901173 ER PT J AU Schrack, J Ferrucci, L AF Schrack, Jennifer Ferrucci, Luigi TI Validation Of The Cosmed K4 b2 Portable Metabolic System In Measuring STEADY-STATE Walking Energy Expenditure SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Schrack, Jennifer] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Ferrucci, Luigi] NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S104 EP S104 DI 10.1249/01.mss.0000321901.61260.ed PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070901401 ER PT J AU Troiano, RP Dodd, KW AF Troiano, Richard P. Dodd, Kevin W. TI Within-Person Differences in Physical Activity Measured by Self-Report and Accelerometer in NHANES 2003-2004 SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Troiano, Richard P.; Dodd, Kevin W.] NCI, Bethesda, MD 20892 USA. EM troianor@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S203 EP S203 DI 10.1249/01.mss.0000322335.37501.da PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070902138 ER PT J AU Walsh, S Liu, DM Metter, EJ Ferrucci, L Roth, SM AF Walsh, Sean Liu, Dongmei Metter, E. Jeffrey Ferrucci, Luigi Roth, Stephen M. TI ACTN3 Genotype is Associated with Muscle Phenotypes in Women across the Adult Age Span SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Meeting Abstract C1 [Walsh, Sean] Cent Connecticut State Univ, New Britain, CT 06050 USA. [Liu, Dongmei; Roth, Stephen M.] Univ Maryland, College Pk, MD 20742 USA. [Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Baltimore, MD 21224 USA. EM walshse@ccsu.edu RI Liu, Dongmei/C-1525-2012 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 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD MAY PY 2008 VL 40 IS 5 SU S BP S191 EP S191 DI 10.1249/01.mss.0000322289.16416.12 PG 1 WC Sport Sciences SC Sport Sciences GA V19KI UT WOS:000208070902092 ER PT J AU Beckham, JC Becker, ME Hamlett-Berry, KW Drury, PD Kang, HK Wiley, MT Calhoun, PS Moore, SD Bright, MA McFall, ME AF Beckham, Jean C. Becker, Mary E. Hamlett-Berry, Kim W. Drury, Pamela D. Kang, Han K. Wiley, Matthew T. Calhoun, Patrick S. Moore, Scott D. Bright, Mary Anne McFall, Miles E. TI Preliminary findings from a clinical demonstration project for veterans returning from Iraq or Afghanistan SO MILITARY MEDICINE LA English DT Article ID NICOTINE REPLACEMENT THERAPY; SMOKING-CESSATION; CIGARETTE-SMOKING; UNITED-STATES; TOBACCO USE; INTERVENTIONS; PERSONNEL; QUITLINE; ACCESS; DEATH AB Military veterans are at high risk for nicotine dependence. This clinical demonstration project used invitational letters, referral to the National Cancer Institute's Smoking Quitline, and local Veteran Affairs prescriptions for tobacco cessation to evaluate whether this low-cost method would potentially reduce smoking in separated veterans who served in Afghanistan and Iraq. Three cohorts (500 each) of recently separated veterans from Afghanistan and Iraq were contacted by survey letters. Interested veterans received follow-up telephone calls using standardized scripts. They were referred to the National Cancer Institute's Smoking Quitline (1-877-44U-QUIT) and offered local Veteran Affairs pharmacologic treatment for smoking cessation. Forty-three percent of respondents who were smokers were interested in the clinical program; of these, 77% participated. At 2 months follow-up, 38% of participants self-reported maintained smoking abstinence. Results suggested that the intervention was feasible and assisted the small number of veterans who participated. C1 [Beckham, Jean C.; Becker, Mary E.; Drury, Pamela D.; Wiley, Matthew T.; Calhoun, Patrick S.; Moore, Scott D.] Durham Vet Adm Med Ctr, Durham, NC 27705 USA. [Beckham, Jean C.; Calhoun, Patrick S.; Moore, Scott D.] Duke Univ, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27710 USA. [Beckham, Jean C.; Calhoun, Patrick S.; Moore, Scott D.] Durham VA Med Ctr, VA Mid Atlant Reg Mental Illness Res Educ & Clin, Durham, NC 27705 USA. [Hamlett-Berry, Kim W.] VA Publ Hlth Strateg, Dept Vet Affairs 13B, Hlth Care Grp, Washington, DC 20420 USA. [Kang, Han K.] Dept Vet Affairs 135, VA Environm Epidemiol Serv, Washington, DC 20422 USA. [Bright, Mary Anne] NCI, Office Canc Informat Serv, Rockville, MD 20852 USA. [McFall, Miles E.] Seattle Vet Adm Med Ctr, Seattle, WA 98108 USA. [McFall, Miles E.] Portland VA Med Ctr, VA Pacific NW Mental Illness Res Educ & Clin Ctr, Portland, OR 97207 USA. RP Beckham, JC (reprint author), Durham Vet Adm Med Ctr, 508 Fulton St,116B, Durham, NC 27705 USA. NR 30 TC 16 Z9 16 U1 1 U2 4 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD MAY PY 2008 VL 173 IS 5 BP 448 EP 451 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 300SY UT WOS:000255846700010 PM 18543565 ER PT J AU Mutter, GL Bergeron, C Deligdisch, L Ferenczy, A Glant, M Merino, M Williams, AR Blithe, DL AF Mutter, George L. Bergeron, Christine Deligdisch, Liane Ferenczy, Alex Glant, Mick Merino, Maria Williams, Alistair Rw Blithe, Diana L. TI The spectrum of endometrial pathology induced by progesterone receptor modulators SO MODERN PATHOLOGY LA English DT Article DE progesterone receptor modulators; endometrium; histology; pathology ID LOW-DOSE MIFEPRISTONE; ANDROGEN RECEPTOR; CANCER; PROLIFERATION; ANTAGONISTS; ASOPRISNIL; ESTROGENS; TRIAL; RISK AB Progesterone receptor modulators (PRM) are hormonally active drugs effective in the management of endometriosis and uterine leiomyomata. The endometrial effects of progestin blockade by PRMs in premenopausal women are currently being evaluated in several clinical trials, but few pathologists have had access to these materials and published information of the histological changes is scanty. Eighty-four endometrial specimens from women receiving one of four different PRMs were reviewed by a panel of seven experienced gynecologic pathologists to develop consensus observations and interpretive recommendations as part of an NIH-sponsored workshop. Although the pathologists were blinded to agent, dose, and exposure interval, the review was intended to provide an overview of the breadth of possible findings, and a venue to describe unique features. Endometrial histology included inactive and normal-appearing cycling endometrium. Overtly premalignant lesions (atypical hyperplasia or EIN) were not seen. In a subset of cases, asymmetry of stromal and epithelial growth resulted in prominent cystically dilated glands with admixed estrogen (mitotic) and progestin (secretory) epithelial effects of a type not encountered in contemporary clinical practice. The variety of endometrial appearances suggested that findings might differ by agent and dose over time according to relationships that must be specified for each agent. The constellation of changes seen in those endometria with cystically dilated glands is so novel that new terminology and diagnostic criteria are required for pathologists to recognize them. The panel has designated these changes as PRM-associated endometrial changes (PAEC). Additional follow-up studies will be needed to fully define their natural history and relationship to specific agents and administration regimens. C1 [Mutter, George L.] Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, Boston, MA 02115 USA. [Bergeron, Christine] Dept Pathol, Lab Pasteur Cerba, Cergy Pontoise, France. [Deligdisch, Liane] Mt Sinai Sch Med, Dept Pathol, New York, NY USA. [Ferenczy, Alex] McGill Univ, Jewish Gen Hosp, Dept Pathol, Montreal, PQ H3T 1E2, Canada. [Glant, Mick] DCL Med Labs Inc, Dept Pathol, Indianapolis, IN USA. [Merino, Maria] NIH, Dept Pathol, Bethesda, MD 20892 USA. [Williams, Alistair Rw] Univ Edinburgh, Dept Pathol, Edinburgh, Midlothian, Scotland. [Blithe, Diana L.] NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD 20892 USA. RP Mutter, GL (reprint author), Brigham & Womens Hosp, Dept Pathol, Div Womens & Perinatal Pathol, 75 Francis St, Boston, MA 02115 USA. EM gmutter@rics.bwh.harvard.edu RI Mutter, George/C-5819-2009; OI Williams, Alistair/0000-0002-7085-4525 NR 19 TC 89 Z9 94 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD MAY PY 2008 VL 21 IS 5 BP 591 EP 598 DI 10.1038/modpathol.2008.19 PG 8 WC Pathology SC Pathology GA 292HH UT WOS:000255256600012 PM 18246050 ER PT J AU Amodu, OK Hartl, DL Roy, SW AF Amodu, Olukemi K. Hartl, Daniel L. Roy, Scott William TI Patterns of polymorphism in genomic regions flanking three highly polymorphic surface antigens in Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE diversifying selection; balancing selection; population history; population genetics ID PLANT ARABIDOPSIS-LYRATA; CIRCUMSPOROZOITE PROTEIN; POSITIVE SELECTION; NATURAL-SELECTION; MALARIA PARASITES; RECENT ORIGIN; DIVERSITY; RECOMBINATION; DETERMINANTS; HYPOTHESIS AB Many surface antigens of the human malaria parasite Plasmodium falciparum show extraordinary diversity, with different alleles being so divergent as to be unalignable in some coding regions. To better understand the population history and modes of selection on such loci, we sequenced genomic regions flanking the highly polymorphic genes merozoite surface protein-1, merozoite surface protein-2, and circumsporozoite protein, from reference isolates of P. falciparum. Diversity was much lower in genomic flanking regions than in the coding sequences. Average pairwise nucleotide diversity for these regions was 0.00088, similar to other genomic regions not thought to be evolving under balancing selection, suggesting against balancing selection acting on promoter regions of these genes. Most observed polymorphisms were singletons. A higher ratio of SNPs to indels than previously reported for P. falciparum was observed. An 11 bp repeat upstream of msp2 showed an intriguing pattern of polymorphism possibly suggestive of purifying selection on total allele length. (C) 2007 Elsevier B.V. All rights reserved. C1 [Roy, Scott William] Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD USA. [Amodu, Olukemi K.; Hartl, Daniel L.; Roy, Scott William] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Amodu, Olukemi K.] Univ Ibadan, Coll Med, Ibadan, Nigeria. RP Roy, SW (reprint author), Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD USA. EM scottwroy@gmail.com OI Amodu, Olukemi/0000-0003-1477-4229 FU NIGMS NIH HHS [GM079536, GM61351] NR 26 TC 1 Z9 2 U1 0 U2 0 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 MAY PY 2008 VL 159 IS 1 BP 1 EP 6 DI 10.1016/j.molbiopara.2007.12.004 PG 6 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 300CS UT WOS:000255802500001 PM 18291540 ER PT J AU Ueda, T Catez, F Gerlitz, G Bustin, M AF Ueda, Tetsuya Catez, Frederic Gerlitz, Gabi Bustin, Michael TI Delineation of the protein module that anchors HMGN proteins to nucleosomes in the chromatin of living cells SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CHROMOSOMAL-PROTEINS; HIGH-MOBILITY; HISTONE H1; MITOTIC PHOSPHORYLATION; BINDING-PROTEIN; HMG-14; DNA; DOMAIN; TRANSCRIPTION; EXPRESSION AB Numerous nuclear proteins bind to chromatin by targeting unique DNA sequences or specific histone modifications. In contrast, HMGN proteins recognize the generic structure of the 147-bp nucleosome core particle. HMGNs alter the structure and activity of chromatin by binding to nucleosomes; however, the determinants of the specific interaction of HMGNs with chromatin are not known. Here we use systematic mutagenesis, quantitative fluorescence recovery after photobleaching, fluorescence imaging, and mobility shift assays to identify the determinants important for the specific binding of these proteins to both the chromatin of living cells and to purified nucleosomes. We find that several regions of the protein affect the affinity of HMGNs to chromatin; however, the conserved sequence RRSARLSA, is the sole determinant of the specific interaction of HMGNs with nucleosomes. Within this sequence, each of the 4 amino acids in the R-S-RL motif are the only residues absolutely essential for anchoring HMGN protein to nucleosomes, both in vivo and in vitro. Our studies identify a new chromatin-binding module that specifically recognizes nucleosome cores independently of DNA sequence or histone tail modifications. C1 [Ueda, Tetsuya; Catez, Frederic; Gerlitz, Gabi; Bustin, Michael] NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. [Catez, Frederic] Univ Lyon 1, F-69003 Lyon, France. [Catez, Frederic] CNRS, Ctr Genet Mol & Cellulaire, UMR5534, F-69622 Villeurbanne, France. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, NIH, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004496-30] NR 42 TC 31 Z9 31 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 MAY PY 2008 VL 28 IS 9 BP 2872 EP 2883 DI 10.1128/MCB.02181-07 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 289IJ UT WOS:000255047900003 PM 18299391 ER PT J AU Conze, DB Wu, CJ Thomas, JA Landstrom, A Ashwell, JD AF Conze, Dietrich B. Wu, Chuan-Jin Thomas, James A. Landstrom, Allison Ashwell, Jonathan D. TI Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and Toll-like receptor-mediated NF-kappa B activation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GAMMA-DEFICIENT MICE; T-CELL-ACTIVATION; KINASE-ACTIVITY; INTERLEUKIN-1 RECEPTOR; ADAPTER PROTEIN; DEFECTIVE INTERLEUKIN-1; SIGNALING PATHWAYS; IMMUNE-RESPONSES; MYD88; TRAF6 AB Stimulation through the interleukin-1 receptor (IL-1R) and some Toll-like receptors (TLRs) induces ubiquitination of TRAF6 and IRAK-1, signaling components required for NF-kappa B and mitogen-activated protein kinase activation. Here we show that although TRAF6 and IRAK-I acquired Lys63 (K63)-linked polyubiquitin chains upon IL-1 stimulation, only ubiquitinated IRAK-1 bound NEMO, the regulatory subunit Of I kappa B kinase (IKK). The sites of IRAK-1 ubiquitination were mapped to Lys134 and Lys][80, and arginine substitution of these residues impaired IL-IR/TLR-mediated IRAK-1 ubiquitination, NEMO binding, and NF-kappa B activation. K63-linked ubiquitination of IRAK-1 required enzymatically active TRAF6, indicating that it is the physiologically relevant E3. Thus, K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-kappa B. C1 [Conze, Dietrich B.; Wu, Chuan-Jin; Landstrom, Allison; Ashwell, Jonathan D.] NCI, NIH, Lab Immun Cell Biol, Bethesda, MD 20892 USA. [Thomas, James A.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75235 USA. RP Ashwell, JD (reprint author), NCI, NIH, Lab Immun Cell Biol, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural NIH HHS NR 55 TC 123 Z9 131 U1 0 U2 7 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 MAY PY 2008 VL 28 IS 10 BP 3538 EP 3547 DI 10.1128/MCB.02098-07 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 297EV UT WOS:000255600800039 PM 18347055 ER PT J AU Csuros, M Rogozin, IB Koonin, EV AF Csuros, Miklos Rogozin, Igor B. Koonin, Eugene V. TI Extremely intron-rich genes in the alveolate ancestors inferred with a flexible maximum-likelihood approach SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE eukaryotic genome evolution; spliceosomal introns; chromalveolates; maximum likelihood; intron-rich ancestors ID SPLICEOSOMAL INTRONS; EUKARYOTIC EVOLUTION; PSI-BLAST; PROTEIN; POSITIONS; ORIGIN; GAIN; CONSERVATION; DATABASE; TREE AB Chromalveolates are a large, diverse supergroup of unicellular eukaryotes that includes Apicomplexa, dinoflagellates, ciliates (three lineages that form the alveolate branch), heterokonts, haptophytes, and cryptomonads (three lineages comprising the chromist branch). All sequenced genomes of chromalveolates have relatively low intron density in protein-coding genes, and few intron positions are shared between chromalveolate lineages. In contrast, genes of different chromalveolates share many intron positions with orthologous genes from other eukaryotic supergroups, in particular, the intron-rich orthologs from animals and plants. Reconstruction of the history of intron gain and loss during the evolution of chromalveolates using a general and flexible maximum-likelihood approach indicates that genes of the ancestors of chromalveolates and, particularly, alveolates had unexpectedly high intron densities. It is estimated that the chromalveolate ancestor had, approximately, two-third of the human intron density, whereas the intron density in the genes of the alveolate ancestor is estimated to be slightly greater than the human intron density. Accordingly, it is inferred that the evolution of chromalveolates was dominated by intron loss. The conclusion that ancestral chromalveolate forms had high intron densities is unexpected because all extant unicellular eukaryotes have relatively few introns and are thought to be unable to maintain numerous introns due to intense purifying selection in their, typically, large populations. It is suggested that, at early stages of evolution, chromalveolates went through major population bottlenecks that were accompanied by intron invasion. C1 [Csuros, Miklos] Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada. [Csuros, Miklos] Coll Budapest Inst Adv Study, Budapest, Hungary. [Rogozin, Igor B.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Csuros, M (reprint author), Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada. EM csuros@iro.umontreal.ca; koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 67 TC 36 Z9 36 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD MAY PY 2008 VL 25 IS 5 BP 903 EP 911 DI 10.1093/molbev/msn039 PG 9 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 290XJ UT WOS:000255156600012 PM 18296415 ER PT J AU Cherukuri, S Hock, R Ueda, T Catez, F Rochman, M Bustin, M AF Cherukuri, Srujana Hock, Robert Ueda, Tetsuya Catez, Frederic Rochman, Mark Bustin, Michael TI Cell cycle-dependent binding of HMGN proteins to chromatin SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GROUP CHROMOSOMAL-PROTEINS; MOBILITY-GROUP PROTEINS; TRANSCRIPTION FACTORS; MITOTIC CHROMATIN; FLUORESCENCE COMPLEMENTATION; HISTONE MODIFICATIONS; DYNAMIC INTERACTION; MASS-SPECTROMETRY; IN-VIVO; PHOSPHORYLATION AB Throughout the cell cycle, the histones remain associated with DNA, but the repertoire of proteins associated with the chromatin fiber continuously changes. The chromatin interaction of HMGNs, a family of nucleosome binding proteins that modulates the structure and activity of chromatin, during the cell cycle is controversial. Immunofluorescence studies demonstrated that HMGNs are not associated with chromatin, whereas live cell imaging indicated that they are present in mitotic chromosomes. To resolve this controversy, we examined the organization of wild-type and mutated HMGN1 and HMGN2 proteins in the cell nucleus by using immunofluorescence studies, live cell imaging, gel mobility shift assays, and bimolecular fluorescence complementation (BiFC). We find that during interphase, HMGNs bind specifically to nucleosomes and form homodimeric complexes that yield distinct BiFC signals. In metaphase, the nucleosomal binding domain of the protein is inactivated, and the proteins associate with chromatin with low affinity as monomers, and they do not form specific complexes. Our studies demonstrate that the mode of binding of HMGNs to chromatin is cell cycle dependent. C1 [Cherukuri, Srujana; Ueda, Tetsuya; Catez, Frederic; Rochman, Mark; Bustin, Michael] Natl Canc Inst, Lab Metab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Hock, Robert] Univ Wurzburg, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. [Catez, Frederic] Univ Lyon 1, F-69003 Lyon, France. [Catez, Frederic] CNRS, Unite Mixte Rech 5534, Ctr Genet Mol & Cellulaire, F-69622 Villeurbanne, France. RP Bustin, M (reprint author), Natl Canc Inst, Lab Metab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Deutsche Forschungsgemeinschaft; NIH; NCI; Jacob and Lena Joels Foundation FX We thank Dr. Tom Kerppola, University of Michigan School of Medicine, for providing the initial vector backbones for BiFC, Dr. Aloys Schepers for HA-tag antibodies, Dr. A. Nagy, Toronto, Canada, For ES cells, Dr. M. J. Soares, University of Kansan Medical Center, for Rcho-1 and Eyal Rand, NCI protein section, for producing growing and analyzing ES cells stably expressing HMGN-YFP. This work was supported by a grant of the Deutsche Forschungsgemeinschaft to R. Hock, by the Intramural Program of NIH, NCI, and by a Jacob and Lena Joels Foundation Visiting Professorship Award, from the Hebrew University, Israel, to MB. NR 38 TC 23 Z9 28 U1 2 U2 4 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 MAY PY 2008 VL 19 IS 5 BP 1816 EP 1824 DI 10.1091/mbc.E07-10-1018 PG 9 WC Cell Biology SC Cell Biology GA 344UE UT WOS:000258952000001 PM 18287527 ER PT J AU Hong, D Ye, L Gagel, R Chintala, L El Naggar, AK Wright, J Kurzirock, R AF Hong, David Ye, Lei Gagel, Robert Chintala, Lakshmi El Naggar, Adel K. Wright, John Kurzirock, Razelle TI Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ENDOCRINE NEOPLASIA TYPE-2; CODON 918 MUTATION; MYELODYSPLASTIC SYNDROME; PROTOONCOGENE MUTATIONS; TYROSINE KINASE; ACTIVATION; CARCINOMA; INHIBITION; PROGNOSIS; DISEASE AB Medullary thyroid carcinoma (MTC) is an uncommon malignancy of hereditary and sporadic presentation. Mutations in the RET proto-oncogene are involved in the pathogenesis of familial MTC and > 50% of the sporadic cases. Currently, there is no effective treatment for recurrent or metastatic MTC. We report here a rapid response to a sorafenib (RET and RAF: kinase and vascular endothelial growth factor receptor inhibitor)-based regimen in a patient with sporadic MTC who had advanced, progressive disease and a novel RET kinase aberration at exon 11 shown in tumor tissue. C1 [Hong, David] MD Anderson Canc Ctr, Div Canc Med, Unit 455, Dept Invest Therapeut Phase Program 1, Houston, TX 77030 USA. [Ye, Lei; Gagel, Robert] MD Anderson Canc Ctr, Dept Internal Med, Houston, TX 77030 USA. [El Naggar, Adel K.] MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Wright, John] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Hong, D (reprint author), MD Anderson Canc Ctr, Div Canc Med, Unit 455, Dept Invest Therapeut Phase Program 1, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM dshong@mdanderson.org FU NCI NIH HHS [5 U01 CA062461] NR 23 TC 31 Z9 31 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 MAY PY 2008 VL 7 IS 5 BP 1001 EP 1006 DI 10.1158/1535-7163.MCT-07-2422 PG 6 WC Oncology SC Oncology GA 301RS UT WOS:000255913900001 PM 18445656 ER PT J AU Alfano, RW Leppla, SH Liu, SH Bugge, TH Herlyn, M Smalley, KS Bromberg-White, JL Duesbery, NS Frankel, AE AF Alfano, Randall W. Leppla, Stephen H. Liu, Shihui Bugge, Thomas H. Herlyn, Meenhard Smalley, Keiran S. Bromberg-White, Jennifer L. Duesbery, Nicholas S. Frankel, Arthur E. TI Cytotoxicity of the matrix metalloproteinase-activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID REGULATED KINASE KINASE; MALIGNANT-MELANOMA; BRAF; INACTIVATION; INHIBITOR; MUTATIONS; INVASION; GROWTH; MATRIX-METALLOPROTEINASE-9; PROTEOLYSIS AB Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)-activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surf ace-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy. C1 [Alfano, Randall W.; Frankel, Arthur E.] Mem Hosp, Scott & White Canc Res Inst, Temple, TX 76502 USA. [Alfano, Randall W.; Frankel, Arthur E.] Texas A&M Univ, Hlth Sci Ctr, Dept Internal Med, Temple, TX USA. [Leppla, Stephen H.; Liu, Shihui] NIAID, Natl Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Bugge, Thomas H.] Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD USA. [Herlyn, Meenhard; Smalley, Keiran S.] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Bromberg-White, Jennifer L.; Duesbery, Nicholas S.] Van Andel Res Inst, Lab Canc & Dev Cell Biol, Grand Rapids, MI USA. RP Frankel, AE (reprint author), Mem Hosp, Scott & White Canc Res Inst, 5701 S Airport Rd, Temple, TX 76502 USA. EM afrankel@swmail.sw.org RI Smalley, Keiran/A-1320-2007; OI Smalley, Keiran/0000-0002-4121-8335; DUESBERY, NICK/0000-0002-4258-5655 FU Intramural NIH HHS [Z01 AI000929-05, Z99 AI999999] NR 30 TC 9 Z9 9 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAY PY 2008 VL 7 IS 5 BP 1218 EP 1226 DI 10.1158/1535-7163.MCT-08-0024 PG 9 WC Oncology SC Oncology GA 301RS UT WOS:000255913900023 PM 18483309 ER PT J AU Gao, R Price, DK Sissung, T Reed, E Figg, WD AF Gao, Rui Price, Douglas K. Sissung, Tristan Reed, Eddie Figg, William D. TI Ethnic disparities in Americans of European descent versus Americans of African descent related to polymorphic ERCC1, ERCC2, XRCC1, and PARP1 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; CELL LUNG-CANCER; PLATINUM-BASED CHEMOTHERAPY; ADVANCED COLORECTAL-CANCER; DNA-REPAIR; BREAST-CANCER; PROGNOSTIC-FACTORS; PROSTATE-CANCER; BASE EXCISION; ANTICANCER CHEMOTHERAPY AB Nucleotide excision repair (NER) and base excision repair (BER) pathways are DNA repair pathways that are important in carcinogenesis and in response to DNA-damaging chemotherapy. ERCC1 and ERCC2 are important molecular markers for NER; XRCC1 and PARP1 are important molecular markers for BER. Functional polymorphisms have been described that are associated with altered expression levels of these genes and with altered DNA repair capability. We assayed genomic DNA from 156 Americans of European descent and 164 Americans of African descent for the allelic frequencies of specific polymorphisms of ERCC1 N118N (500C>T), ERCC1 C8092A, ERCC2 K751Q (2282A > C), XRCC1 R399Q (11301 G > A), XRCC1 R194W (685C>T), and PARP1 V762A (2446T>C). Differences were observed between Americans of European descent and Americans of African descent in the allelic frequencies of the ERCC1 N118N polymorphism (P < 0.000001). Differences were also observed between these two ethnic groups for ERCC2 K751Q (P = < 0.006675), XRCC1 R399Q (P < 0.000001), and PARP1 V762A (P = 0.000001). The ERCC 1 N118N polymorphic variant that is seen most commonly in Americans of European descent is associated with a measurable reduction in NER function. ERCC1-mediated reduction in NER functionality affects the repair of cisplatin-DNA lesions. C1 [Gao, Rui; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, NIH, Bethesda, MD 20892 USA. [Sissung, Tristan; Figg, William D.] NCI, Clin Pharmacol Program, NIH, Bethesda, MD 20892 USA. [Figg, William D.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Gao, Rui] Univ Maryland, College Pk, MD 20742 USA. [Reed, Eddie] Ctr Dis Control, Atlanta, GA 30333 USA. [Reed, Eddie] Ctr Prevent, Atlanta, GA USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, NIH, Room 5A01,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Mendez, Pedro /J-8955-2016; Figg Sr, William/M-2411-2016 OI Mendez, Pedro /0000-0001-6713-7907; FU Intramural NIH HHS [Z01 BC010627-05] NR 56 TC 21 Z9 21 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 MAY PY 2008 VL 7 IS 5 BP 1246 EP 1250 DI 10.1168/1535-7163.MCT-07-2206 PG 5 WC Oncology SC Oncology GA 301RS UT WOS:000255913900026 PM 18483312 ER PT J AU Heimeier, RA Hsia, VS Shi, YB AF Heimeier, Rachel A. Hsia, Victor Shaochung Shi, Yun-Bo TI Participation of Brahma-related gene 1 (BRG1)-associated factor 57 and BRG1-containing chromatin remodeling complexes in thyroid hormone-dependent gene activation during vertebrate development SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID MAMMALIAN SWI/SNF COMPLEXES; XENOPUS-LAEVIS; GLUCOCORTICOID-RECEPTOR; TRANSCRIPTIONAL ACTIVATION; COREPRESSOR COMPLEX; NUCLEAR RECEPTORS; BRG1 COMPLEX; EXPRESSION; BAF57; METAMORPHOSIS AB Multiple cofactors and chromatin remodeling complexes have been identified to contribute to the transcriptional activation regulated by thyroid hormone receptors ( TRs) in vitro. However, their role and function during development in vivo remains to be elucidated. The total dependence of amphibian metamorphosis on thyroid hormone ( T 3) provides a unique vertebrate model for studying the molecular mechanism of TR function in vivo. In this study, we show that the expression of Brahma-related gene 1 ( BRG1), a chromatin-remodeling enzyme, is up-regulated at the climax of Xenopus laevis metamorphosis, whereas BRG1-associated factor 57 ( BAF57), a BRG1-binding protein in BRG1-containing chromatin remodeling complexes, is constitutively expressed during development. Consistently, T 3 treatment of premetamorphic tadpoles led to up-regulation of the expression of BRG1 but not BAF57. Studies using a reconstituted T-3-dependent Xenopus oocyte transcription system, where we could study TR function in the context of chromatin, revealed that BRG1 enhances the transcriptional activation by ligand-bound TRs in a dose-dependent manner, whereas a remodeling-defective BRG1 mutant inhibited the activation, suggesting that this process relies on chromatin remodeling. Additional studies showed that BAF57 interacted with BRG1 in oocytes and enhanced gene activation by TR cooperatively with BRG1 in vivo. Chromatin immunoprecipitation revealed that BAF57 was recruited to the TR-regulated promoter in the presence of TR and T-3. Together, these findings suggest a role of BRG1/ BAF57-containing chromatin remodeling complexes in TR-regulated gene expression during postembryonic development. C1 [Heimeier, Rachel A.; Hsia, Victor Shaochung] NICHHD, Lab Gene Regulat & Dev, Program Cell Regulat & Metab, NIH,Sect Mol Morphogenesis, Bethesda, MD 20892 USA. [Hsia, Victor Shaochung] Univ Louisiana Manroe, Sch Pharm, Dept Basic Pharmaceut Sci, Monroe, LA 71209 USA. RP Shi, YB (reprint author), NICHHD, Lab Gene Regulat & Dev, Program Cell Regulat & Metab, NIH,Sect Mol Morphogenesis, Bldg 18 T,Room 106, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov OI Hsia, Victor/0000-0001-7623-2842 FU Intramural NIH HHS; NCRR NIH HHS [P20 RR016456, P20 RR16456] NR 86 TC 14 Z9 14 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAY PY 2008 VL 22 IS 5 BP 1065 EP 1077 DI 10.1210/me.2007-0492 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 293HW UT WOS:000255327400005 PM 18238828 ER PT J AU Yu, LD Saile, K Swartz, CD He, H Zheng, XL Kissling, GE Di, XD Lucas, S Robboy, SJ Dixon, D AF Yu, Linda Saile, Katrin Swartz, Carol D. He, Hong Zheng, Xiaolin Kissling, Grace E. Di, Xudong Lucas, Shantelle Robboy, Stanley J. Dixon, Darlene TI Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas SO MOLECULAR MEDICINE LA English DT Article ID GROWTH-FACTOR-I; INSULIN-LIKE; HUMAN MYOMETRIUM; GENE-EXPRESSION; TUMOR-GROWTH; CELL-PROLIFERATION; BINDING; FIBROIDS; MYOMAS; CANCER AB Uterine leiomyomas (fibroids) are benign tumors that are prevalent in women of reproductive age. Research suggests that activated receptor tyrosine kinases (RTKs) play an important role in the enhanced proliferation observed in fibroids. In this study, a phospho-RTK array technique was used to detect RTK activity in lelomyomas compared with myometrial tissue. We found that fifteen out of seventeen RTKs evaluated in this study were highly expressed (P < 0.02-0.03) in the leiomyomas, and included the IGF-I/IGF-IR, EGF/EGFR, FGF/FGF-R, HGF/HGF-R, and PDGF/PDGF-R gene families. Due to the higher protein levels of IGF-IR observed in leiomyomas by us in earlier studies, we decided to focus on the activation of the IGF-IR, its downstream effectors, and MAPKp44/42 to confirm our earlier findings: and validate the significance of the increased IGF-IR phosphorylation observed by RTK array analysis in this study. We used immunolocalization, western blot, or immunoprecipitation studies and confirmed that lelomyomas overexpressed IGF-IR beta and phosphorylated IGF-IR beta. Additionally, we showed that the downstream effectors, Shc, Grb2, and MAPKp44/42 (P<0.02-0.001) were also overexpressed and involved in IGF-IR signaling in these tumors, while IRS-I, PI3K, and AKT were not. In vitro studies showed that IGF-I (100 ng/mL) increased the proliferation of uterine leiomyoma cells (UtLM) (P < 0.0001), and that phosphorylated IGF-IR beta, Shc, and MAPKp44/42 were also overexpressed in IGF-I-treated UtLM cells (P < 0.05), similar to the tissue findings. A neutralizing antibody against the IGF-IR beta blocked these effects. These data indicate that overexpression of RTKs and, in particular, activation of the IGF-IR signaling pathway through Shc/Grb2/MAPK are important in mediating uterine leiomyoma growth. These data may provide new anti-tumor targets for noninvasive treatment of fibroids. C1 [Yu, Linda; Saile, Katrin; He, Hong; Zheng, Xiaolin; Di, Xudong; Lucas, Shantelle; Dixon, Darlene] NIEHS, Cellular & Mol Pathol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Swartz, Carol D.] US EPA, Div Environm Carcinogenesis, Res Triangle Pk, NC 27711 USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. [Robboy, Stanley J.] Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA. RP Dixon, D (reprint author), NIEHS, Cellular & Mol Pathol Branch, NIH, Dept Hlth & Human Serv, POB 12233,MDC2-09111 Alexander Dr,Bldg 101 Rm C25, Res Triangle Pk, NC 27709 USA. EM dixon@niehs.nih.gov FU Intramural NIH HHS NR 48 TC 41 Z9 42 U1 0 U2 5 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD MAY-JUN PY 2008 VL 14 IS 5-6 BP 264 EP 275 DI 10.2119/2007-00101.Yu PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 298WA UT WOS:000255716600005 PM 18231572 ER PT J AU Lee, HS Lee, AT Criswell, LA Seldin, MF Amos, CI Carulli, JP Navarrete, C Remmers, EF Kastner, DL Plenge, RM Li, W Gregersen, PK AF Lee, Hye-Soon Lee, Annette T. Criswell, Lindsey A. Seldin, Michael F. Amos, Christopher I. Carulli, John P. Navarrete, Cristina Remmers, Elaine F. Kastner, Daniel L. Plenge, Robert M. Li, Wentian Gregersen, Peter K. TI Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus SO MOLECULAR MEDICINE LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HLA-C GENES; SUSCEPTIBILITY; ASSOCIATION; HAPLOTYPES; ALLELES; GENOME; RECEPTORS; SEVERITY; KIR AB Recent evidence suggests that additional risk loci for RA are present in the major histocompatibility complex (MHC), independent of the class II HLA-DRB1 locus, We have now tested a total of 1,769 SNPs across 7.5Mb of the MHC located from 6p22.2 (26.03 Mb) to 6p21.32 (33,59 Mb) derived from the Illumina 550K Beadchip (Illumina, Son Diego, CA, USA), For an initial analysis in the whole dataset (869 RA CCP + cases, 1, 193 controls), the strongest association signal was observed in markers near the HLA-DRB1 locus, with additional evidence for association extending out into the Class I HLA region, To avoid confounding that may arise due to linkage disequilibrium with DRB1 alleles, we analyzed a subset of the data by matching cases and controls by DRB1 genotype (both alleles matched 1: 1), yielding a set of 372 cases with 372 controls. This analysis revealed the presence of at least two regions of association with RA in the Class I region, independent of DRB1 genotype. SNP alleles found on the conserved Al-B8-DR3 (8, 1) haplotype show the strongest evidence of positive association (P similar to 0.00005) clustered in the region around the HLA-C locus. In addition, we identified risk alleles that are not present on the 8.1 haplotype, with maximal association signals (P similar to 0.001-0.0027) located near the ZNF311 locus. This latter association is enriched in DRB1*0404 individuals. Finally, several additional association signals were found in the extreme centromeric portion of the MHC, in regions containing the DOB1, TAP2, DPB1, and COL11A2 genes, These data emphasize that further analysis of the MHC is likely to reveal genetic risk factors for rheumatoid arthritis that are independent of the DRB1 shared epitope alleles. C1 [Gregersen, Peter K.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Robert S Boas Ctr Gen & Human Genet, Manhasset, NY 11030 USA. [Lee, Hye-Soon] Hanyang Univ, Coll Med, Seoul 133791, South Korea. [Criswell, Lindsey A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Seldin, Michael F.] Univ Calif Davis, Davis, CA 95616 USA. [Amos, Christopher I.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Carulli, John P.] Biogen Idec Inc, Cambridge, MA USA. [Navarrete, Cristina] Natl Blood Serv, London, England. [Remmers, Elaine F.; Kastner, Daniel L.] NIAMSD, Bethesda, MD 20892 USA. [Plenge, Robert M.] Broad Inst Harvard, Cambridge, MA USA. [Plenge, Robert M.] MIT, Cambridge, MA 02139 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol,Dept Med, Boston, MA 02115 USA. RP Gregersen, PK (reprint author), N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Robert S Boas Ctr Gen & Human Genet, 350 Community Dr, Manhasset, NY 11030 USA. EM peterg@nshs.edu OI Li, Wentian/0000-0003-1155-110X FU Intramural NIH HHS; NIAID NIH HHS [R01 AI065841]; NIAMS NIH HHS [R01-AR44222]; PHS HHS [U19 IMAGEN] NR 41 TC 57 Z9 59 U1 0 U2 6 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD MAY-JUN PY 2008 VL 14 IS 5-6 BP 293 EP 300 DI 10.2119/2007-00123.Lee PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 298WA UT WOS:000255716600008 PM 18309376 ER PT J AU Quinn, K Galbraith, SE Sheahan, BJ Atkins, GJ AF Quinn, K. Galbraith, S. E. Sheahan, B. J. Atkins, G. J. TI Effect of intranasal administration of Semliki Forest virus recombinant particles expressing interferon-B on the progression of experimental autoimmune encephalomyelitis SO MOLECULAR MEDICINE REPORTS LA English DT Article DE beta-interferon; Semliki Forest virus vector; experimental autoimmune encephalomyelitis; demyelination ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; REMITTING MULTIPLE-SCLEROSIS; MYELIN BASIC-PROTEIN; GROWTH-FACTOR-BETA; LEWIS RATS; IFN-BETA; GENE-THERAPY; VECTOR; INTERLEUKIN-4 AB The effect of intranasal (IN) administration of Semliki Forest virus (SFV) recombinant particles expressing interferon-beta [IFN-beta, a partially effective treatment for multiple sclerosis (MS)] on the progression of experimental autoimmune encephalomyelitis (EAE, a murine model for MS) was investigated. The murine IFN-beta gene was cloned from SFV-infected mouse brain by RT-PCR into an SFV-enhanced expression vector, pSFV10-E, from which IFN-beta-expressing recombinant particles (rSFV10-E-1FN-beta) were prepared. Expression studies using immunohistochemistry and viral inhibition assay in BHK and murine L929 cells confirmed increased expression of IFN-beta. High level expression in the central nervous system (CNS) following IN inoculation was confirmed by the excision of olfactory bulbs, brain and spinal cord, and the detection of IFN-beta levels in homogenised tissue by ELISA. rSFV10-E-IFN-beta particles were administered IN to C57/B16 mice that had been induced for EAE using the encephalogenic peptide myelin oligodendrocyte glycoprotein (MOG) 35-55. The progression of EAE was measured by clinical score, weight loss and pathology. As previously shown, treatment with empty rSFV10-E particles moderately exacerbated EAE, as did continuous treatment with rSFV10E-IFN-beta particles. Inhibition of disease with rSFV10-E-IFN-beta particles was dependent on the number and timing of treatments. Fewer treatments, administered before the effector stage, led to an improvement in clinical and pathology score. in conclusion, the timing and frequency of IN administration of rSFV10-E-IFN-beta particles are critical to disease outcome, with treatment prior to the effector stage being most effective. C1 [Quinn, K.; Galbraith, S. E.; Atkins, G. J.] Univ Dublin Trinity Coll, Sch Genet & Microbiol, Moyne Inst Prevent Med, Virus Grp, Dublin 2, Ireland. [Galbraith, S. E.; Sheahan, B. J.] Natl Univ Ireland Univ Coll Dublin, Sch Agr Food Sci & Vet Med, Vet Sci Ctr, Dublin 4, Ireland. [Quinn, K.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. [Galbraith, S. E.] Univ Texas Galveston, Dept Pathol, Med Branch, Galveston, TX 77555 USA. RP Atkins, GJ (reprint author), Univ Dublin Trinity Coll, Sch Genet & Microbiol, Moyne Inst Prevent Med, Virus Grp, Dublin 2, Ireland. EM gatkins@tcd.ie OI Galbraith, Sareen/0000-0002-1009-6179 FU National Neuroscience Network of Ireland; European Union 5th Framework Programme; The Multiple Sclerosis Society of Ireland and Enterprise Ireland FX We thank Dorothy Mooney for assistance with the laboratory protocols and Alex Whelan-Buckley for assistance with the histopathological studies. We also thank Margaret Morris-Downes and Alan Jerusalmi for all their assistance and advice in setting up the EAE model. This work was supported by the National Neuroscience Network of Ireland, the European Union 5th Framework Programme, The Multiple Sclerosis Society of Ireland and Enterprise Ireland. NR 28 TC 3 Z9 5 U1 0 U2 2 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 J9 MOL MED REP JI Mol. Med. Rep. PD MAY-JUN PY 2008 VL 1 IS 3 BP 335 EP 342 PG 8 WC Pathology SC Pathology GA 374QE UT WOS:000261058000006 PM 21479414 ER PT J AU Boylan, JA Lawrence, KA Downey, JS Gherardini, FC AF Boylan, Julie A. Lawrence, Kevin A. Downey, Jennifer S. Gherardini, Frank C. TI Borrelia burgdorferi membranes are the primary targets of reactive oxygen species SO MOLECULAR MICROBIOLOGY LA English DT Article ID OXIDATIVE DNA-DAMAGE; HELICOBACTER-PYLORI; LIPID-PEROXIDATION; ESCHERICHIA-COLI; FLUORESCENT-PROBE; DISEASE; MUTATIONS; STRESS; ROLES; DIPHENYL-1-PYRENYLPHOSPHINE AB Spirochetes living in an oxygen-rich environment or when challenged by host immune cells are exposed to reactive oxygen species (ROS). These species can harm/destroy cysteinyl residues, iron-sulphur clusters, DNA and polyunsaturated lipids, leading to inhibition of growth or cell death. Because Borrelia burgdorferi contains no intracellular iron, DNA is most likely not a major target for ROS via Fenton reaction. In support of this, growth of B. burgdorferi in the presence of 5 mM H2O2 had no effect on the DNA mutation rate (spontaneous coumermycin A1 resistance), and cells treated with 10 mM t-butyl hydroperoxide or 10 mM H2O2 show no increase in DNA damage. Unlike most bacteria, B. burgdorferi incorporates ROS-susceptible polyunsaturated fatty acids from the environment into their membranes. Analysis of lipoxidase-treated B. burgdorferi cells by Electron Microscopy showed significant irregularities indicative of membrane damage. Fatty acid analysis of cells treated with lipoxidase indicated that host-derived linoleic acid had been dramatically reduced (50-fold) in these cells, with a corresponding increase in the levels of malondialdehyde by-product (fourfold). These data suggest that B. burgdorferi membrane lipids are targets for attack by ROS encountered in the various stages of the infective cycle. C1 [Boylan, Julie A.; Lawrence, Kevin A.; Gherardini, Frank C.] NIAID, Rocky Mt Lab, Hamilton, MT 59840 USA. [Downey, Jennifer S.] Univ So Calif, Los Angeles, CA USA. RP Gherardini, FC (reprint author), NIAID, Rocky Mt Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM fgherardini@niaid.nih.gov FU Intramural NIH HHS NR 33 TC 40 Z9 41 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD MAY PY 2008 VL 68 IS 3 BP 786 EP 799 DI 10.1111/j.1365-2958.2008.06204.x PG 14 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 283MZ UT WOS:000254641600019 PM 18373524 ER PT J AU Robey, RW Lazarowski, A Bates, SE AF Robey, Robert W. Lazarowski, Alberto Bates, Susan E. TI P-glycoprotein - A clinical target in drug-refractory epilepsy? SO MOLECULAR PHARMACOLOGY LA English DT Article ID CANCER RESISTANCE PROTEIN; BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE; CELLULAR-DISTRIBUTION; ANTIEPILEPTIC DRUGS; PHASE-I; EXPRESSION; ABCG2; TRANSPORTERS; PHENYTOIN AB ATP-binding cassette transporters such as P-glycoprotein (Pgp), multidrug resistance-associated protein, and breast cancer resistance protein are known to transport a wide range of substrates and are highly expressed in the capillary endothelial cells that form part of the blood-brain barrier. It is noteworthy that P-glycoprotein has been shown to be up-regulated in animal models of refractory epilepsy, and adding a Pgp inhibitor to treatment regimens has been shown to reverse the drug-resistant phenotype. Limited data have suggested a role for Pgp in epilepsy in humans as well. However, few epilepsy drugs have been shown to be transported by Pgp, leading to controversy over whether Pgp actually plays a role in drug-resistant epilepsy. In this issue of Molecular Pharmacology, Bauer et al. (p. 1444) demonstrate that glutamate can cause localized up-regulation of Pgp via cyclooxygenase-2 (COX-2) and that this phenomenon can be prevented with COX-2 inhibitors. Localized rather than global up-regulation of Pgp may explain some of the difficulty investigators have had in proving a role for Pgp in epilepsy. The results add new support for future clinical trials targeting Pgp expression in drug-refractory epilepsy. C1 [Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. [Lazarowski, Alberto] Univ Buenos Aires, Sch Pharm & Biochem, Dept Clin Biochem, RA-1053 Buenos Aires, DF, Argentina. [Lazarowski, Alberto] Univ Buenos Aires, E Robertis Neurosci Res Inst, RA-1053 Buenos Aires, DF, Argentina. RP Robey, RW (reprint author), 900 Rockville Pike,Bldg 10 Rm 12C217, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov NR 38 TC 26 Z9 29 U1 1 U2 3 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 MAY PY 2008 VL 73 IS 5 BP 1343 EP 1346 DI 10.1124/mol.108.046680 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VP UT WOS:000255014200003 PM 18314494 ER PT J AU Bauer, B Hartz, AMS Pekcec, A Toellner, K Miller, DS Potschka, H AF Bauer, Bjoern Hartz, Anika M. S. Pekcec, Anton Toellner, Kathrin Miller, David S. Potschka, Heidrun TI Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling SO MOLECULAR PHARMACOLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; NECROSIS-FACTOR-ALPHA; MICROVESSEL ENDOTHELIAL-CELLS; IN-VIVO ACTIVATION; RAT-BRAIN; INCREASED EXPRESSION; STATUS EPILEPTICUS; PILOCARPINE MODEL; DRUG-RESISTANCE; NMDA RECEPTOR AB Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-D-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d] cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders. C1 [Pekcec, Anton; Potschka, Heidrun] Univ Munich, Inst Pharmacol Toxicol & Pharm, D-80539 Munich, Germany. [Bauer, Bjoern; Hartz, Anika M. S.; Miller, David S.] Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. [Bauer, Bjoern] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Toellner, Kathrin] Univ Vet Med, Inst Pharmacol Toxicol & Pharm, Hannover, Germany. RP Potschka, H (reprint author), Univ Munich, Inst Pharmacol Toxicol & Pharm, Koeniginstr 16, D-80539 Munich, Germany. EM potschka@pharmtox.vetmed.uni-muenchen.de OI Potschka, Heidrun/0000-0003-1506-0252; Gualtieri, Fabio/0000-0002-4972-0039 FU Intramural NIH HHS NR 40 TC 111 Z9 118 U1 1 U2 3 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 MAY PY 2008 VL 73 IS 5 BP 1444 EP 1453 DI 10.1124/mol.107.041210 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 288VP UT WOS:000255014200014 PM 18094072 ER PT J AU Chen, CY Opazo, JC Erez, O Uddin, M Santolaya-Forgas, J Goodman, M Grossman, LI Romero, R Wildman, DE AF Chen, Caoyi Opazo, Juan C. Erez, Offer Uddin, Monica Santolaya-Forgas, Joaquin Goodman, Morris Grossman, Lawrence I. Romero, Roberto Wildman, Derek E. TI The human progesterone receptor shows evidence of adaptive evolution associated with its ability to act as a transcription factor SO MOLECULAR PHYLOGENETICS AND EVOLUTION LA English DT Article DE primates; positive selection; hormone activity; parturition; chimpanzee ID HUMAN UTERINE ENDOMETRIUM; MESSENGER-RNA; DNA METHYLATION; B-ISOFORM; REPRODUCTIVE FUNCTIONS; INHIBITORY FUNCTION; GENE INACTIVATION; HUMAN PARTURITION; FETAL MEMBRANES; X INACTIVATION AB The gene encoding the progesterone receptor (PGR) acts as a transcription factor, and participates in the regulation of reproductive processes including menstruation, implantation, pregnancy maintenance, parturition, mammary development, and lactation. Unlike other mammals, primates do not exhibit progesterone withdrawal at the time of parturition. Because progesterone-mediated reproductive features vary among mammals, PGR is an attractive candidate gene for studies of adaptive evolution. Thus, we sequenced the progesterone receptor coding regions in a diverse range of species including apes, Old World monkeys, New World monkeys, prosimian primates, and other mammals. Adaptive evolution occurred on the human and chimpanzee lineages as evidenced by statistically significant increases in nonsynonymous substitution rates compared to synonymous substitution rates. Positive selection was rarely observed in other lineages. In humans, amino acid replacements occurred mostly in a region of the gene that has been shown to have an inhibitory function (IF) on the ability of the progesterone receptor to act as a transcription factor. Moreover, many of the nonsynonymous substitutions in primates occurred in the N-terminus. This suggests that cofactor interaction surfaces might have been altered, resulting in altered progesterone-regulated gene transcriptional effects. Further evidence that the changes conferred an adaptive advantage comes from SNP analysis indicating only one of the IF changes is polymorphic in humans. In chimpanzees, amino acid changes occurred in both the inhibitory and transactivation domains. Positive selection provides the basis for the hypothesis that changes in structure and function of the progesterone receptor during evolution contribute to the diversity of primate reproductive biology, especially in parturition. (c) 2007 Elsevier Inc. All rights reserved. C1 [Chen, Caoyi; Opazo, Juan C.; Uddin, Monica; Goodman, Morris; Grossman, Lawrence I.; Romero, Roberto; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Erez, Offer; Santolaya-Forgas, Joaquin; Romero, Roberto; Wildman, Derek E.] NICHD, Perinatal Res Branch, NIH, DHHS, Bethesda, MD 20892 USA. [Santolaya-Forgas, Joaquin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. [Goodman, Morris] Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. [Wildman, Derek E.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatal Res Branch, NICHD,Sch Med, NIH,DHHS,Hutzel Womens Hosp,Ctr Mol Med & Genet, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu; dwild-man@med.wayne.edu RI Opazo, Juan/A-9363-2009; OI Opazo, Juan/0000-0001-7938-4083 FU Intramural NIH HHS [Z01 HD002400-16] NR 85 TC 15 Z9 32 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1055-7903 J9 MOL PHYLOGENET EVOL JI Mol. Phylogenet. Evol. PD MAY PY 2008 VL 47 IS 2 BP 637 EP 649 DI 10.1016/j.ympev.2007.12.026 PG 13 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 304LD UT WOS:000256110100014 PM 18375150 ER PT J AU Baum, AE Hamshere, M Green, E Cichon, S Rietschel, M Noethen, MM Craddock, N McMahon, FJ AF Baum, A. E. Hamshere, M. Green, E. Cichon, S. Rietschel, M. Noethen, M. M. Craddock, N. McMahon, F. J. TI Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement SO MOLECULAR PSYCHIATRY LA English DT Letter C1 [Baum, A. E.; McMahon, F. J.] US Dept HHS, Natl Inst Hlth, NIMH, Unit Genet Basis Mood & Anxiety Disorders Mood, Bethesda, MD USA. [Baum, A. E.; McMahon, F. J.] US Dept HHS, Natl Inst Hlth, NIMH, Anxiety Disorders Program, Bethesda, MD USA. [Hamshere, M.] Cardiff Univ, Sch Med, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. [Hamshere, M.; Green, E.; Craddock, N.] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales. [Noethen, M. M.] Univ Bonn, Dept Genom, D-5300 Bonn, Germany. [Cichon, S.; Noethen, M. M.] Univ Bonn, Life & Brain Ctr, D-5300 Bonn, Germany. [Cichon, S.; Noethen, M. M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Rietschel, M.] Univ Heidelberg, Cent Inst Mental Hlth, Dept Genet Epidemiol, D-6800 Mannheim, Germany. RP Baum, AE (reprint author), US Dept HHS, Natl Inst Hlth, NIMH, Unit Genet Basis Mood & Anxiety Disorders Mood, Bethesda, MD USA. EM bauma@mail.nih.gov RI McMahon, Francis/A-7290-2009; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS [Z01 MH002842-04, Z01 MH002810-05, Z01 MH002843-04]; Medical Research Council [, G9810900]; Wellcome Trust NR 8 TC 72 Z9 75 U1 0 U2 3 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 MAY PY 2008 VL 13 IS 5 BP 466 EP 467 DI 10.1038/mp.2008.16 PG 2 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 289LY UT WOS:000255057200001 PM 18421293 ER PT J AU Clark, JA Flick, RB Pai, LY Szalayova, I Key, S Conley, RK Deutch, AY Hutson, PH Mezey, E AF Clark, J. A. Flick, R. B. Pai, L-Y Szalayova, I. Key, S. Conley, R. K. Deutch, A. Y. Hutson, P. H. Mezey, E. TI Glucocorticoid modulation of tryptophan hydroxylase-2 protein in raphe nuclei and 5-hydroxytryptophan concentrations in frontal cortex of C57/BI6 mice SO MOLECULAR PSYCHIATRY LA English DT Article DE serotonin; 5-HTP; dexamethasone; corticosterone; mifepristone ID MESSENGER-RNA EXPRESSION; TISSUE-SPECIFIC EXPRESSION; MAJOR DEPRESSION; PINEAL-GLAND; RAT-BRAIN; TPH2 GENE; STEROID REGULATION; INTERMEDIATE LOBE; DORSAL RAPHE; SEROTONIN AB Considerable attention has focused on regulation of central tryptophan hydroxylase (TPH) activity and protein expression. At the time of these earlier studies, it was thought that there was a single central TPH isoform. However, with the recent identification of TPH2, it becomes important to distinguish between regulatory effects on the protein expression and activity of the two isoforms. We have generated a TPH2-specific polyclonal antiserum (TPH2-6361) to study regulation of TPH2 at the protein level and to examine the distribution of TPH2 expression in rodent and human brain. TPH2 immunoreactivity (IR) was detected throughout the raphe nuclei, in lateral hypothalamic nuclei and in the pineal body of rodent and human brain. In addition, a prominent TPH2-IR fiber network was found in the human median eminence. We recently reported that glucocorticoid treatment of C57/BI6 mice for 4 days markedly decreased TPH2 messenger RNA levels in the raphe nuclei, whereas TPH1 mRNA was unaffected. The glucocorticoid-elicited inhibition of TPH2 gene expression was blocked by co-administration of the glucocorticoid receptor antagonist mifepristone (RU-486). Using TPH2-6361, we have extended these findings to show a dose-dependent decrease in raphe TPH2 protein levels in response to 4 days of treatment with dexamethasone; this effect was blocked by co-administration of mifepristone. Moreover, the glucocorticoid-elicited inhibition of TPH2 was functionally significant: serotonin synthesis was significantly reduced in the frontal cortex of glucocorticoid-treated mice, an effect that was blocked by mifepristone co-administration. This study provides further evidence for the glucocorticoid regulation of serotonin biosynthesis via inhibition of TPH2 expression, and suggest that elevated glucocorticoid levels may be relevant to the etiology of psychiatric diseases, such as depression, where hypothalamic-pituitary-adrenal axis dysregulation has been documented. C1 [Clark, J. A.; Flick, R. B.] Merck Res Labs, West Point, PA 19486 USA. [Pai, L-Y] Merck Res Labs, Rahway, NJ USA. [Szalayova, I.; Key, S.; Mezey, E.] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Bethesda, MD USA. RP Clark, JA (reprint author), Merck Res Labs, 770 Sumneytown Pike,Wp26-354, West Point, PA 19486 USA. EM janet_clark@merck.com FU Intramural NIH HHS [ZIA DE000714-07] NR 47 TC 35 Z9 35 U1 1 U2 9 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 MAY PY 2008 VL 13 IS 5 BP 498 EP 506 DI 10.1038/sj.mp.4002041 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 289LY UT WOS:000255057200005 PM 17622221 ER PT J AU Zarate, CA Manji, HK AF Zarate, Carlos A., Jr. Manji, Husseini K. TI Bipolar disorder: Candidate drug targets SO MOUNT SINAI JOURNAL OF MEDICINE LA English DT Review DE antidepressant; bipolar disorder; depression; glutamate; mania; plasticity; treatment ID PROTEIN-KINASE-C; PLACEBO-CONTROLLED TRIAL; MAJOR DEPRESSIVE DISORDER; METABOTROPIC GLUTAMATE RECEPTORS; KAPPA-OPIOID-RECEPTOR; FORCED-SWIM TEST; OPEN-LABEL TRIAL; NICOTINIC ACETYLCHOLINE-RECEPTORS; CELLULAR PLASTICITY CASCADES; GLYCOGEN-SYNTHASE KINASE-3 AB Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even With adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compouunds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin Opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic system), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system; and the hypothalmic-pituitary adrenal axis have all been implicated. Intracelluar pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade. C1 [Zarate, Carlos A., Jr.] NIMH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Res Program, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Lab Mol Pathophysiol & Expt Therapeut, Mood & Anxiety Disorders Res Program, Mark O Hatfield Clin Res Ctr, 10 Ctr Dr,Unit 7 SE,Room 7-3445, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov FU National Institute of Mental Heath; Stanley Medical Research Institute; National Alliance for Research on Schizophrenia And Depression FX The authors acknowledge the support of the Intramural Research Program of the National Institute of Mental Heath, the Stanley Medical Research Institute, and the National Alliance for Research on Schizophrenia And Depression. Carlos A. Zarate Jr and Husseini K. Manji are listed among the inventors On a patent application submitted for the use Of ketamine in depression. They have assigned their rights on the patent to the US government. NR 216 TC 23 Z9 24 U1 5 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0027-2507 EI 1931-7581 J9 MT SINAI J MED JI Mt. Sinai J. Med. PD MAY-JUN PY 2008 VL 75 IS 3 BP 226 EP 247 DI 10.1002/msj.20042 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA 343MT UT WOS:000258858900004 PM 18704977 ER PT J AU Kidd, JM Cooper, GM Donahue, WF Hayden, HS Sampas, N Graves, T Hansen, N Teague, B Alkan, C Antonacci, F Haugen, E Zerr, T Yamada, NA Tsang, P Newman, TL Tuzun, E Cheng, Z Ebling, HM Tusneem, N David, R Gillett, W Phelps, KA Weaver, M Saranga, D Brand, A Tao, W Gustafson, E McKernan, K Chen, L Malig, M Smith, JD Korn, JM McCarroll, SA Altshuler, DA Peiffer, DA Dorschner, M Stamatoyannopoulos, J Schwartz, D Nickerson, DA Mullikin, JC Wilson, RK Bruhn, L Olson, MV Kaul, R Smith, DR Eichler, EE AF Kidd, Jeffrey M. Cooper, Gregory M. Donahue, William F. Hayden, Hillary S. Sampas, Nick Graves, Tina Hansen, Nancy Teague, Brian Alkan, Can Antonacci, Francesca Haugen, Eric Zerr, Troy Yamada, N. Alice Tsang, Peter Newman, Tera L. Tuezuen, Eray Cheng, Ze Ebling, Heather M. Tusneem, Nadeem David, Robert Gillett, Will Phelps, Karen A. Weaver, Molly Saranga, David Brand, Adrianne Tao, Wei Gustafson, Erik McKernan, Kevin Chen, Lin Malig, Maika Smith, Joshua D. Korn, Joshua M. McCarroll, Steven A. Altshuler, David A. Peiffer, Daniel A. Dorschner, Michael Stamatoyannopoulos, John Schwartz, David Nickerson, Deborah A. Mullikin, James C. Wilson, Richard K. Bruhn, Laurakay Olson, Maynard V. Kaul, Rajinder Smith, Douglas R. Eichler, Evan E. TI Mapping and sequencing of structural variation from eight human genomes SO NATURE LA English DT Article ID COPY NUMBER POLYMORPHISM; SEGMENTAL DUPLICATIONS; INVERTED REPEATS; MAP; PREDISPOSES; INVERSION; VARIANTS; REVEALS; GENES AB Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale - particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone- based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high- resolution sequence map of human structural variation - a standard for genotyping platforms and a prelude to future individual genome sequencing projects. C1 [Kidd, Jeffrey M.; Cooper, Gregory M.; Alkan, Can; Antonacci, Francesca; Zerr, Troy; Newman, Tera L.; Tuezuen, Eray; Cheng, Ze; Weaver, Molly; Chen, Lin; Malig, Maika; Smith, Joshua D.; Dorschner, Michael; Stamatoyannopoulos, John; Nickerson, Deborah A.; Eichler, Evan E.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kidd, Jeffrey M.; Cooper, Gregory M.; Alkan, Can; Antonacci, Francesca; Zerr, Troy; Newman, Tera L.; Tuezuen, Eray; Cheng, Ze; Weaver, Molly; Chen, Lin; Malig, Maika; Smith, Joshua D.; Dorschner, Michael; Stamatoyannopoulos, John; Nickerson, Deborah A.; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. [Donahue, William F.; Ebling, Heather M.; Tusneem, Nadeem; David, Robert; Saranga, David; Brand, Adrianne; Tao, Wei; Gustafson, Erik; McKernan, Kevin; Smith, Douglas R.] Agencourt Biosci Corp, Beverly, MA 01915 USA. [Hayden, Hillary S.; Haugen, Eric; Gillett, Will; Phelps, Karen A.; Olson, Maynard V.; Kaul, Rajinder] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA. [Hayden, Hillary S.; Haugen, Eric; Gillett, Will; Phelps, Karen A.; Olson, Maynard V.; Kaul, Rajinder] Univ Washington, Univ Washington Genome Ctr, Seattle, WA 98195 USA. [Sampas, Nick; Yamada, N. Alice; Tsang, Peter; Bruhn, Laurakay] Agilent Technol, Santa Clara, CA 95051 USA. [Graves, Tina; Wilson, Richard K.] Washington Univ, Genome Sequencing Ctr, Sch Med, St Louis, MO 63108 USA. [Hansen, Nancy; Mullikin, James C.] NIH, Human Genome Res Inst, Bethesda, MD 20892 USA. [Teague, Brian; Schwartz, David] Univ Wisconsin, Genet Lab, Madison, WI 53706 USA. [Korn, Joshua M.; McCarroll, Steven A.; Altshuler, David A.] MIT, Broad Inst, Program Med & Populat Genet, Boston, MA 02114 USA. [Korn, Joshua M.; McCarroll, Steven A.; Altshuler, David A.] Harvard Univ, Broad Inst, Boston, MA 02114 USA. [Peiffer, Daniel A.] Illumina Inc, San Diego, CA 92121 USA. RP Eichler, EE (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI McCarroll, Steven/A-8433-2009; Alkan, Can/D-2982-2009; Altshuler, David/A-4476-2009; Cooper, Gregory/D-6914-2011; Antonacci, Francesca/F-5457-2013; OI Alkan, Can/0000-0002-5443-0706; Altshuler, David/0000-0002-7250-4107; Cooper, Gregory/0000-0001-5509-9923; Antonacci, Francesca/0000-0002-5833-6186; McKernan, Kevin/0000-0002-3908-1122; Kidd, Jeffrey/0000-0002-9631-1465; Tuzun, Eray/0000-0002-5550-7816; Haugen, Eric/0000-0001-7444-8981 FU Howard Hughes Medical Institute; NHGRI NIH HHS [P01 HG004120-01, 3 U54 HG002043, HG004120, P01 HG004120, U54 HG002043, U54 HG002043-07S1] NR 42 TC 683 Z9 701 U1 3 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 1 PY 2008 VL 453 IS 7191 BP 56 EP 64 DI 10.1038/nature06862 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 294ID UT WOS:000255398800038 PM 18451855 ER PT J AU Field, D Garrity, G Gray, T Morrison, N Selengut, J Sterk, P Tatusova, T Thomson, N Allen, MJ Angiuoli, SV Ashburner, M Axelrod, N Baldauf, S Ballard, S Boore, J Cochrane, G Cole, J Dawyndt, P De Vos, P dePamphilis, C Edwards, R Faruque, N Feldman, R Gilbert, J Gilna, P Glockner, FO Goldstein, P Guralnick, R Haft, D Hancock, D Hermjakob, H Hertz-Fowler, C Hugenholtz, P Joint, I Kagan, L Kane, M Kennedy, J Kowalchuk, G Kottmann, R Kolker, E Kravitz, S Kyrpides, N Leebens-Mack, J Lewis, SE Li, K Lister, AL Lord, P Maltsev, N Markowitz, V Martiny, J Methe, B Mizrachi, I Moxon, R Nelson, K Parkhill, J Proctor, L White, O Sansone, SA Spiers, A Stevens, R Swift, P Taylor, C Tateno, Y Tett, A Turner, S Ussery, D Vaughan, B Ward, N Whetzel, T Gil, IS Wilson, G Wipat, A AF Field, Dawn Garrity, George Gray, Tanya Morrison, Norman Selengut, Jeremy Sterk, Peter Tatusova, Tatiana Thomson, Nicholas Allen, Michael J. Angiuoli, Samuel V. Ashburner, Michael Axelrod, Nelson Baldauf, Sandra Ballard, Stuart Boore, Jeffrey Cochrane, Guy Cole, James Dawyndt, Peter De Vos, Paul dePamphilis, Claude Edwards, Robert Faruque, Nadeem Feldman, Robert Gilbert, Jack Gilna, Paul Gloeckner, Frank Oliver Goldstein, Philip Guralnick, Robert Haft, Dan Hancock, David Hermjakob, Henning Hertz-Fowler, Christiane Hugenholtz, Phil Joint, Ian Kagan, Leonid Kane, Matthew Kennedy, Jessie Kowalchuk, George Kottmann, Renzo Kolker, Eugene Kravitz, Saul Kyrpides, Nikos Leebens-Mack, Jim Lewis, Suzanna E. Li, Kelvin Lister, Allyson L. Lord, Phillip Maltsev, Natalia Markowitz, Victor Martiny, Jennifer Methe, Barbara Mizrachi, Ilene Moxon, Richard Nelson, Karen Parkhill, Julian Proctor, Lita White, Owen Sansone, Susanna-Assunta Spiers, Andrew Stevens, Robert Swift, Paul Taylor, Chris Tateno, Yoshio Tett, Adrian Turner, Sarah Ussery, David Vaughan, Bob Ward, Naomi Whetzel, Trish Gil, Ingio San Wilson, Gareth Wipat, Anil TI The minimum information about a genome sequence (MIGS) specification SO NATURE BIOTECHNOLOGY LA English DT Article ID REVEALS ADAPTATIONS; ANNOTATION; COLLECTION; SYSTEM AB With the quantity of genomic data increasing at an exponential rate, it is imperative that these data be captured electronically, in a standard format. Standardization activities must proceed within the auspices of open-access and international working bodies. To tackle the issues surrounding the development of better descriptions of genomic investigations, we have formed the Genomic Standards Consortium (GSC). Here, we introduce the minimum information about a genome sequence (MIGS) specification with the intent of promoting participation in its development and discussing the resources that will be required to develop improved mechanisms of metadata capture and exchange. As part of its wider goals, the GSC also supports improving the 'transparency' of the information contained in existing genomic databases. C1 [Field, Dawn; Gray, Tanya; Swift, Paul; Tett, Adrian; Turner, Sarah; Wilson, Gareth] NERC, Ctr Ecol & Hydrol, Oxford OX1 3SR, England. [Garrity, George; Baldauf, Sandra; Cole, James] Michigan State Univ, E Lansing, MI 48824 USA. [Morrison, Norman; Stevens, Robert] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. [Morrison, Norman; Hancock, David] NERC, Environm Bioinformat Ctr, Oxford Ctr Ecol & Hydrol, Oxford OX1 3SR, England. [Selengut, Jeremy; Angiuoli, Samuel V.; Axelrod, Nelson; Haft, Dan; Kagan, Leonid; Kravitz, Saul; Li, Kelvin; Methe, Barbara; Nelson, Karen] J Craig Venter Inst, Rockville, MD 20850 USA. [Sterk, Peter; Cochrane, Guy; Faruque, Nadeem; Hermjakob, Henning; Sansone, Susanna-Assunta; Taylor, Chris; Vaughan, Bob] European Bioinformat Inst, European Mol Biol Lab Outstat, Cambridge CB10 1SD, England. [Tatusova, Tatiana; Mizrachi, Ilene] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Thomson, Nicholas; Hertz-Fowler, Christiane; Parkhill, Julian] Sanger Inst, Cambridge CB10 1SA, England. [Allen, Michael J.; Gilbert, Jack] Plymouth Marine Lab, Plymouth PL1 3DH, Devon, England. [Angiuoli, Samuel V.; White, Owen] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Angiuoli, Samuel V.; White, Owen] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. [Ashburner, Michael] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Baldauf, Sandra] Univ York, Dept Biol, York YO10 5YW, N Yorkshire, England. [Ballard, Stuart] Univ Cambridge, Dept Earth Sci, Natl Inst Environm eSci, Cambridge CB2 3EQ, England. [Boore, Jeffrey] US DOE, Joint Genome Inst, Walnut Creek, CA 94598 USA. [Dawyndt, Peter] Univ Ghent, Dept Appl Math & Comp Sci, B-9000 Ghent, Belgium. [De Vos, Paul] Univ Ghent, Microbiol Lab, B-9000 Ghent, Belgium. [De Vos, Paul] Univ Ghent, BCCM LMG Bacteria Collect, B-9000 Ghent, Belgium. [dePamphilis, Claude] Penn State Univ, Mueller Lab 208, University Pk, PA 16802 USA. [Edwards, Robert] San Diego State Univ, Dept Comp Sci, San Diego, CA 92182 USA. [Edwards, Robert; Maltsev, Natalia] Argonne Natl Lab, Div Math & Comp Sci, Argonne, IL 60439 USA. [Feldman, Robert] SymBio Corp, Menlo Pk, CA 94025 USA. [Gilna, Paul] Univ Calif San Diego, Calif Inst Telecommun & Informat Technol, Calit 2, La Jolla, CA 92093 USA. [Gilna, Paul] Univ Calif Irvine Partnership, La Jolla, CA 92093 USA. [Gloeckner, Frank Oliver; Kottmann, Renzo] Univ Bremen, D-28359 Bremen, Germany. [Gloeckner, Frank Oliver; Kottmann, Renzo] Max Planck Inst Marine Microbiol, Microbial Genom Grp, D-28359 Bremen, Germany. [Goldstein, Philip; Guralnick, Robert] Univ Colorado, Dept Ecol & Evolutionary Biol, Boulder, CO 80309 USA. [Goldstein, Philip; Guralnick, Robert] Univ Colorado, Nat Hist Museum, Boulder, CO 80309 USA. [Hugenholtz, Phil] US DOE, Joint Genome Inst, Microbial Ecol Program, Walnut Creek, CA 94598 USA. [Kane, Matthew; Proctor, Lita] Natl Sci Fdn, Arlington, VA 22230 USA. [Kennedy, Jessie] Napier Univ, Sch Comp, Edinburgh EH10 5DT, Midlothian, Scotland. [Kowalchuk, George] Netherlands Inst Ecol, Dept Terr Microbial Ecol, Ctr Terr Ecol, NL-6666 ZG Heteren, Netherlands. [Kolker, Eugene] BIATECH Inst, Bothell, WA 98011 USA. Univ Washington, Dept Med Educ & Biomed Informat, Div Biomed & Hlth Informat, Seattle, WA 98195 USA. [Kolker, Eugene] Seattle Childrens Hosp Res Inst, Seattle, WA 98101 USA. [Kyrpides, Nikos] US DOE, Genome Biol Program, Joint Genome Inst, Walnut Creek, CA 94598 USA. [Leebens-Mack, Jim] Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. [Lewis, Suzanna E.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Lister, Allyson L.; Lord, Phillip] Newcastle Univ, Sch Comp Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Lister, Allyson L.; Wipat, Anil] Newcastle Univ, Newcastle Gen Hosp, Henry Wellcome Lab Biogerontol Res Div, CISBAN, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. [Markowitz, Victor] Lawrence Berkeley Natl Lab, Computat Res Div, Biol Data Management & Technol Ctr, Berkeley, CA 94720 USA. [Martiny, Jennifer] Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA. [Moxon, Richard] Weatherall Inst Mol Med, Mol Infect Dis Grp, Oxford OX3 9DU, England. [Moxon, Richard] Univ Oxford, John Radcliffe Hosp, Dept Paediat, Oxford OX3 9DU, England. [Nelson, Karen] Howard Univ, Dept Biol, Washington, DC 20059 USA. [Gil, Ingio San] Univ New Mexico, Dept Biol, LTER Network Off, Albuquerque, NM 87171 USA. [Spiers, Andrew] Univ Abertay Dundee, SIMBIOS Ctr, Dundee DD1 1HG, Scotland. [Tateno, Yoshio] Natl Inst Genet, Res Org Informat & Syst, Ctr Informat Biol & DNA Data Bank Japan, Mishima, Shizuoka 4118540, Japan. [Ussery, David] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark. [Ward, Naomi] Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. [Whetzel, Trish] Univ Penn, Sch Med, Ctr Bioinformat, Philadelphia, PA 19104 USA. [Whetzel, Trish] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. RP Field, D (reprint author), NERC, Ctr Ecol & Hydrol, Oxford OX1 3SR, England. EM dfield@ceh.ac.uk RI Gilna, Paul/I-3608-2016; dePamphilis, Claude/P-6652-2016; Kyrpides, Nikos/A-6305-2014; Guralnick, Rob/E-7767-2010; Spiers, Andrew/I-3535-2012; Field, Dawn/C-1653-2010; Angiuoli, Samuel/H-7340-2014; Allen, Michael (Mike)/C-1248-2011; Kowalchuk, George/C-4298-2011; Parkhill, Julian/G-4703-2011; Hugenholtz, Philip/G-9608-2011; Turner, Sarah/K-4683-2012; Dawyndt, Peter/A-1566-2013; Kolker, Eugene/C-6711-2008; Garrity, George/F-7551-2013; De Vos, Paul/J-5392-2013 OI Lewis, Suzanna/0000-0002-8343-612X; Sterk, Peter/0000-0003-1668-7778; Hermjakob, Henning/0000-0001-8479-0262; Baldauf, Sandra/0000-0003-4485-6671; Dawyndt, Peter/0000-0002-1623-9070; Gilna, Paul/0000-0002-6542-0191; Kyrpides, Nikos/0000-0002-6131-0462; Gray, Tanya/0000-0003-1561-7364; Lister, Allyson/0000-0002-7702-4495; Angiuoli, Samuel/0000-0001-9525-4350; Cochrane, Guy/0000-0001-7954-7057; Sansone, Susanna-Assunta/0000-0001-5306-5690; hugenholtz, philip/0000-0001-5386-7925; Taylor, Christopher/0000-0002-9666-798X; Spiers, Andrew/0000-0003-0463-8629; Allen, Michael (Mike)/0000-0001-8504-7171; Parkhill, Julian/0000-0002-7069-5958; Turner, Sarah/0000-0002-8937-6922; Garrity, George/0000-0002-4465-7034; FU Biotechnology and Biological Sciences Research Council [BB/E025080/1]; Intramural NIH HHS [Z99 LM999999]; Medical Research Council [G8225539]; NHGRI NIH HHS [U54 HG004028] NR 32 TC 721 Z9 723 U1 5 U2 47 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 MAY PY 2008 VL 26 IS 5 BP 541 EP 547 DI 10.1038/nbt1360 PG 7 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 299LJ UT WOS:000255756800026 PM 18464787 ER PT J AU Twigger, SN Pruitt, KD Fernandez-Suarez, XM Karolchik, D Worley, KC Maglott, DR Brown, G Weinstock, G Gibbs, RA Kent, J Birney, E Jacob, HJ AF Twigger, Simon N. Pruitt, Kim D. Fernandez-Suarez, Xose M. Karolchik, Donna Worley, Kim C. Maglott, Donna R. Brown, Garth Weinstock, George Gibbs, Richards A. Kent, Jim Birney, Ewan Jacob, Howard J. TI What everybody should know about the rat genome and its online resources SO NATURE GENETICS LA English DT Editorial Material ID DATABASE; GENE; ENSEMBL; MOUSE; INFORMATION; SEQUENCES; ONTOLOGY; BROWSER; BIOLOGY; UPDATE AB It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database. C1 [Twigger, Simon N.; Jacob, Howard J.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Pruitt, Kim D.; Karolchik, Donna] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Fernandez-Suarez, Xose M.; Birney, Ewan] European Bioinformat Inst, Cambridge CB10 1SD, England. [Maglott, Donna R.; Kent, Jim] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. [Worley, Kim C.; Weinstock, George; Gibbs, Richards A.] Baylor Coll Med, Houston, TX 77030 USA. RP Twigger, SN (reprint author), Med Coll Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM simont@hmgc.mcw.edu FU Howard Hughes Medical Institute; Intramural NIH HHS [Z99 LM999999]; NHGRI NIH HHS [U54 HG003273, HG-003273, R01 HG002273, U41 HG002273, P41 HG002273, HG-002273]; NHLBI NIH HHS [R01 HL064541, HL-64541] NR 24 TC 31 Z9 32 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2008 VL 40 IS 5 BP 523 EP 527 DI 10.1038/ng0508-523 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 293WS UT WOS:000255366700017 PM 18443589 ER PT J AU Lettre, G Jackson, AU Gieger, C Schumacher, FR Berndt, SI Sanna, S Eyheramendy, S Voight, BF Butler, JL Guiducci, C Illig, T Hackett, R Heid, IM Jacobs, KB Lyssenko, V Uda, M Boehnke, M Chanock, SJ Groop, LC Hu, FB Isomaa, B Kraft, P Peltonen, L Salomaa, V Schlessinger, D Hunter, DJ Hayes, RB Abecasis, GR Wichmann, HE Mohlke, KL Hirschhorn, JN AF Lettre, Guillaume Jackson, Anne U. Gieger, Christian Schumacher, Fredrick R. Berndt, Sonja I. Sanna, Serena Eyheramendy, Susana Voight, Benjamin F. Butler, Johannah L. Guiducci, Candace Illig, Thomas Hackett, Rachel Heid, Iris M. Jacobs, Kevin B. Lyssenko, Valeriya Uda, Manuela Boehnke, Michael Chanock, Stephen J. Groop, Leif C. Hu, Frank B. Isomaa, Bo Kraft, Peter Peltonen, Leena Salomaa, Veikko Schlessinger, David Hunter, David J. Hayes, Richard B. Abecasis, Goncalo R. Wichmann, H-Erich Mohlke, Karen L. Hirschhorn, Joel N. CA Diabet Genetics Initiative FUSION KORA Prostate Lung Colorectal Ovarian C Nurses' Hlth Study SardiNIA TI Identification of ten loci associated with height highlights new biological pathways in human growth SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; PROTEIN-KINASE-II; GENETIC ASSOCIATION; COMMON VARIANTS; FTO GENE; RISK; PROLIFERATION; POPULATION; LINKAGE; CANCER AB Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet- undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in 410,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for similar to 2% of the population variation in height. Individuals with <= 8 height-increasing alleles and >= 16 height-increasing alleles differ in height by similar to 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait. C1 [Lettre, Guillaume; Voight, Benjamin F.; Guiducci, Candace; Hackett, Rachel; Peltonen, Leena; Hunter, David J.; Hirschhorn, Joel N.] MIT, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02142 USA. [Lettre, Guillaume; Butler, Johannah L.; Hirschhorn, Joel N.] Childrens Hosp, Div Genet & Endocrinol, Boston, MA 02115 USA. [Lettre, Guillaume; Butler, Johannah L.; Hirschhorn, Joel N.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Jackson, Anne U.; Sanna, Serena; Boehnke, Michael; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Gieger, Christian; Eyheramendy, Susana; Illig, Thomas; Heid, Iris M.; Wichmann, H-Erich] GSF Natl Res Ctr Environm & Hlth, Inst Epidemiol, D-85764 Neuherberg, Germany. [Gieger, Christian; Eyheramendy, Susana; Heid, Iris M.; Wichmann, H-Erich] Univ Munich, Dept Epidemiol, Inst Med Informat Biometry & Epidemiol, D-81377 Munich, Germany. [Schumacher, Fredrick R.; Hu, Frank B.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Schumacher, Fredrick R.; Hu, Frank B.; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02115 USA. [Berndt, Sonja I.; Hayes, Richard B.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Sanna, Serena; Uda, Manuela] Cittadella Univ Monserrato, INN, Consiglio Nazl Ric, I-09042 Cagliari, Italy. [Voight, Benjamin F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD 20877 USA. [Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci Diabetes & Endocrinol, Malmo Univ Hosp, S-20502 Malmo, Sweden. [Chanock, Stephen J.] NCI, NIH, DHHS, Lab Translat Genom,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Groop, Leif C.] Univ Helsinki, Dept Med, Helsinki Univ Cent Hosp, Helsinki, Finland. [Groop, Leif C.] Univ Helsinki, Res Program Mol Med, Helsinki, Finland. [Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Isomaa, Bo] Malmska Municipal Hlth Ctr & Hosp, Pietarsaari, Finland. [Isomaa, Bo] Folkhalsan Res Ctr, Helsinki, Finland. [Peltonen, Leena] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Peltonen, Leena] Univ Helsinki, Dept Mol Med, Natl Publ Hlth Inst, FI-00014 Helsinki, Finland. [Peltonen, Leena] Univ Helsinki, Dept Mol Med, Dept Med Genet, FI-00014 Helsinki, Finland. [Salomaa, Veikko] Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, FI-00300 Helsinki, Finland. [Schlessinger, David] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Hirschhorn, Joel N.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hirschhorn, JN (reprint author), MIT, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02142 USA. EM joelh@broad.mit.edu RI Genetic Epidemiology, Innsbruck Med.Univ./C-2095-2008; Abecasis, Goncalo/B-7840-2010; Voight, Benjamin/F-1775-2011; OI sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Gieger, Christian/0000-0001-6986-9554; Hayes, Richard/0000-0002-0918-661X FU Intramural NIH HHS; NCI NIH HHS [5P01CA087969, 5U01CA098233, CA49449, P01 CA087969, R01 CA049449, U01 CA049449, U01 CA098233]; NHGRI NIH HHS [HG02651, R01 HG002651]; NHLBI NIH HHS [HL084729, U01 HL084729]; NIDDK NIH HHS [5 R01 DK 075787, DK62370, DK72193, R01 DK062370, R01 DK072193, R01 DK075787, R56 DK062370, U01 DK062370]; Wellcome Trust [089061] NR 40 TC 364 Z9 373 U1 3 U2 27 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 MAY PY 2008 VL 40 IS 5 BP 584 EP 591 DI 10.1038/ng.125 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 293WS UT WOS:000255366700026 PM 18391950 ER PT J AU Ji, WZ Foo, JN O'Roak, BJ Zhao, H Larson, MG Simon, DB Newton-Cheh, C State, MW Levy, D Lifton, RP AF Ji, Weizhen Foo, Jia Nee O'Roak, Brian J. Zhao, Hongyu Larson, Martin G. Simon, David B. Newton-Cheh, Christopher State, Matthew W. Levy, Daniel Lifton, Richard P. TI Rare independent mutations in renal salt handling genes contribute to blood pressure variation SO NATURE GENETICS LA English DT Article ID NA-CL COTRANSPORTER; GENOME-WIDE ASSOCIATION; CORONARY HEART-DISEASE; BARTTERS-SYNDROME; HYPOKALEMIC ALKALOSIS; GITELMAN-SYNDROME; FRAMINGHAM; CHANNEL; RISK; HYPERCALCIURIA AB The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)- causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits. C1 [Ji, Weizhen; Foo, Jia Nee; O'Roak, Brian J.; Zhao, Hongyu; Simon, David B.; State, Matthew W.; Lifton, Richard P.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. [Ji, Weizhen; Foo, Jia Nee; Simon, David B.; Lifton, Richard P.] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06510 USA. [Zhao, Hongyu] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Larson, Martin G.; Newton-Cheh, Christopher; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [State, Matthew W.] Yale Univ, Ctr Child Study, Sch Med, New Haven, CT 06520 USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. RP Lifton, RP (reprint author), Yale Univ, Sch Med, Dept Genet, 333 Cedar St, New Haven, CT 06510 USA. EM richard.lifton@yale.edu RI Foo, Jia Nee/D-6069-2014; OI Foo, Jia Nee/0000-0001-9899-2308; Larson, Martin/0000-0002-9631-1254; O'Roak, Brian/0000-0002-4141-0095 FU Howard Hughes Medical Institute; NHLBI NIH HHS [N01-HC-25195, N01HC25195, P50 HL055007] NR 46 TC 449 Z9 465 U1 1 U2 17 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 MAY PY 2008 VL 40 IS 5 BP 592 EP 599 DI 10.1038/ng.118 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 293WS UT WOS:000255366700027 PM 18391953 ER PT J AU Zeggini, E Scott, LJ Saxena, R Voight, BF Marchini, JL Hu, T de Bakker, PIW Abecasis, GR Almgren, P Andersen, G Ardlie, K Bostroem, KB Bergman, RN Bonnycastle, LL Borch-Johnsen, K Burtt, NP Chen, H Chines, PS Daly, MJ Deodhar, P Ding, CJ Doney, ASF Duren, WL Elliott, KS Erdos, MR Frayling, TM Freathy, RM Gianniny, L Grallert, H Grarup, N Groves, CJ Guiducci, C Hansen, T Herder, C Hitman, GA Hughes, TE Isomaa, B Jackson, AU Jorgensen, T Kong, A Kubalanza, K Kuruvilla, FG Kuusisto, J Langenberg, C Lango, H Lauritzen, T Li, Y Lindgren, CM Lyssenko, V Marvelle, AF Meisinger, C Midthjell, K Mohlke, KL Morken, MA Morris, AD Narisu, N Nilsson, P Owen, KR Palmer, CNA Payne, F Perry, JRB Pettersen, E Platou, C Prokopenko, I Qi, L Qin, L Rayner, NW Rees, M Roix, JJ Sandbaek, A Shields, B Sjogren, M Steinthorsdottir, V Stringham, HM Swift, AJ Thorleifsson, G Thorsteinsdottir, U Timpson, NJ Tuomi, T Tuomilehto, J Walker, M Watanabe, RM Weedon, MN Willer, CJ Illig, T Hveem, K Hu, FB Laakso, M Stefansson, K Pedersen, O Wareham, NJ Barroso, I Hattersley, AT Collins, FS Groop, L McCarthy, MI Boehnke, M Altshuler, D AF Zeggini, Eleftheria Scott, Laura J. Saxena, Richa Voight, Benjamin F. Marchini, Jonathan L. Hu, Tianle de Bakker, Paul I. W. Abecasis, Goncalo R. Almgren, Peter Andersen, Gitte Ardlie, Kristin Bostroem, Kristina Bengtsson Bergman, Richard N. Bonnycastle, Lori L. Borch-Johnsen, Knut Burtt, Noel P. Chen, Hong Chines, Peter S. Daly, Mark J. Deodhar, Parimal Ding, Chia-Jen Doney, Alex S. F. Duren, William L. Elliott, Katherine S. Erdos, Michael R. Frayling, Timothy M. Freathy, Rachel M. Gianniny, Lauren Grallert, Harald Grarup, Niels Groves, Christopher J. Guiducci, Candace Hansen, Torben Herder, Christian Hitman, Graham A. Hughes, Thomas E. Isomaa, Bo Jackson, Anne U. Jorgensen, Torben Kong, Augustine Kubalanza, Kari Kuruvilla, Finny G. Kuusisto, Johanna Langenberg, Claudia Lango, Hana Lauritzen, Torsten Li, Yun Lindgren, Cecilia M. Lyssenko, Valeriya Marvelle, Amanda F. Meisinger, Christa Midthjell, Kristian Mohlke, Karen L. Morken, Mario A. Morris, Andrew D. Narisu, Narisu Nilsson, Peter Owen, Katharine R. Palmer, Colin N. A. Payne, Felicity Perry, John R. B. Pettersen, Elin Platou, Carl Prokopenko, Inga Qi, Lu Qin, Li Rayner, Nigel W. Rees, Matthew Roix, Jeffrey J. Sandbaek, Anelli Shields, Beverley Sjogren, Marketa Steinthorsdottir, Valgerdur Stringham, Heather M. Swift, Amy J. Thorleifsson, Gudmar Thorsteinsdottir, Unnur Timpson, Nicholas J. Tuomi, Tiinamaija Tuomilehto, Jaakko Walker, Mark Watanabe, Richard M. Weedon, Michael N. Willer, Cristen J. Illig, Thomas Hveem, Kristian Hu, Frank B. Laakso, Markku Stefansson, Kari Pedersen, Oluf Wareham, Nicholas J. Barroso, Ines Hattersley, Andrew T. Collins, Francis S. Groop, Leif McCarthy, Mark I. Boehnke, Michael Altshuler, David CA DIAGRAM Consortium Wellcome Trust Case Control Consor TI Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes SO NATURE GENETICS LA English DT Article ID PROSTATE-CANCER; RISK LOCI; VARIANTS; GENES AB Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D. C1 [Marchini, Jonathan L.; Elliott, Katherine S.; Lindgren, Cecilia M.; Prokopenko, Inga; Rayner, Nigel W.; Roix, Jeffrey J.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Scott, Laura J.; Hu, Tianle; Andersen, Gitte; Bostroem, Kristina Bengtsson; Ding, Chia-Jen; Duren, William L.; Erdos, Michael R.; Freathy, Rachel M.; Jackson, Anne U.; Li, Yun; Meisinger, Christa; Stringham, Heather M.; Watanabe, Richard M.; Willer, Cristen J.; Barroso, Ines] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scott, Laura J.; Andersen, Gitte; Bostroem, Kristina Bengtsson; Duren, William L.; Erdos, Michael R.; Jackson, Anne U.; Li, Yun; Meisinger, Christa; Stringham, Heather M.; Watanabe, Richard M.; Willer, Cristen J.; Barroso, Ines] Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Saxena, Richa; Voight, Benjamin F.; Ardlie, Kristin; Borch-Johnsen, Knut; Burtt, Noel P.; Deodhar, Parimal; Duren, William L.; Gianniny, Lauren; Guiducci, Candace; Hughes, Thomas E.; Kuruvilla, Finny G.; Lauritzen, Torsten] Broad Inst Harvard, Cambridge, MA 02142 USA. [Saxena, Richa; Voight, Benjamin F.; de Bakker, Paul I. W.; Ardlie, Kristin; Kuruvilla, Finny G.; Altshuler, David] MIT, Cambridge, MA 02142 USA. [Saxena, Richa; Voight, Benjamin F.; Daly, Mark J.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, Richa; Voight, Benjamin F.; Abecasis, Goncalo R.; Daly, Mark J.; Altshuler, David] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Saxena, Richa; Kuruvilla, Finny G.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Saxena, Richa; Voight, Benjamin F.; de Bakker, Paul I. W.; Daly, Mark J.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Saxena, Richa; Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Marchini, Jonathan L.] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [de Bakker, Paul I. W.] Brigham & Womens Hosp, Harvard Partners Ctr Genet & Genom, Boston, MA 02115 USA. [Chines, Peter S.; Lyssenko, Valeriya; Nilsson, Peter; Sjogren, Marketa; Groop, Leif] Lund Univ, Dept Clin Sci, Diabet & Endocrinol Res Unit, Malmo Univ Hosp, S-20502 Malmo, Sweden. [Andersen, Gitte; Borch-Johnsen, Knut; Grarup, Niels; Hansen, Torben; Pedersen, Oluf] Steno Diabet Ctr, DK-2820 Copenhagen, Denmark. [Bostroem, Kristina Bengtsson] Skaraborg Inst, S-54130 Skovde, Sweden. [Bergman, Richard N.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Bonnycastle, Lori L.; Chines, Peter S.; Deodhar, Parimal; Erdos, Michael R.; Kubalanza, Kari; Morken, Mario A.; Narisu, Narisu; Rees, Matthew; Swift, Amy J.; Collins, Francis S.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Borch-Johnsen, Knut; Sandbaek, Anelli; Pedersen, Oluf] Univ Aarhus, Fac Hlth Sci, DK-8000 Aarhus, Denmark. [Chen, Hong; Hughes, Thomas E.; Roix, Jeffrey J.] Novartis Inst Biomed Res, Diabet & Metab Dis Area, Cambridge, MA 02139 USA. [Doney, Alex S. F.] Ninewells Hosp & Med Sch, Diabet Res Grp, Div Med & Therapeut, Dundee DD1 9SY, Scotland. [Frayling, Timothy M.; Freathy, Rachel M.; Lango, Hana; Perry, John R. B.; Weedon, Michael N.; Hattersley, Andrew T.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX1 2LU, Devon, England. [Frayling, Timothy M.; Freathy, Rachel M.; Lango, Hana; Perry, John R. B.; Shields, Beverley; Weedon, Michael N.; Hattersley, Andrew T.] Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter EX2 5DW, Devon, England. [Grallert, Harald; Meisinger, Christa; Illig, Thomas] Gesell Strahlenforsch Natl Res Ctr Environm & Hlt, Inst Epidemiol, D-85764 Neuherberg, Germany. [Groves, Christopher J.; Lindgren, Cecilia M.; Owen, Katharine R.; Prokopenko, Inga; Rayner, Nigel W.] Univ Oxford, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LJ, England. [Herder, Christian] Univ Dusseldorf, Inst Clin Diabet Res, German Diabetes Ctr, Leiden Inst, D-40225 Dusseldorf, Germany. [Hitman, Graham A.] Royal London Hosp, Ctr Diabet & Metab Med, London E1 1BB, England. [Isomaa, Bo] Malmska Municipal Hlth Ctr & Hosp, FIN-68601 Pietarsaari, Finland. [Isomaa, Bo] Folkhalsan Res Ctr, FIN-00014 Helsinki, Finland. [Jorgensen, Torben] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, DK-2600 Glostrup, Denmark. [Kong, Augustine; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Stefansson, Kari] deCODE Genet, IS-101 Reykjavik, Iceland. [Kuusisto, Johanna; Laakso, Markku] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. [Kuusisto, Johanna] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [Langenberg, Claudia; Wareham, Nicholas J.] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge CB2 0QQ, England. [Lauritzen, Torsten] Univ Aarhus, Dept Gen Practice, DK-8000 Aarhus, Denmark. [Marvelle, Amanda F.; Mohlke, Karen L.; Qin, Li] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. [Midthjell, Kristian; Platou, Carl; Hveem, Kristian] Norwegian Univ Sci & Technol, HUNT Res Ctr, Dept Publ Hlth & Gen Practice, Fac Med, N-7650 Verdal, Norway. [Palmer, Colin N. A.] Ninewells Hosp & Med Sch, Populat Pharmacogenet Grp, Biomed Res Ctr, Dundee DD1 9SY, Scotland. [Payne, Felicity; Barroso, Ines] Wellcome Trust Sanger Inst, Metab Dis Grp, Cambridge CB10 1SA, England. [Qi, Lu; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Qi, Lu] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Qi, Lu; Hu, Frank B.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Timpson, Nicholas J.] Univ Bristol, MRC Ctr Causal Analyses Translat Epidemiol, Bristol BS2 8PR, Avon, England. [Tuomi, Tiinamaija; Groop, Leif] Univ Helsinki, Helsinki Univ Hosp, Dept Med, FIN-00300 Helsinki, Finland. [Tuomilehto, Jaakko; Altshuler, David] Natl Publ Hlth Inst, Diabet Unit, Dept Epidemiol & Hlth Promot, SF-00300 Helsinki, Finland. [Tuomilehto, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. [Tuomilehto, Jaakko] S Ostrobothnia Cent Hosp, Seinajoki 60220, Finland. [Walker, Mark] Univ Newcastle Upon Tyne, Diabet Res Grp, Sch Clin Med Sci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Watanabe, Richard M.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. [Pettersen, Elin] Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, N-7600 Levanger, Norway. RP McCarthy, MI (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. EM mark.mccarthy@drl.ox.ac.uk; boehnke@umich.edu; altshuler@molbio.mgh.harvard.edu RI Palmer, Colin/C-7053-2008; Grallert, Harald/B-3424-2013; Morris, Andrew/C-2837-2009; Prokopenko, Inga/H-3241-2014; Grarup, Niels/K-2807-2015; Study, GoDARTS/K-9448-2016; Abecasis, Goncalo/B-7840-2010; Altshuler, David/A-4476-2009; Voight, Benjamin/F-1775-2011; Lango Allen, Hana/G-9026-2012; Hu, Tianle/H-9105-2012; de Bakker, Paul/B-8730-2009; Meisinger, Christine/B-5358-2014; Fox, Laura /C-6249-2016; OI Palmer, Colin/0000-0002-6415-6560; Prokopenko, Inga/0000-0003-1624-7457; Grarup, Niels/0000-0001-5526-1070; Altshuler, David/0000-0002-7250-4107; Lango Allen, Hana/0000-0002-7803-8688; de Bakker, Paul/0000-0001-7735-7858; Freathy, Rachel/0000-0003-4152-2238; Zeggini, Eleftheria/0000-0003-4238-659X; Tuomi, Tiinamaija/0000-0002-8306-6202; Jorgensen, Torben/0000-0001-9453-2830; Timpson, Nicholas/0000-0002-7141-9189; Payne, Felicity/0000-0003-4228-581X FU Department of Health [DHCS/07/07/008]; Intramural NIH HHS; Medical Research Council [G0000649, G0600705, G0601261, MC_U106179471]; NCI NIH HHS [P01 CA087969, CA87969]; NHGRI NIH HHS [HG002651, N01HG65403, R01 HG002651, U01 HG004171, U01 HG004399, Z01 HG000024]; NHLBI NIH HHS [HL084729, U01 HL084729]; NIDA NIH HHS [U54 DA021519]; NIDDK NIH HHS [DK062370, DK072193, DK58845, P30 DK040561, P30 DK040561-12, R01 DK029867, R01 DK058845, R01 DK062370, R01 DK072193, R56 DK062370, U01 DK062370]; Wellcome Trust [072960, 076113, 077016, 079557, 090532, GR072960] NR 27 TC 1141 Z9 1179 U1 7 U2 105 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAY PY 2008 VL 40 IS 5 BP 638 EP 645 DI 10.1038/ng.120 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 293WS UT WOS:000255366700033 PM 18372903 ER PT J AU Martin, R O'Shea, J Birnbaum, LS Luebke, R AF Martin, Roland O'Shea, John Birnbaum, Linda S. Luebke, Robert TI Striking the balance in multiple sclerosis SO NATURE MEDICINE LA English DT Editorial Material C1 [Martin, Roland] Univ Hamburg, Med Ctr, Inst Neuroimmunol & Clin Multiple Sclerosis Res, Eppendorf, Germany. [O'Shea, John] Natl Inst Arthritis & Musculoskeletal & Skin Dis, Bethesda, MD USA. [Birnbaum, Linda S.] US EPA, Expt Toxicol Div, Res Triangle Pk, NC 27711 USA. RP Martin, R (reprint author), Univ Hamburg, Med Ctr, Inst Neuroimmunol & Clin Multiple Sclerosis Res, Eppendorf, Germany. NR 0 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 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2008 VL 14 IS 5 BP 491 EP 491 DI 10.1038/nm0508-491 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 298IQ UT WOS:000255681800016 PM 18463656 ER PT J AU Mendez, I Vinuela, A Astradsson, A Mukhida, K Hallett, P Robertson, H Tierney, T Holness, R Dagher, A Trojanowski, JQ Isacson, O AF Mendez, Ivar Vinuela, Angel Astradsson, Arnar Mukhida, Karim Hallett, Penelope Robertson, Harold Tierney, Travis Holness, Renn Dagher, Alain Trojanowski, John Q. Isacson, Ole TI Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years SO NATURE MEDICINE LA English DT Article ID ALPHA-SYNUCLEIN; SUBSTANTIA-NIGRA; LEWY BODIES; STEM-CELLS; TRANSPLANTATION AB Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis of midbrain dopamine neuron degeneration and future use of cell replacement therapies. C1 [Vinuela, Angel; Astradsson, Arnar; Hallett, Penelope; Tierney, Travis; Isacson, Ole] Harvard Univ, Belmont, MA 02478 USA. [Vinuela, Angel; Astradsson, Arnar; Hallett, Penelope; Tierney, Travis; Isacson, Ole] McLean Hosp, US Natl Inst Neurol Disorders & Stroke, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. [Mendez, Ivar; Mukhida, Karim; Robertson, Harold; Holness, Renn] Dalhousie Univ, Halifax, NS B3H 3A7, Canada. [Mendez, Ivar; Mukhida, Karim; Robertson, Harold; Holness, Renn] Queen Elizabeth 2 Hlth Sci Ctr, Div Neurosurg, Halifax, NS B3H 3A7, Canada. [Mendez, Ivar; Mukhida, Karim; Robertson, Harold; Holness, Renn] Queen Elizabeth 2 Hlth Sci Ctr, Dept Anat & Neurobiol, Halifax, NS B3H 3A7, Canada. [Mendez, Ivar; Mukhida, Karim; Robertson, Harold; Holness, Renn] Queen Elizabeth 2 Hlth Sci Ctr, Dept Pharmacol, Halifax, NS B3H 3A7, Canada. [Tierney, Travis] Massachusetts Gen Hosp, Neurosci Serv, Boston, MA 02114 USA. [Dagher, Alain] McGill Univ, Montreal, PQ H3A 2B4, Canada. [Dagher, Alain] Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ H3A 2B4, Canada. [Trojanowski, John Q.] Univ Penn, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med, Inst Aging,NINDS Udall Parkinsons Dis Res Ctr Exc, Philadelphia, PA 19104 USA. RP Isacson, O (reprint author), Harvard Univ, 115 Mill St, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu OI Hallett, Penelope/0000-0002-8858-9096 FU NINDS NIH HHS [NS 053488, P50 NS 39793, P50 NS039793, P50 NS039793-08, P50 NS053488] NR 15 TC 230 Z9 239 U1 1 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2008 VL 14 IS 5 BP 507 EP 509 DI 10.1038/nm1752 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 298IQ UT WOS:000255681800030 PM 18391961 ER PT J AU Perruche, S Zhang, P Liu, YZ Saas, P Bluestone, JA Chen, WJ AF Perruche, Sylvain Zhang, Pin Liu, Yongzhong Saas, Philippe Bluestone, Jeffrey A. Chen, WanJun TI CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells SO NATURE MEDICINE LA English DT Article ID ANTI-CD3 MONOCLONAL-ANTIBODY; TGF-BETA; DENDRITIC CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; FOXP3 EXPRESSION; SELF-TOLERANCE; ACTIVATION; RECEPTOR; MICE; SUPPRESSION AB Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-beta ( TGF-beta) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-beta upon ingestion of apoptotic T cells, which induces CD4(+)Foxp3(+) regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody-mediated prevention of myelin oligodendrocyte glycoprotein-induced acute experimental autoimmune encephalomyelitis ( EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody-induced immune tolerance is associated with TGF-beta production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance. C1 [Perruche, Sylvain; Zhang, Pin; Liu, Yongzhong; Chen, WanJun] NIDCR, Mucosal Immunol Unit, Oral Infect & Immun Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Saas, Philippe] Univ Franche Comte, Inst Nacl Sante & Rech Med, UMR645, IFR133,Etablissement Francais Sang Bourgogne Fran, F-25020 Besancon, France. [Bluestone, Jeffrey A.] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. RP Chen, WJ (reprint author), NIDCR, Mucosal Immunol Unit, Oral Infect & Immun Branch, US Natl Inst Hlth, 30 Convent Dr, Bethesda, MD 20892 USA. EM wchen@mail.nih.gov RI SAAS, Philippe/M-3550-2015; OI SAAS, Philippe/0000-0002-8857-9939 FU NIAID NIH HHS [R37AI46643] NR 46 TC 124 Z9 128 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAY PY 2008 VL 14 IS 5 BP 528 EP 535 DI 10.1038/nm1749 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 298IQ UT WOS:000255681800033 PM 18438416 ER PT J AU Shroff, H Galbraith, CG Galbraith, JA Betzig, E AF Shroff, Hari Galbraith, Catherine G. Galbraith, James A. Betzig, Eric TI Live-cell photoactivated localization microscopy of nanoscale adhesion dynamics SO NATURE METHODS LA English DT Article ID PROTEIN AB We demonstrate live-cell super-resolution imaging using photoactivated localization microscopy (PALM). The use of photon-tolerant cell lines in combination with the high resolution and molecular sensitivity of PALM permitted us to investigate the nanoscale dynamics within individual adhesion complexes (ACs) in living cells under physiological conditions for as long as 25 min, with half of the time spent collecting the PALM images at spatial resolutions down to similar to 60 nm and frame rates as short as 25 s. We visualized the formation of ACs and measured the fractional gain and loss of individual paxillin molecules as each AC evolved. By allowing observation of a wide variety of nanoscale dynamics, live-cell PALM provides insights into molecular assembly during the initiation, maturation and dissolution of cellular processes. C1 [Shroff, Hari; Betzig, Eric] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Galbraith, Catherine G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Galbraith, James A.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Shroff, H (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus,19700 Helix Dr, Ashburn, VA 20147 USA. EM shroffh@janelia.hhmi.org RI Shroff, Hari/E-7247-2016 OI Shroff, Hari/0000-0003-3613-8215 FU Intramural NIH HHS [, ZIA EB000074-07] NR 15 TC 436 Z9 445 U1 17 U2 174 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 MAY PY 2008 VL 5 IS 5 BP 417 EP 423 DI 10.1038/NMETH.1202 PG 7 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 294NB UT WOS:000255411700018 PM 18408726 ER PT J AU Sanacora, G Zarate, CA Krystal, JH Manji, HK AF Sanacora, Gerard Zarate, Carlos A. Krystal, John H. Manji, Husseini K. TI Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID METHYL-D-ASPARTATE; MAJOR DEPRESSIVE DISORDER; EXCITATORY AMINO-ACIDS; OBSESSIVE-COMPULSIVE DISORDER; ANTERIOR CINGULATE CORTEX; NMDA RECEPTOR COMPLEX; AGONIST D-CYCLOSERINE; BIPOLAR-I DISORDER; OPEN-LABEL TRIAL; STAR-ASTERISK-D AB Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. To date, the monoaminergic systems (serotonergic, noradrenergic and dopaminergic) in the brain have received the greatest attention in neurobiological studies of mood disorders, and most therapeutics target these systems. However, there is growing evidence that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in mood-disorder pathophysiology as well as the efficacy of glutamatergic agents in mood disorders. We also discuss exciting new prospects for the development of improved therapeutics for these devastating disorders. C1 [Zarate, Carlos A.; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. [Sanacora, Gerard; Krystal, John H.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov FU Intramural NIH HHS [Z01 MH002828-05, Z01 MH002857-03]; NIMH NIH HHS [K02 MH076222, K02MH076222] NR 181 TC 405 Z9 418 U1 5 U2 35 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAY PY 2008 VL 7 IS 5 BP 426 EP 437 DI 10.1038/nrd2462 PG 12 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 294QF UT WOS:000255419900016 PM 18425072 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI How to succeed in science: a concise guide for young biomedical scientists. Part I: taking the plunge SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review AB Biomedical research has never been more intellectually exciting or practically important to society. Ironically, pursuing a career as a biomedical scientist has never been more difficult. Here I provide unvarnished advice for young biomedical scientists on the difficulties that lie ahead and on how to find the right laboratories for training in the skills that you will need to succeed. Although my advice is geared towards succeeding in the United States, many aspects apply to other countries. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM JYEWDELL@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS [Z01 AI001055-01] NR 3 TC 5 Z9 5 U1 1 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD MAY PY 2008 VL 9 IS 5 BP 413 EP 416 DI 10.1038/nrm2389 PG 4 WC Cell Biology SC Cell Biology GA 292KQ UT WOS:000255265300016 PM 18401348 ER PT J AU Deshpande, N Metter, EJ Ling, S Conwit, R Ferrucci, L AF Deshpande, Nandini Metter, E. Jeffery Ling, Shari Conwit, Robin Ferrucci, Luigi TI Physiological correlates of age-related decline in vibrotactile sensitivity SO NEUROBIOLOGY OF AGING LA English DT Article DE vibrotactile sensitivity; vibration perception threshold; aging; peripheral nerve function ID INFORMATION-PROCESSING CHANNELS; DIABETES-MELLITUS; THRESHOLDS; INFLAMMATION; TOUCH; DYSFUNCTION; NEUROPATHY; RECEPTORS; VIBRATION; HEIGHT AB The purpose of this study was to describe age-related changes in vibrotactile sensitivity in participants of the Baltimore Longitudinal Study of Aging and to identify factors that are associated with impairment in vibrotactile sensitivity independent of age. Participants (n = 523, age: 26-95 years) underwent measurements of vibration perception threshold (VPT, 100 Hz) under the 2nd metatarsal head, glucose tolerance, serum inflammatory markers, nerve conduction parameters, movement time and cognition. Univariate and multivahate regression analyses were performed to identify factors that predicted VPT independent of age. Structural equation modeling was used to describe relationships between these variables. VPT was progressively higher with older age. Adjusting for age and height, VPT was similar in men and women and the slope of age-related decline was similar in the two genders. Age, height, peroneal nerve conduction velocity and peroneal nerve amplitude were independent predictors of VPT. Structural equation model demonstrated a direct relationship between peripheral nerve function and VPT. Height and circulating inflammatory markers may influence age-related decline in vibrotactile sensitivity through their negative impacts on peripheral nerve function. Published by Elsevier Inc. C1 [Deshpande, Nandini; Metter, E. Jeffery; Ferrucci, Luigi] NIA, Longitudinal Study Sect, Clin Res Branch, Natl Inst Hlth,Harbor Hosp, Baltimore, MD 21225 USA. [Ling, Shari] NIA, Translat Res & Med Serv Sect, Clin Res Branch, Natl Inst Hlth,Harbor Hosp, Baltimore, MD 21225 USA. [Conwit, Robin] NINDS, Natl Inst Hlth, Ctr Neurosci, Rockville, MD 20850 USA. RP Deshpande, N (reprint author), NIA, Longitudinal Study Sect, Clin Res Branch, Natl Inst Hlth,Harbor Hosp, 3001 S Hanover St, Baltimore, MD 21225 USA. EM deshpanden@mail.nih.gov FU Intramural NIH HHS [Z01 AG000015-49] NR 39 TC 21 Z9 24 U1 1 U2 3 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 MAY PY 2008 VL 29 IS 5 BP 765 EP 773 DI 10.1016/j.neurobiolaging.2006.12.002 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 286NS UT WOS:000254853200012 PM 17222481 ER PT J AU Kamal, MA Klein, P Luo, WM Li, YZ Holloway, HW Tweedie, D Greig, NH AF Kamal, Mohammad A. Klein, Peter Luo, Weiming Li, Yazhou Holloway, Harold W. Tweedie, David Greig, Nigel H. TI Kinetics of human serum butyrylcholinesterase inhibition by a novel experimental alzheimer therapeutic, dihydrobenzodioxepine cymserine SO NEUROCHEMICAL RESEARCH LA English DT Article DE Alzheimer's disease; butyrylcholinestrase; acetylcholinesterase; anticholinesterase; cymserine; phenserine; bisnorcymserine; enzyme inhibition kinetics; new kinetic constants ID HYDROLYZE ACETYLCHOLINE; TORPEDO-CALIFORNICA; DISEASE; BRAIN; PHENSERINE; CHOLINESTERASES; BINDING; SITES AB Cholinergic loss is the single most replicated neurotransmitter deficiency in Alzheimer's disease (AD) and has led to the use of acetylcholinesterase inhibitors (AChE-Is) and unselective cholinesterase inhibitors (ChE-Is) as the mainstay of treatment. AChE-Is and ChE-Is, however, induce dose-limiting adverse effects. Recent studies indicate that selective butyrylcholinesterase inhibitors (BuChE-Is) elevate acetylcholine (ACh) in brain, augment long-term potentiation, and improve cognitive performance in rodents without the classic adverse actions of AChE-Is and ChE-Is. BuChE-Is thereby represent a new strategy to ameliorate AD, particularly since AChE activity is depleted in AD brain, in line with ACh levels, whereas BuChE activity is elevated. Our studies have focused on the design and development of cymserine analogues to induce selective time-dependent brain BuChE inhibition, and on the application of innovative and quantitative enzyme kinetic analyses to aid selection of drug candidates. The quantitative interaction of the novel inhibitor, dihydrobenzodioxepine cymserine (DHBDC), with human BuChE was characterized. DHBDC demonstrated potent concentration-dependent binding with BuChE. The IC50 and specific new kinetic constants, such as K-T50, P-PC, K-T1/2 and R-I, were determined at dual substrate concentrations of 0.10 and 0.60 mM butyrylthiocholine and reaction times, and are likely attainable in humans. Other classical kinetic parameters such as K-ia, K-ma, V-ma and V-mi were also determined. In synopsis, DHBDC proved to be a highly potent competitive inhibitor of human BuChE in comparison to its structural analogue, cymserine, and represents an interesting drug candidate for AD. C1 [Kamal, Mohammad A.] Enzymoics, Hebersham, NSW 2770, Australia. [Klein, Peter] Sydney Inst, Ultimo, NSW, Australia. [Luo, Weiming; Li, Yazhou; Holloway, Harold W.; Tweedie, David; Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH,Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Kamal, MA (reprint author), Enzymoics, 7 Peterlee Pl, Hebersham, NSW 2770, Australia. EM makamal@optusnet.com.au; Greign@grc.nia.nih.gov RI Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; OI Kamal, Mohammad/0000-0003-1862-173X; Kamal, Mohammad Amjad/0000-0003-0088-0565 FU Intramural NIH HHS [, Z01 AG000311-08] NR 34 TC 32 Z9 34 U1 0 U2 7 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 MAY PY 2008 VL 33 IS 5 BP 745 EP 753 DI 10.1007/s11064-007-9490-y PG 9 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 277TT UT WOS:000254238300004 PM 17985237 ER PT J AU Lee, HJ Ertley, RN Rapoport, SI Bazinet, RP Rao, JS AF Lee, Ho-Joo Ertley, Renee N. Rapoport, Stanley I. Bazinet, Richard P. Rao, Jagadeesh S. TI Chronic administration of lamotrigine downregulates COX-2 mRNA and protein in rat frontal cortex SO NEUROCHEMICAL RESEARCH LA English DT Article DE lamotrigine; brain; arachidonic acid; cPLA(2); COX-2; bipolar disorder ID CYTOSOLIC PHOSPHOLIPASE A(2); CENTRAL-NERVOUS-SYSTEM; DNA-BINDING ACTIVITY; BIPOLAR-I DISORDER; ARACHIDONIC-ACID; BRAIN PHOSPHOLIPIDS; UNANESTHETIZED RAT; DOUBLE-BLIND; DOCOSAHEXAENOIC ACID; CHRONIC LITHIUM AB Chronic administration to rats of mood-stabilizers that are effective against mania in bipolar disorder, is reported to downregulate markers of the brain arachidonic acid cascade. We hypothesized that chronic administration of lamotrigine, which is used to treat depression and rapid cycling in bipolar disorder, might do so as well. Male CDF rats were administered a therapeutically relevant dose of lamotrigine (10 mg/kg) or vehicle intragastrically once daily for 42 days. Protein levels of isoforms of phospholipase A(2) (PLA(2)) and of cyclooxygenase (COX), and the mRNA level of COX-2, were quantified in the frontal cortex using immunoblotting and RT-PCR, respectively. Compared to vehicle-treated rats, chronic lamotrigine significantly decreased frontal cortex protein and mRNA levels of COX-2 without altering protein levels of the PLA(2) isoforms. Consistent with the hypothesis, lamotrigine and other mood-stabilizers have a common downregulatory action on COX-2 expression in rat brain, which may account in part for their efficacy in bipolar disorder. C1 [Lee, Ho-Joo; Ertley, Renee N.; Rapoport, Stanley I.; Bazinet, Richard P.; Rao, Jagadeesh S.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. [Bazinet, Richard P.] Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. 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 FU Intramural NIH HHS NR 40 TC 29 Z9 29 U1 0 U2 2 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 MAY PY 2008 VL 33 IS 5 BP 861 EP 866 DI 10.1007/s11064-007-9526-3 PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 277TT UT WOS:000254238300018 PM 18080190 ER PT J AU Matarin, M Simon-Sanchez, J Fung, HC Scholz, S Gibbs, JR Hernandez, DG Crews, C Britton, A De Vrieze, FW Brott, TG Brown, RD Worrall, BB Silliman, S Case, LD Hardy, JA Rich, SS Meschia, JF Singleton, AB AF Matarin, Mar Simon-Sanchez, Javier Fung, Hon-Chung Scholz, Sonja Gibbs, J. Raphael Hernandez, Dena G. Crews, Cynthia Britton, Angela De Vrieze, Fabienne Wavrant Brott, Thomas G. Brown, Robert D., Jr. Worrall, Bradford B. Silliman, Scott Case, L. Douglas Hardy, John A. Rich, Stephen S. Meschia, James F. Singleton, Andrew B. TI Structural genomic variation in ischemic stroke SO NEUROGENETICS LA English DT Article DE stroke; cerebral ischemia; genetics; copy number variants ID EPSTEIN-BARR VIRUS; PHOSPHODIESTERASE 4D; WIDE ASSOCIATION; COPY-NUMBER; PDE4D GENE; CELL-LINE; POPULATION; POLYMORPHISMS; CLASSIFICATION; SCALE AB Technological advances in molecular genetics allow rapid and sensitive identification of genomic copy number variants (CNVs). This, in turn, has sparked interest in the function such variation may play in disease. While a role for copy number mutations as a cause of Mendelian disorders is well established, it is unclear whether CNVs may affect risk for common complex disorders. We sought to investigate whether CNVs may modulate risk for ischemic stroke (IS) and to provide a catalog of CNVs in patients with this disorder by analyzing copy number metrics produced as a part of our previous genome-wide single-nucleotide polymorphism (SNP)-based association study of ischemic stroke in a North American white population. We examined CNVs in 263 patients with ischemic stroke (IS). Each identified CNV was compared with changes identified in 275 neurologically normal controls. Our analysis identified 247 CNVs, corresponding to 187 insertions (76%; 135 heterozygous; 25 homozygous duplications or triplications; 2 heterosomic) and 60 deletions (24%; 40 heterozygous deletions; 3 homozygous deletions; 14 heterosomic deletions). Most alterations (81%) were the same as, or overlapped with, previously reported CNVs. We report here the first genome-wide analysis of CNVs in IS patients. In summary, our study did not detect any common genomic structural variation unequivocally linked to IS, although we cannot exclude that smaller CNVs or CNVs in genomic regions poorly covered by this methodology may confer risk for IS. The application of genome-wide SNP arrays now facilitates the evaluation of structural changes through the entire genome as part of a genome-wide genetic association study. C1 [Fung, Hon-Chung; Crews, Cynthia; De Vrieze, Fabienne Wavrant; Singleton, Andrew B.] NIA, Neurogenet Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Matarin, Mar; Simon-Sanchez, Javier; Scholz, Sonja; Hernandez, Dena G.; Britton, Angela; Singleton, Andrew B.] NIA, Mol Genet Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. [Simon-Sanchez, Javier] CSIC, Unitat Genet Mol, Dept Genom & Proteom, Inst Biomed Valencia, Valencia 46010, Spain. [Fung, Hon-Chung] Chang Gung Univ, Dept Neurol, Chang Gung Mem Hosp, Taipei, Taiwan. [Fung, Hon-Chung] Chang Gung Univ, Coll Med, Taipei, Taiwan. [Fung, Hon-Chung; Hardy, John A.] UCL, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London, England. [Case, L. Douglas] Wake Forest Univ Hlt Sci, Biostat Sect, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Brott, Thomas G.; Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32256 USA. [Brown, Robert D., Jr.] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA. [Worrall, Bradford B.] Univ Virginia, Dept Neurol, Charlottesville, VA 22908 USA. [Worrall, Bradford B.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. [Silliman, Scott] Univ Florida, Coll Med, Dept Neurol, Jacksonville, FL 32256 USA. [Rich, Stephen S.; Singleton, Andrew B.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, Natl Inst Hlth, 35 Convent Dr, Bethesda, MD 20892 USA. EM Singleta@mail.nih.gov RI Gibbs, J. Raphael/A-3984-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Matarin, Mar/F-1771-2016; OI Matarin, Mar/0000-0002-4717-5735; Scholz, Sonja/0000-0002-6623-0429 FU Medical Research Council [G0701075]; NINDS NIH HHS [K08 NS045802, K08 NS045802-04] NR 43 TC 15 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD MAY PY 2008 VL 9 IS 2 BP 101 EP 108 DI 10.1007/s10048-008-0119-3 PG 8 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 289DA UT WOS:000255034000004 PM 18288507 ER PT J AU Chuang, KH Van Gelderen, P Merkle, H Bodurka, J Ikonomidou, VN Koretsky, AP Duyn, JH Talagala, SL AF Chuang, Kai-Hsiang Van Gelderen, Peter Merkle, Hellmut Bodurka, Jerzy Ikonomidou, Vasiliki N. Koretsky, Alan P. Duyn, Jeff H. Talagala, S. Lalith TI Mapping resting-state functional connectivity using perfusion MRI SO NEUROIMAGE LA English DT Article DE cerebral blood flow; arterial spin labeling; resting-state fluctuations; functional connectivity; sensorimotor cortex ID CEREBRAL-BLOOD-FLOW; BOLD SIGNAL; HUMAN BRAIN; PHYSIOLOGICAL NOISE; DEFAULT MODE; OXYGEN-CONSUMPTION; MOTOR CORTEX; 3.0 TESLA; FMRI; FLUCTUATIONS AB Resting-state, low-frequency (< 0.08 Hz) fluctuations of blood oxygenation level-dependent ( BOLD) magnetic resonance signal have been shown to exhibit high correlation among functionally connected regions. However, correlations of cerebral blood flow (CBF) fluctuations during the resting state have not been extensively studied. The main challenges of using arterial spin labeling perfusion magnetic resonance imaging to detect CBF fluctuations are low sensitivity, low temporal resolution, and contamination from BOLD. This work demonstrates CBF-based quantitative functional connectivity mapping by combining continuous arterial spin labeling (CASL) with a neck labeling coil and a multi-channel receiver coil to achieve high perfusion sensitivity. In order to reduce BOLD contamination, the CBF signal was extracted from the CASL signal time course by high frequency filtering. This processing strategy is compatible with sinc interpolation for reducing the timing mismatch between control and label images and has the flexibility of choosing an optimal filter cutoff frequency to minimize BOLD fluctuations. Most subjects studied showed high CBF correlation in bilateral sensorimotor areas with good suppression of BOLD contamination. Root-mean-square CBF fluctuation contributing to bilateral correlation was estimated to be 29 +/- 19% (N = 13) of the baseline perfusion, while BOLD fluctuation was 0.26 +/- 0.14% of the mean intensity ( at 3 T and 12.5 ms echo time). Published by Elsevier Inc. C1 [Talagala, S. Lalith] NINDS, NIH MRI Res Facil, NIH, Bethesda, MD 20892 USA. [Bodurka, Jerzy] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. [Chuang, Kai-Hsiang; Van Gelderen, Peter; Merkle, Hellmut; Ikonomidou, Vasiliki N.; Koretsky, Alan P.; Duyn, Jeff H.] NIH, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Talagala, SL (reprint author), NINDS, NIH MRI Res Facil, NIH, 10 Ctr Dr,Room B1D69, Bethesda, MD 20892 USA. EM talagala@nih.gov RI Duyn, Jozef/F-2483-2010; Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural NIH HHS [Z01 NS002989-08, Z99 NS999999] NR 64 TC 59 Z9 59 U1 2 U2 8 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 MAY 1 PY 2008 VL 40 IS 4 BP 1595 EP 1605 DI 10.1016/j.neuroimage.2008.01.006 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 293PL UT WOS:000255347100017 PM 18314354 ER PT J AU Matsuura, K Miura, K Taki, M Tabata, H Inaba, N Kawano, K Miles, FA AF Matsuura, K. Miura, K. Taki, M. Tabata, H. Inaba, N. Kawano, K. Miles, F. A. TI Ocular following responses of monkeys to the competing motions of two sinusoidal gratings SO NEUROSCIENCE RESEARCH LA English DT Article DE visual motion; ocular following responses; winner-take-all; nonlinear interactions; mutual inhibition ID LATENCY DISPARITY-VERGENCE; PURSUIT EYE-MOVEMENTS; CORTICAL AREA MST; CEREBELLAR VENTRAL PARAFLOCCULUS; TAKE-ALL MECHANISM; PURKINJE-CELLS; TRANSPARENT MOTION; VISUAL-CORTEX; BINOCULAR DISPARITY; SUPERIOR COLLICULUS AB Ocular following responses (OFRs) were elicited in monkeys at short latencies (similar to 50 ms) by applying motion in the form of successive 1/4-wavelength steps to each of two overlapping vertical sine-wave gratings that had different spatial frequencies. In the first experiment, the two sine waves had spatial frequencies in the ratio 3:5 and moved in opposite directions. The initial OFRs showed a highly nonlinear dependence on the relative contrasts of the competing sine waves. On average, when the contrast of one was less than a third of that of the other then the one with the lower contrast became ineffective - as though suppressed - and the OFR was entirely determined by the sine wave of higher contrast: winner-take-all. In a second experiment, the two sine waves had spatial frequencies in the ratio 3:7 and moved in the same direction (though at different speeds). The initial OFRs again showed a highly nonlinear dependence on the relative contrasts of the competing sine waves, with a winner-take-all outcome when the contrasts of the two sine waves were sufficiently different. In both experiments, the nonlinear dependence on the relative contrasts of the competing sine waves was well described by a contrast-weighted-average model with just two free parameters. These findings were very similar to those of [Sheliga, B.M., Kodaka, Y., FitzGibbon, E.J., Miles, F.A., 2006c. Human ocular following initiated by competing image motions: evidence for a winner-take-all mechanism. Vision Res. 46, 2041-2060] on the human OFR, indicating that the monkey is a good animal model for studying the nonlinear interactions that emerge when competing motions are used. (c) 2008 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 [Miura, K.] Kyoto Univ, Nanomed Merger Educ Unit, Kyoto 6068501, Japan. [Matsuura, K.; Tabata, H.; Inaba, N.; Kawano, K.] Kyoto Univ, Grad Sch Med, Dept Integrat Brain Sci, Kyoto 6068501, Japan. [Taki, M.] Kyoto Prefectural Univ Med, Dept Otolaryngol Head & Neck Surg, Kyoto, Japan. [Miles, F. A.] NIH, Sensorimotor Res Lab, NEI, Bethesda, MD 20892 USA. RP Miura, K (reprint author), Kyoto Univ, Nanomed Merger Educ Unit, Konoe Cho, Kyoto 6068501, Japan. EM kmiura@brain.med.kyoto-u.ac.jp OI Inaba, Naoko/0000-0002-0073-275X FU Intramural NIH HHS [Z01 EY000153-24] NR 67 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 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD MAY PY 2008 VL 61 IS 1 BP 56 EP 69 DI 10.1016/j.neures.2008.01.010 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 304PY UT WOS:000256122600008 PM 18316135 ER PT J AU Pessah, IN Seegal, RF Lein, PJ LaSalle, J Yee, BK Van De Water, J Berman, RF AF Pessah, Isaac N. Seegal, Richard F. Lein, Pamela J. LaSalle, Janine Yee, Benjamin K. Van De Water, Judy Berman, Robert F. TI Immunologic and neurodevelopmental susceptibilities of autism SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 11th Meeting of the International-Neurotoxicology-Association CY JUN, 2007 CL Pacific Grove, CA SP Int Neurotoxicol Assoc DE autism; ADHD; organochlorines; mercury; polychlorinated biphenyls; organophosphate; neuroimmunology ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; RECEPTOR SUBUNIT GENES; DEFICIT HYPERACTIVITY DISORDER; AMINOBUTYRIC-ACID RECEPTOR; POSTNATAL MATERNAL CONTRIBUTIONS; MYELIN BASIC-PROTEIN; POLY I-C; POLYCHLORINATED-BIPHENYLS; SPECTRUM DISORDERS; ANGELMAN-SYNDROME AB Symposium 5 focused on research approaches that are aimed at understanding common patterns of immunological and neurological dysfunction contributing to neurodevelopmental disorders such as autism and ADHD. The session focused on genetic, epigenetic, and environmental factors that might act in concert to influence autism risk, severity and co-morbidities, and immunological and neurobiological targets as etiologic contributors. The immune system of children at risk of autism may be therefore especially susceptible to psychological stressors, exposure to chemical triggers, and infectious agents. Identifying early biomarkers of risk provides tangible approaches toward designing studies in animals and humans that yield a better understanding of environmental risk factors, and can help identify rational intervention strategies to mitigate these risks. (C) 2008 Elsevier Inc. All rights reserved. C1 [Pessah, Isaac N.] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Pessah, Isaac N.; Van De Water, Judy; Berman, Robert F.] Univ Calif Davis, NIEHS EPA Ctr Childrens Environm Hlth, Davis, CA 95616 USA. [Seegal, Richard F.] Wadsworth Ctr, New York State Dept Hlth, Albany, NY USA. [Lein, Pamela J.] Swiss Fed Inst Technol, Zurich, Switzerland. [LaSalle, Janine] Oregon Hlth & Sci Univ, CROET, Portland, OR 97201 USA. [Yee, Benjamin K.; Van De Water, Judy; Berman, Robert F.] Univ Calif Davis, Sch Med, Davis, CA 95616 USA. RP Pessah, IN (reprint author), Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, 1 Shields Ave, Davis, CA 95616 USA. EM inpessah@ucdavis.edu RI LaSalle, Janine/A-4643-2008 OI LaSalle, Janine/0000-0002-3480-2031 FU NCRR NIH HHS [P51 RR000169, P51 RR000169-430203, P51 RR000169-440203, P51 RR000169-440235, P51 RR000169-455782, P51 RR000169-455792]; NICHD NIH HHS [HD 40936, R03 HD040936]; NIEHS NIH HHS [P01 ES011269-07, ES 010338, ES 014901, ES 015171, ES 11263, ES 11269, P01 ES011263, P01 ES011269, P01 ES011269-01, P01 ES011269-010003, P01 ES011269-01S1, P01 ES011269-01S10003, P01 ES011269-02, P01 ES011269-020003, P01 ES011269-03, P01 ES011269-030003, P01 ES011269-04, P01 ES011269-040003, P01 ES011269-04S1, P01 ES011269-04S2, P01 ES011269-05, P01 ES011269-050003, P01 ES011269-05S1, P01 ES011269-06, P01 ES011269-060003, P01 ES011269-068848, P01 ES011269-06S1, P01 ES011269-070003, P01 ES011269-07S1, P30 ES005707, P30 ES005707-119009, P30 ES005707-129009, P30 ES005707-139009, P30 ES005707-149009, P30 ES005707-159009, P42 ES010338, R01 ES014901, R01 ES015171, R01 ES015171-01, R01 ES015171-02, R13 ES015672, R13 ES015672-01, R56 ES014901]; NIGMS NIH HHS [GM 041292, R01 GM041292] NR 210 TC 24 Z9 24 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X EI 1872-9711 J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAY PY 2008 VL 29 IS 3 SI SI BP 532 EP 545 DI 10.1016/j.neuro.2008.02.006 PG 14 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 317MV UT WOS:000257025200021 PM 18394707 ER PT J AU Peterson, RT Nass, R Boyd, WA Freedman, JH Dong, K Narahashi, T AF Peterson, Randall T. Nass, Richard Boyd, Windy A. Freedman, Jonathan H. Dong, Ke Narahashi, Toshio TI Use of non-mammalian alternative models for neurotoxicological study SO NEUROTOXICOLOGY LA English DT Article; Proceedings Paper CT 11th Meeting of the International-Neurotoxicology-Association CY JUN, 2007 CL Pacific Grove, CA SP Int Neurotoxicol Assoc DE C. elegans; Parkinson's; zebrafish; neurotoxicological studies; insects; insecticides ID GATED CHLORIDE CHANNELS; RESISTANT SODIUM-CHANNELS; ROOT GANGLION NEURONS; HUMAN ALPHA-SYNUCLEIN; CAENORHABDITIS-ELEGANS; PARKINSONS-DISEASE; COCKROACH NEURONS; XENOPUS OOCYTES; C-ELEGANS; PYRETHROID INSECTICIDES AB The field of neurotoxicology needs to satisfy two opposing demands: the testing of a growing list of chemicals, and resource limitations and ethical concerns associated with testing using traditional mammalian species. National and international government agencies have defined a need to reduce, refine or replace mammalian species in toxicological testing with alternative testing methods and mammalian models. Toxicological assays using alternative animal models may relieve some of this pressure by allowing testing of more compounds while reducing expense and using fewer mammals. Recent advances in genetic technologies and, the strong conservation between human and non-mammalian genomes allow for the dissection of the molecular pathways involved in neurotoxicological responses and neurological diseases using genetically tractable organisms. In this review, applications of four non-mammalian species, zebrafish, cockroach, Drosophila, and Caenorhabditis elegans, in the investigation of neurotoxicology and neurological diseases are presented. (C) 2008 Elsevier Inc. All rights reserved. C1 [Peterson, Randall T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Nass, Richard] Indiana Univ, Sch Med, Ctr Environm Hlth, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. [Boyd, Windy A.; Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, NIH, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. [Boyd, Windy A.; Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, NIH, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Dong, Ke] Michigan State Univ, Pesticide Res Ctr, E Lansing, MI 48824 USA. [Narahashi, Toshio] Northwestern Univ, Feinberg Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. RP Narahashi, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. EM narahashi@northwestern.edu OI Boyd, Windy/0000-0003-3803-3716 FU NINDS NIH HHS [R01 NS014143-27] NR 99 TC 80 Z9 83 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAY PY 2008 VL 29 IS 3 SI SI BP 546 EP 555 DI 10.1016/j.neuro.2008.04.006 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 317MV UT WOS:000257025200022 PM 18538410 ER PT J AU Sharlin, D Tighe, D Gilbert, M Zoeller, RT AF Sharlin, David Tighe, Daniel Gilbert, Mary Zoeller, R. Thomas TI The balance between oligodendrocyte and astrocyte production in major white matter tracts is linearly related to serum total thyroxine SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the Neurobehavioral-Teratology-Society/48th Annual Meeting of the Teratology-Society/21st Annual Meeting of the Organization of Teratology Information Specialists CY JUN 28-JUL 02, 2008 CL Monterey, CA SP Neurobehav Teratol Soc, Teratol Soc C1 [Sharlin, David; Tighe, Daniel] NIDDK, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sharlin, David; Zoeller, R. Thomas] Univ Massachusetts, Amherst, MA 01003 USA. [Gilbert, Mary] US EPA, ORD, NHEERL, Div Neurotoxicol, Washington, DC 20460 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2008 VL 30 IS 3 MA NBTS6 BP 244 EP 245 DI 10.1016/j.ntt.2008.03.009 PG 2 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 321KH UT WOS:000257303100017 ER PT J AU Zoeller, R Bansal, R Giera, S Ortiz, T Tighe, D Sharlin, D Gilbert, M AF Zoeller, Robert Bansal, Ruby Giera, Stefanie Ortiz, Theresa Tighe, Daniel Sharlin, David Gilbert, Mary TI Thyroid disruption and brain development: What is it that we don't know? SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the Neurobehavioral-Teratology-Society/48th Annual Meeting of the Teratology-Society/21st Annual Meeting of the Organization of Teratology Information Specialists CY JUN 28-JUL 02, 2008 CL Monterey, CA SP Neurobehav Teratol Soc, Teratol Soc C1 [Zoeller, Robert; Bansal, Ruby; Giera, Stefanie; Ortiz, Theresa; Tighe, Daniel; Sharlin, David] Univ Massachusetts, Amherst, MA 01003 USA. [Tighe, Daniel] Harvard Univ, Cambridge, MA 02138 USA. [Sharlin, David] NIDDK, NIH, Bethesda, MD 20892 USA. [Gilbert, Mary] US EPA, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2008 VL 30 IS 3 MA NBTS17 BP 248 EP 248 DI 10.1016/j.ntt.2008.03.020 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 321KH UT WOS:000257303100028 ER PT J AU von Ehrenstein, OS Mikolajczyk, RT Zhang, J AF von Ehrenstein, O. S. Mikolajczyk, R. T. Zhang, J. TI Intrauterine growth during different time windows in relation to mental development at 13 months postpartum SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the Neurobehavioral-Teratology-Society/48th Annual Meeting of the Teratology-Society/21st Annual Meeting of the Organization of Teratology Information Specialists CY JUN 28-JUL 02, 2008 CL Monterey, CA SP Neurobehav Teratol Soc, Teratol Soc C1 [von Ehrenstein, O. S.; Mikolajczyk, R. T.; Zhang, J.] NICHHD, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2008 VL 30 IS 3 MA NBTS43 BP 256 EP 256 DI 10.1016/j.ntt.2008.03.046 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 321KH UT WOS:000257303100054 ER PT J AU Graham, D Noailles, P Cadet, J AF Graham, Devon Noailles, Pierre Cadet, Jean TI Differential neurochemical consequences of an escalating dose-binge regimen followed by single-day multiple-dose methamphetamine challenges SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Meeting Abstract CT 32nd Annual Meeting of the Neurobehavioral-Teratology-Society/48th Annual Meeting of the Teratology-Society/21st Annual Meeting of the Organization of Teratology Information Specialists CY JUN 28-JUL 02, 2008 CL Monterey, CA SP Neurobehav Teratol Soc, Teratol Soc C1 [Graham, Devon] Cincinnati Childrens Res Fdn, Cincinnati, OH USA. [Noailles, Pierre; Cadet, Jean] NIDA, DHHS, NIH, IRP, Bethesda, MD 20892 USA. OI Graham, Devon/0000-0003-0318-4602 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAY-JUN PY 2008 VL 30 IS 3 MA NBTS49 BP 258 EP 258 DI 10.1016/j.ntt.2008.03.052 PG 1 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 321KH UT WOS:000257303100060 ER PT J AU Althabe, F Buekens, P Bergel, E Belizan, JM Campbell, MK Moss, N Hartwell, T Wright, LL AF Althabe, Fernando Buekens, Pierre Bergel, Eduardo Belizan, Jose M. Campbell, Marci K. Moss, Nancy Hartwell, Tyler Wright, Linda L. CA Guidelines Trial Grp TI A behavioral intervention to improve obstetrical care SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIALS; 3RD STAGE; IMPLEMENTATION STRATEGIES; LABOR; MANAGEMENT; EPISIOTOMY; BALANCE; WOMEN AB Background: Implementation of evidence-based obstetrical practices remains a significant challenge. Effective strategies to disseminate and implement such practices are needed. Methods: We randomly assigned 19 hospitals in Argentina and Uruguay to receive a multifaceted behavioral intervention (including selection of opinion leaders, interactive workshops, training of manual skills, one-on-one academic detailing visits with hospital birth attendants, reminders, and feedback) to develop and implement guidelines for the use of episiotomy and management of the third stage of labor or to receive no intervention. The primary outcomes were the rates of prophylactic use of oxytocin during the third stage of labor and of episiotomy. The main secondary outcomes were postpartum hemorrhage and birth attendants' readiness to change their behavior with regard to episiotomies and management of the third stage of labor. The outcomes were measured at baseline, at the end of the 18-month intervention, and 12 months after the end of the intervention. Results: The rate of use of prophylactic oxytocin increased from 2.1% at baseline to 83.6% after the end of the intervention at hospitals that received the intervention and from 2.6% to 12.3% at control hospitals (P=0.01 for the difference in changes). The rate of use of episiotomy decreased from 41.1% to 29.9% at hospitals receiving the intervention but remained stable at control hospitals, with preintervention and postintervention values of 43.5% and 44.5%, respectively (P<0.001 for the difference in changes). The intervention was also associated with reductions in the rate of postpartum hemorrhage of 500 ml or more (relative rate reduction, 45%; 95% confidence interval [CI], 9 to 71) and of 1000 ml or more (relative rate reduction, 70%; 95% CI, 16 to 78). Birth attendants' readiness to change also increased in the hospitals receiving the intervention. The effects on the use of episiotomy and prophylactic oxytocin were sustained 12 months after the end of the intervention. Conclusions: A multifaceted behavioral intervention increased the prophylactic use of oxytocin during the third stage of labor and reduced the use of episiotomy. (ClinicalTrials.gov number, NCT00070720; Current Controlled Trials number, ISRCTN82417627.). C1 [Althabe, Fernando; Belizan, Jose M.] IECS, Buenos Aires, DF, Argentina. [Buekens, Pierre] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Bergel, Eduardo] UN Dev Program UN Populat Fund WHO World Bank Spe, Geneva, Switzerland. [Campbell, Marci K.] Univ N Carolina, Chapel Hill, NC USA. [Moss, Nancy; Wright, Linda L.] NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. [Hartwell, Tyler] Res Triangle Inst Int, Res Triangle Pk, NC USA. RP Althabe, F (reprint author), IECS, Viamonte 2146,3er Piso,C1056ABH, Buenos Aires, DF, Argentina. EM althabef@gmail.com RI Campbell, Michelle/B-5793-2008; OI Belizan, Jose/0000-0002-8412-3010 FU FIC NIH HHS [D43 TW005492]; NICHD NIH HHS [U01 HD40477, U01 HD40636]; NIDDK NIH HHS [DK 56350] NR 43 TC 84 Z9 89 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 1 PY 2008 VL 358 IS 18 BP 1929 EP 1940 DI 10.1056/NEJMsa071456 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 294ER UT WOS:000255387900007 PM 18450604 ER PT J AU Hadi, M Bacharach, SL Whatley, M Libutti, SK Straus, SE Rao, VK Wesley, R Carrasquillo, JA AF Hadi, Mohiuddin Bacharach, Stephen L. Whatley, Millie Libutti, Steven K. Straus, Stephen E. Rao, V. Koneti Wesley, Robert Carrasquillo, Jorge A. TI Glucose and insulin variations in patients during the time course of a FDG-PET study and implications for the "glucose-coffected" SUV SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE PET; PET/CT; glucose; insulin; variability; FDG-PET ID STANDARDIZED UPTAKE VALUES; LUNG-CANCER; BLOOD-GLUCOSE; FLUORINE-18-FLUORODEOXYGLUCOSE UPTAKE; F-18 FLUORODEOXYGLUCOSE; BIOLOGICAL VARIATION; BODY-SIZE; THERAPY; CHEMOTHERAPY; VARIABILITY AB Introduction: 2-Deoxy-2[F-18]fluoro-D-glucose (FDG) positron emission tomography (PET) has an established role in the evaluation of cancer. Generally, tumor uptake and response to treatment are evaluated using the standardized uptake value (SUV). Some authors have proposed correcting SUV for glucose levels. Insulin is also thought to influence tumor uptake by changing uptake in other tissues. However, little attention has been paid to understanding the variability of glucose or insulin during a single PET study. Method: We studied the biological and instrumental variability of glucose and insulin measurements in 71 nondiabetic patients undergoing FDG-PET studies. Multiple glucose measurements were obtained in all 71 subjects, and in 69 of these 71 subjects, multiple serum insulin measurements were made. We determined the coefficient of observed variation (CVow) and the coefficient of variation attributable to biological variability (CVbv) for both glucose and insulin. Results: The mean glucose concentration was 78.9 +/- 13.5 mg/dl. The mean insulin value was 6.49 +/- 5.92 mu U/ml. The weighted mean CVow and CVbv was 5.0% and 3.6%, respectively, for glucose and 14.2% and 8.3%, respectively, for insulin. Conclusions: Variations in the range of 3.6% are observed in glucose measurements during the time course of an FDG scan even after accounting for analytical error; larger variations of 8.3% are observed in insulin levels, Therefore, corrections of SUV for blood glucose, especially if obtained from single measurements, can introduce additional errors of at least this much. Published by Elsevier Inc. C1 [Hadi, Mohiuddin; Bacharach, Stephen L.] UCSF, Dept Radiol, San Francisco, CA 94158 USA. [Whatley, Millie] NIH, Dept Nucl Med, Bethesda, MD 20892 USA. [Libutti, Steven K.] NIH, Surg Branch, NCI, Bethesda, MD 20892 USA. [Straus, Stephen E.; Rao, V. Koneti] NIH, Lab Clin Infect Dis, NIAID, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Biostat Serv, Ctr Clin, Bethesda, MD 20892 USA. [Carrasquillo, Jorge A.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. RP Hadi, M (reprint author), UCSF, Dept Radiol, San Francisco, CA 94158 USA. EM dochadi@gmail.com RI Carrasquillo, Jorge/E-7120-2010; Hadi, Mohiuddin/H-5682-2012 NR 33 TC 14 Z9 14 U1 1 U2 4 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 MAY PY 2008 VL 35 IS 4 BP 441 EP 445 DI 10.1016/j.nucmedbio.2008.02.007 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 305EU UT WOS:000256161400006 PM 18482681 ER PT J AU Sprague, DR Fujita, M Ryu, YH Liow, JS Pike, VW Innis, RB AF Sprague, David R. Fujita, Masahiro Ryu, Yong Hoon Liow, Jeih-San Pike, Victor W. Innis, Robert B. TI Whole-body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 radioligand [C-11](R)-rolipram: comparison of two-dimensional planar, bisected and quadrisected image analyses SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE [C-11](R)-rolipram; positron emission tomography; dosimetry; biodistribution ID ROLIPRAM; RAT; PET; EXPRESSION; BRAIN; IV; PHARMACOKINETICS; INHIBITOR; BINDING; RABBIT AB Introduction: [C-11](R)-Rolipram is a selective radioligand for positron emission tomography (PET) imaging of phosphodiesterase 4, an enzyme that metabolizes 3',5'-cyclic adenosine monophosphate. The aim of this study was to estimate the human radiation absorbed dose of the radioligand based on its biodistribution in both monkeys and humans. Methods: Whole-body PET images were acquired for 2 h after injecting [C-11](R)-rolipram in eight healthy humans and three monkeys. The simple method of using a single two-dimensional (2D) planar image was compared to more time-consuming methods that used two (bisected) or four (quadrisected) tomographic images in the anteroposterior direction. Results: Effective dose was 4.8 mu Gy/MBq based on 2D planar images. The effective dose was only slightly lower by 1% and 5% using the bisected and quadrisected images, respectively. Nevertheless, the two tomographic methods may have more accurately estimated the exposure of some organs (e.g., kidneys) that are asymmetrically located in the body or have radioactivity that appears to overlap on 2D planar images. Monkeys had a different biodistribution pattern compared to humans (e.g., greater urinary excretion) such that their data overestimated the effective dose in humans by 40%. Conclusions: The effective dose of [C-11](R)-rolipram was modest and comparable to that of other C-11-labeled radioligands. The simple and far less time-consuming 2D planar method provided accurate and somewhat more conservative estimates of effective dose than the two tomographic methods. Although monkeys are commonly used to estimate human radiation exposures, their data gave a considerable overestimation for this radioligand. (C) 2008 Elsevier Inc. All rights reserved. C1 [Sprague, David R.; Fujita, Masahiro; Ryu, Yong Hoon; Liow, Jeih-San; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM masahiro.fujita@nih.gov FU Intramural NIH HHS [Z01 MH002852-03, Z01 MH002852-01]; NIMH NIH HHS [Z01 MH002795] NR 24 TC 9 Z9 9 U1 2 U2 4 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 MAY PY 2008 VL 35 IS 4 BP 493 EP 500 DI 10.1016/j.nucmedbio.2008.02.004 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 305EU UT WOS:000256161400012 PM 18482687 ER PT J AU Zhou, RZ Blanco, L Garcia-Diaz, M Bebenek, K Kunkel, TA Povirk, LF AF Zhou, Rui-Zhe Blanco, Luis Garcia-Diaz, Miguel Bebenek, Katarzyna Kunkel, Thomas A. Povirk, Lawrence F. TI Tolerance for 8-oxoguanine but not thymine glycol in alignment-based gap filling of partially complementary double-strand break ends by DNA polymerase in human nuclear extracts SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CELL-FREE-EXTRACTS; MAMMALIAN-CELLS; IN-VITRO; 3'-PHOSPHOGLYCOLATE TERMINI; LIGASE-IV; LAMBDA; REPAIR; MECHANISMS; KU; DAMAGE AB Ionizing radiation induces various clustered DNA lesions, including double-strand breaks (DSBs) accompanied by nearby oxidative base damage. Previous work showed that, in HeLa nuclear extracts, DSBs with partially complementary 3 overhangs and a one-base gap in each strand are accurately rejoined, with the gaps being filled by DNA polymerase . To determine the possible effect of oxidative base damage on this process, plasmid substrates were constructed containing overhangs with 8-oxoguanine or thymine glycol in base-pairing positions of 3-base (-ACG or -GTA) 3 overhangs. In this context, 8-oxoguanine was well tolerated by the end-joining machinery when present at one end of the break, but not when present at both ends. Thymine glycol was less well tolerated than 8-oxoguanine, reducing gap filling and accurate rejoining by at least 10-fold. The results suggest that complex DSBs can be accurately rejoined despite the presence of accompanying base damage, but that nonplanar bases constitute a major barrier to this process and promote error-prone joining. A chimeric DNA polymerase, in which the catalytic domain of polymerase was replaced with that of polymerase , could not substitute for polymerase in these assays, suggesting that this domain is specifically adapted for gap filling on aligned DSB ends. C1 [Zhou, Rui-Zhe; Povirk, Lawrence F.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. [Zhou, Rui-Zhe; Povirk, Lawrence F.] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA. [Blanco, Luis] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa CSIC UAM, E-28049 Madrid, Spain. [Garcia-Diaz, Miguel; Bebenek, Katarzyna; Kunkel, Thomas A.] Natl Inst Environm Sci, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Garcia-Diaz, Miguel; Bebenek, Katarzyna; Kunkel, Thomas A.] Natl Inst Environm Sci, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Povirk, LF (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. EM lpovirk@vcu.edu RI Blanco, Luis/I-1848-2015 FU Intramural NIH HHS; NCI NIH HHS [R01 CA040615, CA40615] NR 29 TC 14 Z9 14 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 MAY PY 2008 VL 36 IS 9 BP 2895 EP 2905 DI 10.1093/nar/gkn126 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 305JB UT WOS:000256173200015 PM 18385158 ER PT J AU Bobe, G Barrett, KG Mentor-Marcel, RA Safflotti, U Young, MR Colburn, NH Albert, PS Bennink, MR Lanza, E AF Bobe, Gerd Barrett, Kathleen G. Mentor-Marcel, Roycelynn A. Safflotti, Umberto Young, Matthew R. Colburn, Nancy H. Albert, Paul S. Bennink, Maurice R. Lanza, Elaine TI Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in Azoxymethane-Induced Ob/Ob mice SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID PHASEOLUS-VULGARIS L.; DRY BEANS; FERULIC ACID; CANCER RISK; F344 RATS; CONSUMPTION; SUPPRESSION; REDUCE; OLIGOSACCHARIDES; PROLIFERATION AB Based on the protective effects of cooked dry bean consumption in a human intervention study, we evaluated which fraction of cooked dry beans is responsible for its cancer-preventive effects. Cooked navy beans (whole beans), the insoluble fraction (bean residue) or soluble fraction of the 60% (vol:vol) ethanol extract of cooked navy beans (bean extract), or a modified AIN-93G diet (16.6% fat including 12.9% lard) as control diet were fed to 160 male obese ob/ob mice after 2 azoxymethane injections. In comparison to control-fed mice, dysplasia, adenomas, or adenocarcinomas were detected in fewer mice on either bean fraction diet (percent reduction from control: whole beans 54%, P = 0.10; bean residue 81 %, P = 0.003; bean extract 91 %, P = 0.007), and any type of colon lesions, including focal hyperplasia, were found in fewer mice on each of the 3 bean diets percent reduction from control: whole bean 56%, P= 0.04; bean residue 67 %, P = 0.01; bean extract 87 %, P = 0.0003. These results suggest that both the soluble and the insoluble fraction of the extract contribute to the cancer-protective effect of cooked navy beans. C1 [Bobe, Gerd; Mentor-Marcel, Roycelynn A.; Young, Matthew R.; Colburn, Nancy H.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Bobe, Gerd; Mentor-Marcel, Roycelynn A.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol,Div Canc Prevent, Natl Inst Hlth, Bethesda, MD 20892 USA. [Barrett, Kathleen G.; Bennink, Maurice R.] Michigan State Univ, Dept Food Sci & Human Nutr, E Lansing, MI 48824 USA. [Safflotti, Umberto; Lanza, Elaine] NCI, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Albert, Paul S.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Natl Canc Inst, Bethesda, MD 20892 USA. RP Bobe, G (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, 1050 Boyles St,Bldg 576,Rm 110, Frederick, MD 21702 USA. EM bobeg@mail.nih.gov FU Intramural NIH HHS [Z01 BC010025-12] NR 50 TC 26 Z9 26 U1 0 U2 6 PU LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS PI PHILADELPHIA PA 325 CHESTNUT STREET, STE 800, PHILADELPHIA, PA 19106 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PD MAY-JUN PY 2008 VL 60 IS 3 BP 373 EP 381 DI 10.1080/01635580701775142 PG 9 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 309DB UT WOS:000256439800011 PM 18444172 ER PT J AU Qi, L Zhang, CL Greenberg, A Hu, FB AF Qi, Lu Zhang, Cuilin Greenberg, Andrew Hu, Frank B. TI Common variations in perilipin gene, central obesity, and risk of type 2 diabetes in US women SO OBESITY LA English DT Article ID INSULIN-RESISTANCE; ADIPOCYTE LIPOLYSIS; METABOLIC-SYNDROME; LIPID-METABOLISM; ADIPOSE-TISSUE; 11482G-GREATER-THAN-A POLYMORPHISM; ENERGY-BALANCE; VISCERAL FAT; HAPLOTYPE; ASSOCIATION AB Objective: The variations in perilipin gene (PLIN) were previously associated with obesity and insulin sensitivity. We examined whether PLIN variability was associated with diabetes risk and obesity status modified such associations. Methods and Procedures: We conducted a nested case-control study of 431 incident cases of type 2 diabetes and 791 healthy control women from the Nurses' Health Study. Obesity was defined by BMI or waist circumference (central obesity). Results: In the sample of all participants, PLIN variations were not significantly associated with the incidence of diabetes. The central obesity status (by National Cholesterol Education Program Adult Treatment Panel III definition of waist circumference > 35 inches) significantly interacted with PLIN polymorphisms in relation to diabetes risk (P for interaction = 0.027, 0.009, and 0.02 for rs2289487, rs8179043, and rs894160, respectively). In nonobese (central) women, carriers of rs2289487, rs8179043, and rs894160 had significantly greater risk of type 2 diabetes, adjusting for diabetes risk factors (odds ratio (OR) = 1.52, 1.03-2.25; 1.54, 1.07-2.23; and 1.57, 1.09-2.27, respectively). Haplotypes possessing the three polymorphisms were also significantly associated with diabetes risk (global test, P = 0.01). As compared with the most common haplotype 111, haplotype 222 and 211 (1 codes the common and 2 codes the minor alleles) were associated with 44% (OR = 1.44, 95% confidence interval (CI) 1.09-1.91; P = 0.01) and 70% (OR = 1.70, 95% CI 1.04-2.77; P = 0.03) greater risk, respectively. The PLIN variations were not significantly associated with the disease risk among women with central obesity. Discussion: Our data indicate that central obesity may modify the associations between PLIN variations and diabetes risk in women. C1 [Qi, Lu; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Zhang, Cuilin] NICHHD, Epidemiol Branch, Div Epidemiol, Rockville, MD USA. [Greenberg, Andrew] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu FU NCI NIH HHS [P01 CA087969, CA87969]; NIDDK NIH HHS [R01 DK058845, DK58845] NR 42 TC 18 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2008 VL 16 IS 5 BP 1061 EP 1065 DI 10.1038/oby.2008.26 PG 5 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 297DP UT WOS:000255597600020 PM 18356850 ER PT J AU Engeli, S Heusser, K Janke, J Gorzelniak, K Batkai, S Pacher, P Harvey-White, J Luft, FC Jordan, J AF Engeli, Stefan Heusser, Karsten Janke, Juergen Gorzelniak, Kerstin Batkai, Sandor Pacher, Pal Harvey-White, Judith Luft, Friedrich C. Jordan, Jens TI Peripheral endocannabinoid system activity in patients treated with sibutramine SO OBESITY LA English DT Article ID RECEPTOR ANTAGONIST SR141716; ADIPOSE-TISSUE; RISK-FACTORS; OBESITY; CELLS; DYSREGULATION; ANANDAMIDE; ACTIVATION; LEPTIN AB Objective: The endocannabinoid system (ECS) promotes weight gain and obesity-associated metabolic changes. Weight loss interventions may influence obesity-associated risk indirectly through modulation of the peripheral ECS. We investigated the effect of acute and chronic treatment with sibutramine on components of the peripheral ECS. Methods and Procedures: Twenty obese otherwise healthy patients received randomized, double-blind, crossover treatment with placebo and 15 mg/day sibutramine for 5 days each, followed by 12 weeks open-label sibutramine treatment. We determined circulating anandamide and 2-arachidonoylglycerol and expression levels of endocannabinoid genes in subcutaneous abdominal adipose tissue biopsies. Results: Body weight was stable during the acute treatment period and decreased by 6.0 +/- 0.8 kg in those patients completing 3 months of sibutramine treatment (P < 0.05). Circulating endocannabinoids and the expression of ECS genes did not change with acute or chronic sibutramine treatment. Discussion: The ECS is activated in obesity. We did not find any influence of 5% body weight loss induced by sibutramine on circulating levels of endocannabinoids and adipose-tissue expression of endocannabinoid genes in obese subjects. These data confirm our previous findings on dietary weight loss and suggest that the dysregulation of the ECS may be a cause rather than a consequence of obesity. C1 [Engeli, Stefan; Heusser, Karsten; Janke, Juergen; Gorzelniak, Kerstin; Luft, Friedrich C.; Jordan, Jens] Charite & HELIOS Klinikum, Fac Med, Franz Volhard Clin Res Ctr, Berlin, Germany. [Batkai, Sandor; Pacher, Pal; Harvey-White, Judith] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Engeli, S (reprint author), Charite & HELIOS Klinikum, Fac Med, Franz Volhard Clin Res Ctr, Berlin, Germany. EM stefan.engeli@charite.de RI Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014; OI Pacher, Pal/0000-0001-7036-8108; Luft, Friedrich/0000-0002-8635-1199; Heusser, Karsten/0000-0002-2571-5585 FU Intramural NIH HHS [Z01 AA000375-02, Z99 AA999999] NR 16 TC 9 Z9 9 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD MAY PY 2008 VL 16 IS 5 BP 1135 EP 1137 DI 10.1038/oby.2008.47 PG 3 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 297DP UT WOS:000255597600031 PM 18356837 ER PT J AU Myslobodsky, M AF Myslobodsky, M. TI Molecular network of obesity: what does it promise for pharmacotherapy? SO OBESITY REVIEWS LA English DT Review DE modularity; networks; neuropeptides; polypharmacy ID CORTICOTROPIN-RELEASING HORMONE; CENTRAL-NERVOUS-SYSTEM; BEHAVIORAL SYNDROMES; APPETITE REGULATION; MEMORY PERFORMANCE; COMPLEX NETWORKS; NEUROPEPTIDE-Y; ENERGY-BALANCE; BRAIN NETWORKS; FOOD-INTAKE AB There is growing evidence that receptors that respond to orexigenic and anorexigenic signals of respective neuropeptides are also implicated in cognitive, emotional, sensory and motor functions. How do these signals trigger a particular appetitive function while also acting in so different contexts in controlling non-appetitive behaviours? This perspective seeks an answer in their peculiar modular organization when each module planted in complex networks controlling appetite is also engaged in different domains. Network analysis may be essential in considering pharmacotherapeutic interventions and, in particular, when anticipating untoward central effects of agents explored from a therapeutic point of view. C1 [Myslobodsky, M.] Howard Univ, Grad Sch, Washington, DC 20059 USA. [Myslobodsky, M.] NIH, NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Myslobodsky, M (reprint author), NIH, NIMH, Clin Brain Disorders Branch, 10 Ctr Dr,4S-235 MSC 1379, Bethesda, MD 20892 USA. EM myslobom@mail.nih.gov NR 82 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1467-7881 J9 OBES REV JI Obes. Rev. PD MAY PY 2008 VL 9 IS 3 BP 236 EP 245 DI 10.1111/j.1467-789X.2007.00424.x PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 289NQ UT WOS:000255061600005 PM 18034789 ER PT J AU Brubaker, L Handa, VL Bradley, CS Connolly, A Moalli, P Brown, MB Weber, A AF Brubaker, Linda Handa, Victoria L. Bradley, Catherine S. Connolly, AnnaMarie Moalli, Pamela Brown, Morton B. Weber, Anne CA Pelv Floor Disorders Network TI Sexual function 6 months after first delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID URINARY-INCONTINENCE; MATERNAL SEXUALITY; FECAL INCONTINENCE; PRIMIPAROUS WOMEN; PERINEAL TRAUMA; CHILDBIRTH; HEALTH; QUESTIONNAIRE; PREGNANCY; MORBIDITY AB OBJECTIVE: To explore the association of anal sphincter laceration and sexual function 6 months postpartum in the Childbirth and Pelvic Symptoms (CAPS) cohort. METHODS: The primary CAPS study, a prospective cohort study, was designed to estimate the postpartum prevalence and incidence of urinary and fecal incontinence. Three cohorts of new mothers (vaginal delivery with a third- or fourth-degree anal sphincter tear, vaginal delivery without a third- or fourth-degree anal sphincter tear, and cesarean delivery without labor) were compared at 6 months postpartum. Sexual function was assessed with the Pelvic Organ Prolapse/Urinary Incontinence/Sexual Function Short Form Questionnaire (PISQ-12). Urinary and fecal incontinence were assessed using the Medical Epidemiological and Social Aspects of Aging questionnaire and the Fecal Incontinence Severity Index, which is embedded within the Modified Manchester Health Questionnaire. RESULTS: Most women (459 [90%]) of those with partners reported sexual activity at the 6-month visit. Fewer women whose delivery was complicated by anal sphincter laceration reported sexual activity when compared with those who delivered vaginally without sphincter laceration (88 compared with 94%, P=.028). The mean PISQ-12 score (39 +/- 4) did not differ between delivery groups (P=.92). Pain (responses of "sometimes," "usually," or "always") during sex affected one of three sexually active women (164 [36%]). CONCLUSION: At 6 months postpartum, primiparous women who delivered with anal sphincter laceration are less likely to report sexual activity. C1 [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Johns Hopkins Univ, Dept Obstet & Gynecol, Baltimore, MD USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Loyola Univ, Med Ctr, Dept Obstet Gynecol, Maywood, IL 60153 USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Univ Iowa, Dept Obstet & Gynecol, Iowa City, IA 52242 USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Univ N Carolina, Dept Obstet & Gynecol, Chapel Hill, NC USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Univ Pittsburgh, Dept Obstet & Gynecol, Pittsburgh, PA USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Brubaker, Linda; Handa, Victoria L.; Bradley, Catherine S.; Connolly, AnnaMarie; Moalli, Pamela; Brown, Morton B.; Weber, Anne; Pelv Floor Disorders Network] NICHHD, NIH, Bethesda, MD 20892 USA. RP Brubaker, L (reprint author), Loyola Univ, Med Ctr, Dept Obstet Gynecol, S 1st Ave, Maywood, IL 60153 USA. EM LBrubaker@lumc.edu FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U01 HD041249, U01 HD41249, U10 HD41248, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41267, U10 HD41268, U10 HD41269, U10 HD041248, U10 HD041250, U10 HD041250-06, U10 HD041261, U10 HD041263, U10 HD041267, U10 HD041268, U10 HD041269] NR 14 TC 36 Z9 37 U1 1 U2 16 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 MAY PY 2008 VL 111 IS 5 BP 1040 EP 1044 DI 10.1097/AOG.0b013e318169cdee PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 295DK UT WOS:000255455000003 PM 18448733 ER PT J AU Zhang, J Liu, YH Meikle, S Zheng, JC Sun, WY Li, Z AF Zhang, Jun Liu, Yinghui Meikle, Susan Zheng, Junchi Sun, Wenyu Li, Zhu TI Cesarean delivery on maternal request in Southeast China SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID OUTCOMES; HEALTH AB OBJECTIVE: To estimate the incidence of overall cesarean delivery and cesarean delivery on maternal request in southeast China in the past decade. METHODS: We used data from a population-based maternal and child health surveillance system, which covers 21 cities and counties in two provinces in southeast China. We examined the rate of cesarean delivery and cesarean delivery on maternal request in 1.1 million singleton births from 1994 to early 2006. Cesarean delivery on maternal request was defined as a prelabor cesarean delivery for a singleton gestation without contraindications for vaginal delivery at 38 weeks of gestation or later. RESULTS: During the 13-year study period, the percentage of women who had high school or higher education increased from 13% to 46%. The overall cesarean rate increased from 22% in 1994 to 60% in 2003 and moderated to 56% in 2006. The corresponding rates of cesarean delivery on maternal request (per 100 all deliveries) were 0.8%, 22%, and 20%, respectively. The rates varied enormously among cities and counties. In some areas, cesarean delivery on maternal request accounted for half of all cesarean births. The patterns of rate change were diverse and uneven, and the pattern of risk factors changed substantially between 1994 and 2006. Nulliparity, higher education, older maternal age, having been delivered at provincial or county hospitals, and women's occupations were previously associated with rate of cesarean delivery on maternal request. The rate of cesarean delivery on maternal request no longer varies by age, hospital level, or occupation. CONCLUSION: The rate of cesarean delivery increased dramatically in southeast China in the past decade. Cesarean delivery on maternal request was the predominant contributor to the increase. C1 [Zhang, Jun; Liu, Yinghui; Meikle, Susan; Zheng, Junchi; Sun, Wenyu; Li, Zhu] NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Jun; Liu, Yinghui; Meikle, Susan; Zheng, Junchi; Sun, Wenyu; Li, Zhu] Peking Univ, Hlth Sci Ctr, Beijing 100871, Peoples R China. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov NR 16 TC 70 Z9 84 U1 1 U2 8 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 MAY PY 2008 VL 111 IS 5 BP 1077 EP 1082 DI 10.1097/AOG.0b013e31816e349e PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 295DK UT WOS:000255455000008 PM 18448738 ER PT J AU Levens, ED Potlog-Nahari, C Armstrong, AY Wesley, R Premkumar, A Blithe, DL Blocker, W Nieman, LK AF Levens, Eric D. Potlog-Nahari, Clariss Armstrong, Alicia Y. Wesley, Robert Premkumar, Ahalya Blithe, Diana L. Blocker, Wendy Nieman, Lynnette K. TI CDB-2914 for uterine leiomyomata treatment - A randomized controlled trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Gynecologic-Investigation CY MAR 14-17, 2007 CL Reno, NV SP Soc Gynecol Invest ID NORMALLY CYCLING WOMEN; ANTIPROGESTIN; MIFEPRISTONE; FIBROIDS AB OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T1) daily or to placebo (PLC) for 3 cycles or 90-102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914-29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90-102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251. C1 [Levens, Eric D.; Potlog-Nahari, Clariss; Armstrong, Alicia Y.; Wesley, Robert; Premkumar, Ahalya; Blithe, Diana L.; Blocker, Wendy; Nieman, Lynnette K.] NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Levens, Eric D.; Potlog-Nahari, Clariss; Armstrong, Alicia Y.; Wesley, Robert; Premkumar, Ahalya; Blithe, Diana L.; Blocker, Wendy; Nieman, Lynnette K.] NIH, Warren G Magnuson Clin Ctr, Dept Biostat Serv, Bethesda, MD 20892 USA. [Levens, Eric D.; Potlog-Nahari, Clariss; Armstrong, Alicia Y.; Wesley, Robert; Premkumar, Ahalya; Blithe, Diana L.; Blocker, Wendy; Nieman, Lynnette K.] NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Levens, Eric D.; Potlog-Nahari, Clariss; Armstrong, Alicia Y.; Wesley, Robert; Premkumar, Ahalya; Blithe, Diana L.; Blocker, Wendy; Nieman, Lynnette K.] NICHHD, Contracep & Reprod Hlth Branch, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), NICHD, Reprod Biol & Med Branch, NIH, Bldg 10,CRC,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@mail.nih.gov FU Intramural NIH HHS [Z01 HD000637-14] NR 20 TC 82 Z9 87 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAY PY 2008 VL 111 IS 5 BP 1129 EP 1136 DI 10.1097/AOG.0b013e3181705d0e PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 295DK UT WOS:000255455000015 PM 18448745 ER PT J AU Samanic, CM Kogevinas, M Silverman, DT Tardon, A Serra, C Malats, N Real, FX Carrato, A Garcia-Closas, R Sala, M Lloreta, J Rothman, N Dosemeci, M AF Samanic, C. M. Kogevinas, M. Silverman, D. T. Tardon, A. Serra, C. Malats, N. Real, F. X. Carrato, A. Garcia-Closas, R. Sala, M. Lloreta, J. Rothman, N. Dosemeci, M. TI Occupation and bladder cancer in a hospital-based case-control study in Spain SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID LOWER URINARY-TRACT; RISK-FACTORS; EXPOSURE; SMOKING; EPIDEMIOLOGY; HEALTH; IOWA; MEN AB Objectives: We investigated the association between occupation and bladder cancer in a hospital-based case control study conducted in Spain. Methods: 1219 patients with transitional cell carcinoma of the urinary bladder and 1271 controls selected from 18 hospitals in Spain between June 1998 and September 2000 provided detailed information on life-time occupational history, smoking habits, medical history, and other factors. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) for each occupation and industry, adjusting for age, hospital region, smoking duration, and employment in a high-risk occupation for bladder cancer. Results: Statistically significant increased risks were observed among men employed as machine operators in the printing industry (OR 5.4; 95% CI 1.6 to 17.7), among men employed in the transportation equipment industry (OR 1.6; 95% CI 1.1 to 2.6) and among those who had worked for >= 10 years in the electrical/gas/sanitary services (OR 3.9; 95% CI 1.5 to 10.4) and in hotels and other lodgings (OR 3.1; 95% CI 1.3 to 7.3). Men who worked as miscellaneous mechanics and repairers ( OR 2.0; 95% CI 1.1 to 3.6) and as supervisors in production occupations (OR 2.1; 95% CI 1.2 to 3.6) also had excess risks for bladder cancer. Male farmers and those who worked in crop and livestock production had decreased risks for bladder cancer. We found no significant associations between occupation or industry and bladder cancer risk among women. Conclusions: We did not observe excess bladder cancer risk for many of the occupations identified as being a priori at high risk. Examination of more detailed job exposure information should help clarify these associations. C1 [Samanic, C. M.; Silverman, D. T.; Rothman, N.; Dosemeci, M.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Kogevinas, M.; Malats, N.] Inst Municipal Invest Med, Ctr Res Environm Epidemiol, E-08003 Barcelona, Spain. [Kogevinas, M.] Univ Crete, Sch Med, Iraklion, Greece. [Tardon, A.] Univ Oviedo, Oviedo, Spain. [Serra, C.] Corp Parc Tauli, Sabadell, Spain. [Serra, C.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Occupat Hlth Res Unit, Barcelona, Spain. [Real, F. X.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. [Real, F. X.] Inst Municipal Invest Med, Barcelona, Spain. [Carrato, A.] Hosp Gen Elche, Elche, Spain. [Garcia-Closas, R.] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. [Sala, M.] Dept Hlth, Sabadell, Spain. [Lloreta, J.] Hosp Mar, Dept Pathol, Barcelona, Spain. [Lloreta, J.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona, Spain. RP Samanic, CM (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,Room 8003, Rockville, MD 20852 USA. EM samanicc@mail.nih.gov RI sala, maria/A-2593-2011; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Fernandez , Irene/E-5705-2016; Martinez, Esther/H-2562-2013; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; Sala Serra, Maria/0000-0002-5516-5967; Real, Francisco X/0000-0001-9501-498X; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS; NCI NIH HHS [N02-CP-11015] NR 38 TC 29 Z9 29 U1 3 U2 13 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD MAY PY 2008 VL 65 IS 5 BP 347 EP 353 DI 10.1136/oem.2007.035816 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 290KB UT WOS:000255120600011 PM 17951336 ER PT J AU t Mannetje, A Dryson, E Walls, C McLean, D McKenzie, F Maule, M Cheng, S Cunningham, C Kromhout, H Boffetta, P Blair, A Pearce, N AF 't Mannetje, A. Dryson, E. Walls, C. McLean, D. McKenzie, F. Maule, M. Cheng, S. Cunningham, C. Kromhout, H. Boffetta, P. Blair, A. Pearce, N. TI High risk occupations for non-Hodgkin's lymphoma in New Zealand: case-control study SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID MULTICENTER CASE-CONTROL; SOFT-TISSUE SARCOMA; CANCER INCIDENCE; HEMATOPOIETIC CANCER; MALIGNANT-LYMPHOMA; PESTICIDE USERS; EMPIRICAL-BAYES; MORTALITY; WORKERS; EXPOSURE AB Objectives: Previous studies into occupational risk factors for non-Hodgkin's lymphoma (NHL) in New Zealand have indicated that farmers and meat workers are at increased risk for these neoplasms. A new nationwide case-control study was conducted to assess whether previously observed associations persist and to identify other occupations that may contribute to the risk of NHL in the New Zealand population. Methods: A total of 291 incident cases of NHL (age 25 70 years) notified to the New Zealand Cancer Registry during 2003 and 2004, and 471 population controls, were interviewed face-to-face. The questionnaire collected demographic information and a full occupational history. The relative risk for NHL associated with ever being employed in particular occupations and industries was calculated by unconditional logistic regression adjusting for age, sex, smoking, ethnicity and socioeconomic status. Estimates were subsequently semi-Bayes adjusted to account for the large number of occupations and industries being considered. Results: An elevated NHL risk was observed for field crop and vegetable growers (OR 2.74, 95% CI 1.04 to 7.25) and horticulture and fruit growing (OR 2.28, 95% CI 1.37 to 3.79), particularly for women (OR 3.44, 95% CI 0.62 to 18.9; OR 3.15, 95% CI 1.50 to 6.61). Sheep and dairy farming was not associated with an increased risk of NHL. Meat processors had an elevated risk (OR 1.97, 95% CI 0.97 to 3.97), as did heavy truck drivers (OR 1.98, 95% CI 0.92 to 4.24), workers employed in metal product manufacturing (OR 1.92, 95% CI 1.12 to 3.28) and cleaners (OR 2.11, 95% CI 1.21 to 3.65). After semi-Bayes adjustment the elevated risks for horticulture and fruit growing, metal product manufacturing and cleaners remained statistically significant, representing the most robust findings of this study. Conclusions: This study has confirmed that crop farmers and meat workers remain high risk occupations for NHL in New Zealand, and has identified several other occupations and industries of high NHL risk that merit further study. C1 [Maule, M.] Univ Turin, Canc Epidemiol Unit, CeRMS, I-10124 Turin, Italy. [Maule, M.] Univ Turin, Canc Epidemiol Unit, CPO Piemonte, I-10124 Turin, Italy. [Cunningham, C.] Massey Univ, Res Ctr Maori Hlth & Dev, Wellington, New Zealand. [Kromhout, H.] Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TC Utrecht, Netherlands. [Boffetta, P.] Int Agcy Res Canc, F-69372 Lyon, France. [Blair, A.] NCI, Occupat & Environm Epidemiol Branch, Washington, DC USA. RP t Mannetje, A (reprint author), Massey Univ, Ctr Publ Hlth Res, Wellington Campus,Private Box 756, Wellington, New Zealand. EM a.mannetje@massey.ac.nz OI Pearce, Neil/0000-0002-9938-7852 NR 45 TC 17 Z9 17 U1 2 U2 10 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD MAY PY 2008 VL 65 IS 5 BP 354 EP 363 DI 10.1136/oem.2007.035014 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 290KB UT WOS:000255120600012 PM 18032530 ER PT J AU Olshavsky, NA Groh, EM Comstock, CES Morey, LM Wang, Y Revelo, MP Burd, C Meller, J Knudsen, KE AF Olshavsky, N. A. Groh, E. M. Comstock, C. E. S. Morey, L. M. Wang, Y. Revelo, M. P. Burd, C. Meller, J. Knudsen, K. E. TI Cyclin D3 action in androgen receptor regulation and prostate cancer SO ONCOGENE LA English DT Article DE cell cycle; prostatic adenocarcinoma; CDK; PSA and G1 ID VITAMIN-D-RECEPTOR; D-DEPENDENT KINASE; ESTROGEN-RECEPTOR; TRANSCRIPTIONAL ACTIVITY; CELL-LINES; D1-DEPENDENT KINASE; BINDING DOMAIN; GROWTH-FACTOR; CO-REPRESSOR; G(1) PHASE AB Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a ligand-dependent transcription factor. AR activation controls G1-S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa. C1 [Olshavsky, N. A.; Groh, E. M.; Comstock, C. E. S.; Morey, L. M.; Wang, Y.; Knudsen, K. E.] Univ Cincinnati, Coll Med, Vontz Ctr Mol Studies, Dept Cell & Canc Biol, Cincinnati, OH 45267 USA. [Revelo, M. P.] Univ Utah, Dept Pathol & Lab Med, Salt Lake City, UT USA. [Burd, C.] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Meller, J.; Knudsen, K. E.] Univ Cincinnati, Coll Med, UC Canc Ctr, Cincinnati, OH USA. [Meller, J.] Univ Cincinnati, Coll Med, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Knudsen, K. E.] Univ Cincinnati, Coll Med, Ctr Environm Genet, Cincinnati, OH 45267 USA. RP Knudsen, KE (reprint author), Univ Cincinnati, Coll Med, Vontz Ctr Mol Studies, Dept Cell & Canc Biol, 3125 Eden Ave,ML0521, Cincinnati, OH 45267 USA. EM Karen.Knudsen@uc.edu RI Meller, Jaroslaw/A-1971-2011; OI Meller, Jaroslaw/0000-0002-1162-8253; Comstock, Clay/0000-0001-5867-1489; Burd, Craig/0000-0002-6899-6751 FU NCI NIH HHS [CA099996, CA116777, T32 CA117846, T32-CA117846]; NIEHS NIH HHS [T32-ES07250] NR 69 TC 15 Z9 16 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2008 VL 27 IS 22 BP 3111 EP 3121 DI 10.1038/sj.onc.1210981 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 301LL UT WOS:000255897600004 PM 18084330 ER PT J AU Jiao, W Lin, HM Datta, J Braunschweig, T Chung, JY Hewitt, SM Rane, SG AF Jiao, W. Lin, H-M Datta, J. Braunschweig, T. Chung, J-Y Hewitt, S. M. Rane, S. G. TI Aberrant nucleocytoplasmic localization of the retinoblastoma tumor suppressor protein in human cancer correlates with moderate/poor tumor differentiation SO ONCOGENE LA English DT Article DE RB; CDK; cancer; export; localization; differentiation ID RING-FINGER DOMAIN; CELL-CYCLE; NUCLEAR EXPORT; BREAST-CANCER; GENE-PRODUCT; PHOSPHORYLATION; CDK4; EXPRESSION; MELANOMA; MECHANISM AB Inactivation of the retinoblastoma (RB) tumor suppressor pathway, via elevated cyclin-dependent kinase (CDK) activity, is observed in majority of human cancers. Since CDK deregulation is evident in most cancer cells, pharmacological CDK inhibition has become an attractive therapeutic strategy in oncology. We recently showed that an oncogenic CDK4R24C mutation alters the subcellular localization of the normally nuclear RB phosphoprotein. Here, using 71 human cancer cell lines and over 300 primary human cancer tissues, we investigated whether changes in RB subcellular localization occur during human cancer progression. We uncover that diverse human cancers and their derived cell lines, particularly those with poor tumor differentiation, display significant cytoplasmic mislocalization of ordinarily nuclear RB. The nucleocytoplasmically distributed RB was derived via CDK-dependent and Exportin1-mediated nuclear export. Indeed, cytoplasmically mislocalized RB could be efficiently confined to the nucleus by pharmacologically reducing CDK activity or by inhibiting the Exportin1-mediated nuclear export pathway. Our observations uncover a post-translational CDK-dependent mechanism of RB inactivation and suggest that cytoplasmically localized RB may harbor a tumor promoting function. We propose that RB inactivation, via aberrant nucleocytoplasmic transport, may disrupt normal cell differentiation programs and accelerate the cancer process. These results are evidence that tumor cells modulate the protein transport machinery thereby making the protein transport process a viable therapeutic target. C1 [Lin, H-M; Rane, S. G.] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Jiao, W.; Lin, H-M; Datta, J.; Rane, S. G.] Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. [Braunschweig, T.; Chung, J-Y; Hewitt, S. M.] NCI, Pathol Lab, Tissue Array Res Program, Bethesda, MD 20892 USA. RP Rane, SG (reprint author), NIDDKD, Diabet Branch, NIH, CRC 5-5940,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ranes@mail.nih.gov OI Datta, Jashodeep/0000-0003-2869-1571; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural NIH HHS NR 52 TC 25 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2008 VL 27 IS 22 BP 3156 EP 3164 DI 10.1038/sj.onc.1210970 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 301LL UT WOS:000255897600008 PM 18071317 ER PT J AU Frech, MS Torre, KM Robinson, GW Furth, PA AF Frech, M. S. Torre, K. M. Robinson, G. W. Furth, P. A. TI Loss of cyclin D1 in concert with deregulated estrogen receptor a expression induces DNA damage response activation and interrupts mammary gland morphogenesis SO ONCOGENE LA English DT Article DE ER alpha; cyclin D1; cyclin E; DNA damage; mammary gland ID CARCINOMA IN-SITU; BREAST-CANCER; PRECANCEROUS BREAST; INSTABILITY; LESIONS; CELLS AB We have previously shown that increased and deregulated estrogen receptor alpha expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ER alpha-mediated mammary tumorigenesis, we crossed ER alpha-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ER alpha-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERa in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ER alpha-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ER alpha-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ER alpha-overexpressing breast cancers. C1 [Frech, M. S.; Torre, K. M.; Furth, P. A.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Robinson, G. W.] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Frech, MS (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. EM msf25@georgetown.edu RI Robinson, Gertraud/I-2136-2012 FU NCI NIH HHS [R01 CA112176-05, R01 CA112176, 1R01CA112176] NR 23 TC 10 Z9 10 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2008 VL 27 IS 22 BP 3186 EP 3193 DI 10.1038/sj.onc.1210974 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 301LL UT WOS:000255897600011 PM 18071314 ER PT J AU Szabova, L Chrysovergis, K Yamada, SS Holmbeck, K AF Szabova, L. Chrysovergis, K. Yamada, S. S. Holmbeck, K. TI MT1-MMP is required for efficient tumor dissemination in experimental metastatic disease SO ONCOGENE LA English DT Article DE MT1-MMP; PyMT; mammary cancer; metastasis; collagen; proteolysis ID MATRIX METALLOPROTEINASES; PERICELLULAR PROTEOLYSIS; EXTRACELLULAR-MATRIX; BREAST CARCINOMAS; CANCER INVASION; DEFICIENT MICE; MEMBRANE; EXPRESSION; CELLS; ANGIOGENESIS AB Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV-polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT + glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMP deficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibbroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process. C1 [Szabova, L.; Chrysovergis, K.; Yamada, S. S.; Holmbeck, K.] Natl Inst Dent & Craniofacial Res, Matrix Metalloproteinase Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. RP Holmbeck, K (reprint author), Natl Inst Dent & Craniofacial Res, Matrix Metalloproteinase Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 125,30 Convent Dr,MSC 4380, Bethesda, MD 20892 USA. EM kenn.holmbeck@nih.gov NR 38 TC 45 Z9 47 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2008 VL 27 IS 23 BP 3274 EP 3281 DI 10.1038/sj.onc.1210982 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 304LQ UT WOS:000256111400006 PM 18071307 ER PT J AU Mizuno, T Yamasaki, N Miyazaki, K Tazaki, T Koller, R Oda, H Honda, Z Ochi, M Wolff, L Honda, H AF Mizuno, T. Yamasaki, N. Miyazaki, K. Tazaki, T. Koller, R. Oda, H. Honda, Z-i Ochi, M. Wolff, L. Honda, H. TI Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice SO ONCOGENE LA English DT Article DE chronic myelogenous leukemia; blast crisis; transgenic mice; p210BCR/ABL; Notch1 ID CHRONIC MYELOGENOUS LEUKEMIA; RETROVIRAL INSERTIONAL MUTAGENESIS; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; BCR-ABL; MYELOPROLIFERATIVE DISEASE; CELL LEUKEMIA; BLAST CRISIS; GENE; CML AB Chronic myelogenous leukemia (CML) is a hematopoietic disorder, which begins as indolent chronic phase but inevitably progresses to fatal blast crisis. p210BCR/ABL, a constitutively active tyrosine kinase, is responsible for disease initiation but molecular mechanism(s) underlying disease evolution remains largely unknown. To explore this process, we employed retroviral insertional mutagenesis to CML-exhibiting p210BCR/ABL transgenic mice (Tg). Virus infection induced acute lymphoblastic leukemia (ALL) in p210BCR/ABL Tg with a higher frequency and in a shorter latency than wild-type littermates, and inverse PCR detected two retrovirus common integration sites (CISs) in p210BCR/ABL Tg tumors. Interestingly, one CIS was the transgene itself, where retrovirus integrations induced upregulation of p210BCR/ABL and production of truncated BCR/ABL with an enhanced kinase activity. Another CIS was Notch1 gene, where retrovirus integrations resulted in overexpression of Notch1 and generation of Notch1 lacking the C-terminal region (Notch1DC) associated with stable expression of its activated product, C-terminal-truncated Notch intracellular domain (NICDDC). In addition, generation of Tg for both p210BCR/ABL and Notch1DC developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1DC/NICDDC with p210BCR/ABL involving Stat5-mediated pathway. These results demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induces acute leukemia in a transgenic model for CML. C1 [Mizuno, T.; Yamasaki, N.; Miyazaki, K.; Tazaki, T.; Honda, H.] Hiroshima Univ, Dept Dev Biol, Res Inst Radiat Biol & Med, Minami Ku, Hiroshima 7348553, Japan. [Mizuno, T.; Ochi, M.] Hiroshima Univ, Sch Med, Dept Orthoped Surg, Hiroshima, Japan. [Koller, R.; Wolff, L.] NCI, Cellular Oncol Lab, Leukemogenesis Sect, Bethesda, MD 20892 USA. [Oda, H.] Tokyo Womens Med Univ, Dept Pathol, Tokyo, Japan. [Honda, Z-i] Univ Tokyo, Grad Sch Sci, Dept Allergy & Rheumatol, Fac Med, Tokyo 113, Japan. RP Honda, H (reprint author), Hiroshima Univ, Dept Dev Biol, Res Inst Radiat Biol & Med, Minami Ku, 1-2-3 Kasumi, Hiroshima 7348553, Japan. EM hhonda@hiroshima-u.ac.jp NR 38 TC 17 Z9 18 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY PY 2008 VL 27 IS 24 BP 3465 EP 3474 DI 10.1038/sj.onc.1211007 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 307HL UT WOS:000256309900011 PM 18193087 ER PT J AU Giordano, SH Fang, SY Duan, ZG Kuo, YF Hortobagyi, GN Goodwin, JS AF Giordano, Sharon H. Fang, Shenying Duan, Zhigang Kuo, Yong-Fang Hortobagyi, Gabriel N. Goodwin, James S. TI Use of intravenous bisphosphonates in older women with breast cancer SO ONCOLOGIST LA English DT Article DE breast cancer; elderly; metastatic ID PLACEBO-CONTROLLED TRIAL; BONE METASTASES; SKELETAL COMPLICATIONS; ZOLEDRONIC ACID; DOUBLE-BLIND; AMERICAN SOCIETY; CLINICAL COURSE; PAMIDRONATE; CARCINOMA; EFFICACY AB Introduction. i. v. bisphosphonates reduce skeletal events in women with bone metastases from breast cancer, but little is known about the prevalence and duration of bisphosphonate use. Methods. Patients were identified from the Surveillance, Epidemiology, and End Results-Medicare database who were aged >= 65 years and were diagnosed with invasive breast cancer in 1995-2002. Healthcare Common Procedure Coding System codes were used to identify patients treated with pamidronate and zoledronic acid. Descriptive statistics were used to describe patterns of use. Multivariate analyses were performed to determine the predictors of bisphosphonate use. Results. In total, 55,864 women with breast cancer were included, with 307,467 person-years of follow-up. Overall, 1.26% of women with all stages of breast cancer received i. v. bisphosphonates. In 2004, 2% of all breast cancer patients and 32% of patients with distant stage disease received bisphosphonates. Approximately two thirds of patients treated with bisphosphonates received zoledronic acid and one third received pamidronate in 2004. Multivariate analyses showed that patients who were >= 75 years old were less likely to receive bisphosphonates ( 75-79 years versus 65-69 years: odds ratio [OR], 0.81; 95% confidence interval [CI], 0.70-0.93; 80 + years versus 65-69 years: OR, 0.49; 95% CI, 0.42-0.57). The use of bisphosphonates dramatically increased over time. The majority of living patients were continued on i. v. bisphosphonates once started (83% at 1 year, 64% at 3 years, 50% at 5 years), but the median survival time after initiation of i. v. bisphosphonates was only 21 months. Conclusions. i. v. bisphosphonates appear to be underused in patients with metastatic breast cancer, particularly among those patients > 75 years of age. C1 [Giordano, Sharon H.; Fang, Shenying; Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA. [Duan, Zhigang] NIH, Bethesda, MD 20892 USA. [Kuo, Yong-Fang; Goodwin, James S.] Univ Texas Med Branch Galveston, Sealy Ctr Aging, Galveston, TX USA. RP Giordano, SH (reprint author), 1515 Holcombe Blvd,Box 1354, Houston, TX 77030 USA. EM sgiordan@mdanderson.org FU NCI NIH HHS [1K07 CA 109064-04, K05 CA134923, K07 CA109064] NR 28 TC 15 Z9 15 U1 1 U2 3 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1083-7159 J9 ONCOLOGIST JI Oncologist PD MAY PY 2008 VL 13 IS 5 BP 494 EP 502 DI 10.1634/theoncologist.2007-0200 PG 9 WC Oncology SC Oncology GA 307KO UT WOS:000256318000003 PM 18515734 ER PT J AU Castro, K Mitchell, S Rowe, T Jacobs, M AF Castro, Kathleen Mitchell, Sandra Rowe, Tiffany Jacobs, Myra TI A chronic graft-versus-host disease (cGVHD) telephone support group: Partnering with an advocacy organization to address an underserved population of cancer survivors SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Castro, Kathleen; Mitchell, Sandra] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. [Rowe, Tiffany; Jacobs, Myra] Natl Bone Marrow Transplant Link, Southfield, MI USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 2816 BP 514 EP 514 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700124 ER PT J AU Muir, C Steakley, C AF Muir, Christine Steakley, Caryn TI A model to increase clinical trial accural SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Muir, Christine; Steakley, Caryn] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 2886 BP 523 EP 523 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700153 ER PT J AU Miller, B Gonzalez, E Stadler, K Grater, J Kluhsman, B O'Grady, M AF Miller, Bonnie Gonzalez, Evelyn Stadler, Kathryn Grater, Joyce Kluhsman, Brenda O'Grady, Margaret TI Oncology nurses as key stakeholders in development and implementation of state cancer control plans SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Miller, Bonnie] Fox Chase Canc Ctr, Fox Chase Canc Ctr Partners, Philadelphia, PA 19111 USA. [Gonzalez, Evelyn] Natl Canc Inst, Canc Informat Serv, Philadelphia, PA USA. [Stadler, Kathryn] PAC3, Philadelphia, PA USA. [Grater, Joyce] Univ Pittsburgh, Pittsburgh, PA USA. [Kluhsman, Brenda] Appalachia Community Canc Network, Hershey, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 2905 BP 525 EP 525 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700161 ER PT J AU Flores, I Ershler, W AF Flores, Irene Ershler, William TI Managing neutropenia in older cancer patients receiving chemotherapy in a community setting SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Flores, Irene] Inst Adv Studies Aging, Gaithersburg, MD USA. [Ershler, William] NIA, Gaithersburg, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 2912 BP 526 EP 527 PG 2 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700165 ER PT J AU Calzone, K Jenkins, J Yates, J Cusack, G McBride, C AF Calzone, Kathleen Jenkins, Jean Yates, Jan Cusack, Georgie McBride, Coleen TI Evaluation of the integration of genetics and genomics into nursing practice SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Calzone, Kathleen] NCI, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. [Jenkins, Jean; McBride, Coleen] Natl Human Genom Res Inst, Bethesda, MD USA. [Yates, Jan; Cusack, Georgie] NIH, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 2993 BP 539 EP 539 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700206 ER PT J AU Booher, S AF Booher, Susan TI Creating a pathway to best clinical practice for cutaneous T-CELL lymphoma SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 [Booher, Susan] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAY PY 2008 VL 35 IS 3 MA 3044 BP 547 EP 547 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 298NF UT WOS:000255693700233 ER PT J AU Christen, WG Glynn, RJ Chew, EY Buring, JE AF Christen, William G. Glynn, Robert J. Chew, Emily Y. Buring, Julie E. TI Vitamin E and age-related cataract in a randomized trial of woman SO OPHTHALMOLOGY LA English DT Article ID NUCLEAR LENS OPACITIES; BLUE-MOUNTAINS-EYE; BEAVER DAM EYE; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; NUTRIENT INTAKE; CLINICAL-TRIAL; RISK-FACTORS; NUTRITIONAL SUPPLEMENTS; ANTIOXIDANT VITAMINS AB Objective: To investigate whether vitamin E supplementation decreases the risk of age-related cataract in women. Design: Randomized, double-masked, placebo-controlled trial. Participants: Thirty-nine thousand eight hundred seventy-six apparently healthy female health professionals aged 45 years or older. Intervention: Participants were assigned randomly to receive either 600 IU natural-source vitamin E on alternate days or placebo and were followed up for presence of cataract for an average of 9.7 years. Main Outcome Measure: Age-related cataract defined as an incident, age-related lens opacity, responsible for a reduction in best-corrected visual acuity to 20/30 or worse, based on self-report and confirmed by medical record review. Results: There was no significant difference between the vitamin E and placebo groups in the incidence of cataract (1159 vs. 1217 cases; relative risk [RR], 0.96; 95% confidence interval [CI], 0.88-1.04). In subgroup analyses of subtypes, there were no significant effects of vitamin E on the incidence of nuclear (1056 vs. 1127 cases; RR, 0.94; 95% CI, 0.87-1.02), cortical (426 vs. 461 cases; RR, 0.93; 95% CI, 0.81-1.06), or posterior subcapsular cataract (357 vs. 359 cases; RR, 1.00; 95% CI, 0.86-1.16). Results were similar for extraction of cataract and subtypes. There was no modification of the lack of effect of vitamin E on cataract by baseline categories of age, cigarette smoking, multivitamin use, or several other possible risk factors for cataract. Conclusions: These data from a large trial of apparently healthy female health professionals with 9.7 years of treatment and follow-up indicate that 600 IU natural-source vitamin E taken every other day provides no benefit for age-related cataract or subtypes. C1 [Buring, Julie E.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Cambridge, MA 02138 USA. [Chew, Emily Y.] NIH, NEI, Bethesda, MD USA. [Glynn, Robert J.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Christen, William G.; Glynn, Robert J.; Buring, Julie E.] Harvard Univ, Sch Med, Div Prevent Med, Dept Med,Brigham & Womens Hosp, Boston, MA 02115 USA. RP Christen, WG (reprint author), 900 Commonwealth Ave E, Boston, MA 02215 USA. EM wchristen@rics.bwh.harvard.edu FU Intramural NIH HHS [Z99 EY999999]; NCI NIH HHS [CA 47988]; NEI NIH HHS [EY 06633]; NHLBI NIH HHS [HL 43851] NR 55 TC 23 Z9 23 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD MAY PY 2008 VL 115 IS 5 BP 822 EP 829 DI 10.1016/j.ophtha.2007.06.040 PG 8 WC Ophthalmology SC Ophthalmology GA 297KA UT WOS:000255614400011 PM 18067963 ER PT J AU Salafia, CM Zhang, J Charles, AK Bresnahan, M Shrout, P Sun, W Maas, EM AF Salafia, Carolyn M. Zhang, Jun Charles, Adrian K. Bresnahan, Michaeline Shrout, Patrick Sun, Wenyu Maas, Elizabeth M. TI Placental characteristics and birthweight SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE birthweight; placenta; placental weight; placental characteristics; Collaborative Perinatal Project ID INTRAUTERINE GROWTH RESTRICTION; MEDIATION; FLOW AB Standard gross placental measures capture dimensions relevant to specific placental functions. Our objective was to determine their accountability independent of placental weight for variance in birthweight, an important proxy for intrauterine 'adequacy' in fetal origins studies. The sample consisted of 24 152 singleton liveborn children of the Collaborative Perinatal Project delivered from 34 to 42 completed weeks gestation, with complete data for six placental measures (placental disc shape, umbilical cord length, distance from cord insertion to nearest margin, large diameter, small diameter, placental thickness) and placental weight. Associations between birthweight and placental measures were examined using multiple linear regression. Placental weight alone accounted for 36.6% of birthweight variation; the six other placental measures accounted for 28.1%. Combined, all placental measures accounted for 39.1% of birthweight variation. Seven maternal characteristics (age, height, weight, parity, socio-economic status, cigarette use, and race) were investigated to determine whether their known associations with birthweight were mediated by placental markers. Analysis suggested that the impact of all maternal characteristics except smoking was consistent with mediation by placental characteristics. C1 [Salafia, Carolyn M.; Bresnahan, Michaeline] Columbia Univ, Mailman Sch Publ Hlth, Coll Phys & Surg, Dept Epidemiol, New York, NY 10032 USA. [Bresnahan, Michaeline] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Shrout, Patrick] NYU, Dept Psychol, New York, NY 10003 USA. [Salafia, Carolyn M.; Maas, Elizabeth M.] EarlyPath Clin & Res Diagnost, Larchmt, NY USA. [Zhang, Jun; Sun, Wenyu] NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. [Charles, Adrian K.] Princess Margaret Hosp, Dept Pathol, Perth, WA, Australia. RP Salafia, CM (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Coll Phys & Surg, Dept Epidemiol, 722 W 168th St, New York, NY 10032 USA. EM sala.acm@aol.com OI Charles, Adrian/0000-0002-3193-1065 FU NIMH NIH HHS [1 K23 MH067857-01] NR 21 TC 52 Z9 53 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAY PY 2008 VL 22 IS 3 BP 229 EP 238 DI 10.1111/j.1365-3016.2008.00935.x PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 289NS UT WOS:000255061800003 PM 18426518 ER PT J AU Strouse, JJ Takemoto, CM Keefer, JR Kato, GJ Casella, JF AF Strouse, John J. Takemoto, Clifford M. Keefer, Jeffrey R. Kato, Gregory J. Casella, James F. TI Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease SO PEDIATRIC BLOOD & CANCER LA English DT Article DE acute chest syndrome; cohort study; corticosteroids; sickle cell disease; transfusions ID TRANSFUSION; ANEMIA; STROKE; ASTHMA; DEATH; LIFE; PAIN AB Background. Acute chest syndrome (ACS) is a frequent cause of hospitalization and mortality in children with sickle cell disease. Transfusion is often required to prevent respiratory failure and treatment with dexamethasone may reduce the length of admission and the need for transfusions. We performed a retrospective cohort study to evaluate risk factors for readmission and prolonged hospitalization after different treatments for ACS. Procedure. We identified patients <22 years of age hospitalized with ACS at Johns Hopkins Hospital from January 1998 to April 2004 using the hospitals discharge database and by reviewing dictated summaries. Results. We identified 65 patients with 129 episodes of ACS (mean age 12.5 years, range 1.2-21.9 years). Thirty-nine episodes were treated with corticosteroids and 51 with transfusions. Patients were readmitted within 14 days after 23 episodes (18%). Readmission was strongly associated with report of an inhaler or nebulizer at home [odds ratio (OR) 6.0, P<0.05], diastolic BP at 48 hr (OR 1.8 per 10 mm increase, P<0.01), corticosteroids (OR 20, P<0.005), or transfusion (OR 0.03, P< 0.05). Treatment with corticosteroids alone (P<0.05) and older age (P<0.001) were associated with longer hospitalization. Conclusions. These results demonstrate a greatly elevated independent risk of readmission after ACS in children with asthma and after treatment with corticosteroids and a protective effect of transfusion. Although dexamethasone has documented efficacy for reducing the duration of ACS, the substantial risk of readmission for pain should limit its use. C1 [Strouse, John J.; Takemoto, Clifford M.; Keefer, Jeffrey R.; Kato, Gregory J.; Casella, James F.] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Baltimore, MD 21205 USA. [Kato, Gregory J.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. RP Strouse, JJ (reprint author), Johns Hopkins Univ, Sch Med, Div Pediat Hematol, 720 Rutland Ave,Ross 1125, Baltimore, MD 21205 USA. EM jstrous1@jhmi.edu RI Strouse, John/A-2690-2008; Kato, Gregory/I-7615-2014 OI Strouse, John/0000-0003-0341-1457; Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [Z01 CL008070-04, Z99 HL999999, ZIA HL006014-02]; NCRR NIH HHS [K12RR01627] NR 23 TC 36 Z9 36 U1 0 U2 1 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 MAY PY 2008 VL 50 IS 5 BP 1006 EP 1012 DI 10.1002/pbc.21336 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 283NL UT WOS:000254642900013 PM 17849474 ER PT J AU Ferrari, A Montello, M Budd, T Bleyer, A AF Ferrari, Andrea Montello, Michael Budd, Troy Bleyer, Archie TI The challenges of clinical trials for adolescents and young adults with cancer SO PEDIATRIC BLOOD & CANCER LA English DT Article; Proceedings Paper CT Symposium on Adolescent and Young Adult Oncology CY 2006 CL Geneva, SWITZERLAND SP SIOP DE clinical trials outcome ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PROTOCOLS; DIFFERENCE; SURVIVAL; CHILDREN AB In the United States, Europe, and Australia, and probably all countries of the world, older adolescents and young adults with cancer are under-represented in clinical trials of therapies that could improve their outcome. Simultaneously, the survival and mortality rates in these patients have mirrored the clinical trial accrual pattern, with little improvement compared with younger and older patients. This suggests that the relative lack of participation of adolescent and young adult patients in clinical trials has lessened their chances for as good an outcome as that enjoyed by patients in other age groups. Thus, increased availability of and participation in clinical trials is of paramount important if the current deficits in outcome in young adults and older adolescents are to be eliminated. Regardless of whether there is a causal relationship, the impact of low clinical trial activity on furthering our scientific knowledge and management of cancer during adolescence and early adulthood is detrimental. C1 [Ferrari, Andrea] Ist Nazl Tumori, Pediat Oncol Unit, I-20133 Milan, Italy. [Montello, Michael; Budd, Troy] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Bleyer, Archie] St Charles Hosp, Canc Treatment Ctr, Bend, OR USA. RP Ferrari, A (reprint author), Ist Nazl Tumori, Pediat Oncol Unit, Via G Venezian 1, I-20133 Milan, Italy. EM andrea.ferrari@istitutotumori.mi.it OI Ferrari, Andrea/0000-0002-4724-0517 NR 18 TC 58 Z9 60 U1 0 U2 1 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 MAY PY 2008 VL 50 IS 5 SU S BP 1101 EP 1104 DI 10.1002/pbc.21459 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 286CE UT WOS:000254822200005 PM 18360838 ER PT J AU Adams-Chapman, I Hansen, NI Stoll, BJ Higgins, R AF Adams-Chapman, Ira Hansen, Nellie I. Stoll, Barbara J. Higgins, Rose CA NICHD Research Network TI Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion SO PEDIATRICS LA English DT Article DE hydrocephalus; neuromotor outcome; prematurity ID INTRAVENTRICULAR HEMORRHAGE; VENTRICULAR DILATATION; SCHOOL-AGE; CEREBROSPINAL-FLUID; RANDOMIZED-TRIAL; PRETERM INFANTS; CHILDREN; GROWTH; BORN; PREVENTION AB OBJECTIVE. We aimed to evaluate neurodevelopmental and growth outcomes among extremely low birth weight infants who had severe intraventricular hemorrhage that required shunt insertion compared with infants without shunt insertion. METHODS. Infants who were born in 1993-2002 with birth weights of 401 to 1000 g were enrolled in a very low birth weight registry at medical centers that participate in the National Institute of Child Health and Human Development Neonatal Research Network, and returned for follow-up at 18 to 22 months' corrected age were studied. Eighty-two percent of survivors completed follow-up, and 6161 children were classified into 5 groups: group 1, no intraventricular hemorrhage/no shunt (n = 5163); group 2, intraventricular hemorrhage grade 3/no shunt (n = 459); group 3, intraventricular hemorrhage grade 3/shunt (n = 103); group 4, intraventricular hemorrhage grade 4/no shunt (n = 311); and group 5, intraventricular hemorrhage grade 4/shunt (n = 125). Group comparisons were evaluated with chi(2) and Wilcoxon tests, and regression models were used to compare outcomes after adjustment for covariates. RESULTS. Children with severe intraventricular hemorrhage and shunts had significantly lower scores on the Bayley Scales of Infant Development IIR compared with children with no intraventricular hemorrhage and with children with intraventricular hemorrhage of the same grade and no shunt. Infants with shunts were at increased risk for cerebral palsy and head circumference at the < 10th percentile at 18 months' adjusted age. Greatest differences were observed between children with shunts and those with no intraventricular hemorrhage on these outcomes. CONCLUSIONS. This large cohort study suggests that extremely low birth weight children with severe intraventricular hemorrhage that requires shunt insertion are at greatest risk for adverse neurodevelopmental and growth outcomes at 18 to 22 months compared with children with and without severe intraventricular hemorrhage and with no shunt. Long-term follow-up is needed to determine whether adverse outcomes persist or improve over time. C1 [Adams-Chapman, Ira; Stoll, Barbara J.] Emory Univ, Sch Med, Dept Pediat, Div Neonatol, Atlanta, GA 30303 USA. [Hansen, Nellie I.] RTI Int, Res Triangle Pk, NC USA. [Higgins, Rose] NICHHD, Ctr Res Mothers & Childrens, NIH, Bethesda, MD 20892 USA. RP Adams-Chapman, I (reprint author), Emory Univ, Sch Med, Dept Pediat, Div Neonatol, 46 Jesse Hill Jr Dr SE, Atlanta, GA 30303 USA. EM ira_adams-chapman@oz.ped.emory.edu RI Myers , Gary /I-4901-2013 OI Myers , Gary /0000-0003-4317-015X FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [M01 RR001032, M01 RR002172, M01 RR002635, M01 RR006022, M01 RR007122, M01 RR008084, M01 RR016587, M01 RR1032, M01 RR16587, M01 RR2172, M01 RR2635, M01 RR30, M01 RR39, M01 RR44, M01 RR6022, M01 RR633, M01 RR70, M01 RR7122, M01 RR750, M01 RR80, M01 RR8084, M01 RR997, UL1 RR024139, UL1 RR24139]; NICHD NIH HHS [U01 HD036790, U01 HD36790, U10 HD021364, U10 HD021373, U10 HD021385, U10 HD021397, U10 HD027851, U10 HD027851-19, U10 HD027853, U10 HD027856, U10 HD027871, U10 HD027880, U10 HD027904, U10 HD034167, U10 HD034216, U10 HD040461, U10 HD040492, U10 HD040498, U10 HD040521, U10 HD040689, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34216, U10 HD40461, U10 HD40492, U10 HD40498, U10 HD40521, U10 HD40689] NR 39 TC 71 Z9 73 U1 1 U2 4 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 MAY PY 2008 VL 121 IS 5 BP E1167 EP E1177 DI 10.1542/peds.2007-0423 PG 11 WC Pediatrics SC Pediatrics GA 295VL UT WOS:000255501900060 PM 18390958 ER PT J AU Kapogiannis, BG Soe, MM Nesheim, SR Sullivan, KM Abrams, E Farley, J Palumbo, P Koenig, LJ Bulterys, M AF Kapogiannis, Bill G. Soe, Minn M. Nesheim, Steven R. Sullivan, Kevin M. Abrams, Elaine Farley, John Palumbo, Paul Koenig, Linda J. Bulterys, Marc TI Trends in bacteremia in the pre- and post-highly active antiretroviral therapy era among HIV-infected children in the US Perinatal AIDS Collaborative Transmission Study (1986-2004) SO PEDIATRICS LA English DT Article DE pediatric HIV/AIDS; bacteremia incidence; HAART ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-DEFICIENCY-SYNDROME; INVASIVE PNEUMOCOCCAL INFECTIONS; BACTERIAL-INFECTIONS; INTRAVENOUS IMMUNOGLOBULIN; TYPE-1-INFECTED CHILDREN; UNINFECTED CHILDREN; ANTIBODY-RESPONSE; HAART ERA; DISEASE AB OBJECTIVE. HIV-infected children are at high risk for bacteremia. Highly active antiretroviral therapy has reduced rates of opportunistic infections; less is known about its effect on pediatric bacteremia rates. Thus, we sought to determine its impact on bacteremia incidence in HIV-infected children. METHODS. Children born during 1986-1998 were followed until 2004 in the Perinatal AIDS Collaborative Transmission Study. We determined the pre- and post-highly active antiretroviral therapy (before and after January 1, 1997) incidence of bacteremia among HIV-infected children and characterized the CD4% temporal declines and mortality among patients with and those without incident bacteremias. RESULTS. Among 364 children, 68 had 118 documented bacteremias, 97 before and 21 after January 1, 1997. Streptococcus pneumoniae constituted 56 (58%) pre- and 13 (62%) post-highly active antiretroviral therapy cases. The incidence rate ratio of bacteremias comparing post-versus pre-highly active antiretroviral therapy was 0.3 overall and 0.2, 0.2, and 0.4 among children aged 0 to 24, 25 to 48, and 49 to 72 months, respectively. Kaplan-Meier analysis for time to first bacteremia in children born during the pre- highly active antiretroviral therapy compared with the post-highly active antiretroviral therapy era revealed that 69% and 94%, respectively, remained bacteremia free at a median follow-up of 6 years. The Cox proportional hazards model also showed a significant reduction of bacteremias in the post-highly active antiretroviral therapy era, even after controlling for gender and race. Among children < 6 years of age, those who experienced bacteremia had faster temporal CD4% decline than those who never had bacteremia. Survival analysis revealed that HIV-infected children with bacteremia experienced higher overall mortality when controlling for gender, race, and clinic site. CONCLUSIONS. A significant decrease in bacteremia incidence and a prolongation in the time to first bacteremia incident were seen in the post-highly active antiretroviral therapy era. Children with a steeper decline of CD4 T cells were more likely to develop bacteremia. Children who experienced bacteremia had an associated higher mortality than their bacteremia-free counterparts. C1 [Kapogiannis, Bill G.; Nesheim, Steven R.] Emory Univ, Sch Med, Dept Pediat, Div Infect Dis, Atlanta, GA USA. [Kapogiannis, Bill G.] Emory Univ, Sch Med, Dept Med, Atlanta, GA USA. [Soe, Minn M.; Sullivan, Kevin M.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA USA. [Abrams, Elaine] Harlem Hosp Med Ctr, Dept Pediat, New York, NY 10037 USA. [Farley, John] Univ Maryland, Dept Pediat, Baltimore, MD 21201 USA. [Palumbo, Paul] Univ Med & Dent New Jersey, Dept Pediat, Newark, NJ 07103 USA. [Koenig, Linda J.; Bulterys, Marc] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV STD & TB Prevent, Atlanta, GA USA. RP Kapogiannis, BG (reprint author), NICHHD, Ctr Res Mothers & Children, Pediat Adolescent & Maternal AIDS Branch, 6100 Execut Blvd,Room 4B11J, Bethesda, MD 20892 USA. EM kapogiannisb@mail.nih.gov FU PHS HHS [U64/CCU404456, U64/CCU202219, U64/CCU306825, U64/CCU207228] NR 54 TC 14 Z9 14 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAY PY 2008 VL 121 IS 5 BP E1229 EP E1239 DI 10.1542/peds.2007-0871 PG 11 WC Pediatrics SC Pediatrics GA 295VL UT WOS:000255501900069 PM 18450865 ER PT J AU Tate, JE Simonsen, L Viboud, C Steiner, C Patel, MM Curns, AT Parashar, UD AF Tate, Jacqueline E. Simonsen, Lone Viboud, Cecile Steiner, Claudia Patel, Manish M. Curns, Aaron T. Parashar, Umesh D. TI Trends in intussusception hospitalizations among US infants, 1993-2004: Implications for monitoring the safety of the new rotavirus vaccination program SO PEDIATRICS LA English DT Article DE intussusception; rotavirus vaccine; vaccine safety monitoring ID UNITED-STATES; ADENOVIRUS INFECTION; CHILDREN; CHILDHOOD; DIARRHEA; EPIDEMIOLOGY; ASSOCIATION; MANAGEMENT; AUSTRALIA; AGE AB OBJECTIVES. In 2006, a new rotavirus vaccine was recommended for routine immunization of US infants. Because a previous rotavirus vaccine was withdrawn in 1999 after it was associated with intussusception, monitoring for this adverse event with the new vaccine is important. The objectives of this study were to assess intussusception hospitalizations trends among US infants for 1993 to 2004; provide estimates of hospitalization rates for intussusception for 2002-2004; and assess variations in background rates by age, race/ethnicity, and surgical management. METHODS. By using the Healthcare Cost and Utilization Project's State Inpatient Database that captures US hospital discharges from 16 states representing 49% of the birth cohort during 1993-2004 and from 35 states representing 85% of the birth cohort in 2002-2004, we examined hospitalizations among infants (< 12 months of age) with an International Classification of Disease, Ninth Revision, Clinical Modification code for intussusception (560.0). Incidence rates were calculated by using census data, and rate ratios with 95% confidence intervals were calculated by using Poisson regression data. RESULTS. Annual intussusception hospitalization rates declined 25% from 1993 to 2004 but have remained stable at similar to 35 cases per 100 000 infants since 2000. Rates were very low for infants younger than 9 weeks (< 5 per 100 000) then increased rapidly, peaking at similar to 62 per 100 000 at 26 to 29 weeks, before declining gradually to 26 per 100 000 at 52 weeks. Compared with rates among non-Hispanic white infants (27 per 100 000), rates were greater among non-Hispanic black infants (37 per 100 000) and Hispanic infants (45 per 100 000); however, rates did not differ by race/ethnicity for infants who were younger than 16 weeks. CONCLUSIONS. This assessment of US hospitalizations provides up-to-date and nationally representative prevaccine rates of intussusception. Because rates varied almost 12-fold by week of age and to a lesser extent by race/ethnicity during the age of vaccination, adjusting baseline rates to reflect the demographics of the vaccinated population will be crucial for assessing risk for intussusception after rotavirus vaccination. C1 [Tate, Jacqueline E.; Patel, Manish M.; Curns, Aaron T.; Parashar, Umesh D.] Ctr Dis Control & Prevent, Div Viral Dis, Epidemiol Branch, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. [Simonsen, Lone] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Viboud, Cecile] Fogarty Int Ctr, NIH, Bethesda, MD USA. [Steiner, Claudia] Agcy Healthcare Res & Qual, Ctr Delivery Org & Markets, Rockville, MD USA. RP Tate, JE (reprint author), 1600 Clifton Rd NE,MS-A47, Atlanta, GA 30333 USA. EM jqt8@cdc.gov OI Simonsen, Lone/0000-0003-1535-8526 FU Intramural NIH HHS [Z99 TW999999] NR 38 TC 52 Z9 52 U1 0 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAY PY 2008 VL 121 IS 5 BP E1125 EP E1132 DI 10.1542/peds.2007-1590 PG 8 WC Pediatrics SC Pediatrics GA 295VL UT WOS:000255501900054 PM 18450856 ER PT J AU Noel, P Gan, W Kiley, J AF Noel, Patricia Gan, Weiniu Kiley, James TI Molecular phenotyping for severe asthma SO PERSONALIZED MEDICINE LA English DT Article ID EXHALED BREATH CONDENSATE; GENE-EXPRESSION AB Asthma is a heterogeneous disorder presenting with many phenotypes. Precise phenotypic definition has eluded the medical research community for years, despite recognition of different disease subtypes. Brasier and colleagues sought to discriminate asthma phenotypes on the basis of cytokine profiles in bronchoalveolar lavage samples from 84 patients with mild-moderate and severe asthma. Their results demonstrated that this molecular phenotyping approach could be applied to categorizing asthma into subtypes based on pathobiology. This article will discuss the potential advantages of applying molecular phenotyping approaches to asthma and lung disease in general in the perspective of personalized medicine. C1 [Noel, Patricia; Gan, Weiniu; Kiley, James] NHLBI, Div Lung Dis, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Kiley, J (reprint author), NHLBI, Div Lung Dis, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM kileyj@nhlbi.nih.gov NR 15 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 MAY PY 2008 VL 5 IS 3 BP 301 EP 304 DI 10.2217/17410541.5.3.301 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 304QU UT WOS:000256124800020 ER PT J AU Meletiadis, J Chanock, S Walsh, TJ AF Meletiadis, Joseph Chanock, Stephen Walsh, Thomas J. TI Defining targets for investigating the pharmacogenomics of adverse drug reactions to antifungal agents SO PHARMACOGENOMICS LA English DT Review DE antifungal drug; mechanisms of toxicity; pharmacogenomics; SNP ID GENOME-WIDE ASSOCIATION; LIPOSOMAL AMPHOTERICIN-B; HUMAN SERUM-ALBUMIN; INVASIVE FUNGAL-INFECTIONS; P-GLYCOPROTEIN EXPRESSION; N-DEACETYL KETOCONAZOLE; HUMAN LIVER-MICROSOMES; LIPID TRANSFER PROTEIN; GENETIC POLYMORPHISMS; BREAST-CANCER AB Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies. C1 [Meletiadis, Joseph; Chanock, Stephen; Walsh, Thomas J.] NCI, NIH, Pediat Oncol Branch, Bethesda, MD 20814 USA. [Meletiadis, Joseph] Attikon Univ, Gen Hosp, Lab Clin Microbiol, Athens 12462, Greece. RP Meletiadis, J (reprint author), NCI, NIH, Pediat Oncol Branch, Bethesda, MD 20814 USA. EM jmeletiadis@med.uoa.gr NR 209 TC 10 Z9 10 U1 1 U2 6 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 MAY PY 2008 VL 9 IS 5 BP 561 EP 584 DI 10.2217/14622416.9.5.561 PG 24 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 331DS UT WOS:000257993500013 PM 18466103 ER PT J AU Brenner, M Hearing, VJ AF Brenner, Michaela Hearing, Vincent J. TI The protective role of melanin against UV damage in human skin SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Review ID INDUCED DNA-DAMAGE; CULTURED HUMAN MELANOCYTES; CYCLOBUTANE PYRIMIDINE DIMERS; ULTRAVIOLET-A RADIATION; SQUAMOUS-CELL CARCINOMA; TUMOR-NECROSIS-FACTOR; IN-SITU REPAIR; HUMAN-EPIDERMIS; VITAMIN-D; ENHANCES MELANOGENESIS AB Human skin is repeatedly exposed to UVR that influences the function and survival of many cell types and is regarded as the main causative factor in the induction of skin cancer. It has been traditionally believed that skin pigmentation is the most important photoprotective factor, as melanin, besides functioning as a broadband UV absorbent, has antioxidant and radical scavenging properties. Besides, many epidemiological studies have shown a lower incidence for skin cancer in individuals with darker skin compared to those with fair skin. Skin pigmentation is of great cultural and cosmetic importance, yet the role of melanin in photoprotection is still controversial. This article outlines the major acute and chronic effects of UVR on human skin, the properties of melanin, the regulation of pigmentation and its effect on skin cancer prevention. C1 [Brenner, Michaela; Hearing, Vincent J.] NIH, Natl Canc Inst, Cell Biol Lab, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NIH, Natl Canc Inst, Cell Biol Lab, Bldg 10, Bethesda, MD 20892 USA. EM hearingv@nih.gov FU Intramural NIH HHS [Z01 BC010784-01] NR 134 TC 240 Z9 254 U1 8 U2 78 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAY-JUN PY 2008 VL 84 IS 3 BP 539 EP 549 DI 10.1111/j.1751-1097.2007.00226.x PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 296BL UT WOS:000255518400002 PM 18435612 ER PT J AU Chodick, G Kleinerman, RA Linet, MS Fears, T Kwok, RK Kimlin, MG Alexander, BH Freedman, DM AF Chodick, Gabriel Kleinerman, Ruth A. Linet, Martha S. Fears, Tom Kwok, Richard K. Kimlin, Michael G. Alexander, Bruce H. Freedman, Daryl M. TI Agreement between diary records of time spent outdoors and personal ultraviolet radiation dose measurements SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID SOLAR UVR EXPOSURES; SUN EXPOSURE; RADIOLOGIC TECHNOLOGISTS; CHILDREN; RELIABILITY; DOSIMETRY; CANCER; QUESTIONNAIRE; ADOLESCENTS; VALIDITY AB Little is known about the validity of self-recorded sun exposure and time spent outdoors for epidemiological research. The aims of the current study were to assess how well participants' self-recorded time outdoors compared to objective measurements of personal UVR doses. We enrolled 124 volunteers aged 40 and above who were identified from targeted subgroups of US radiologic technologists. Each volunteer was instructed to wear a polysulfone (PS) dosimeter to measure UVR on their left shoulder and to complete a daily activity diary, listing all activities undertaken in each 30 min interval between 9:00 A.M. and 5:00 P.M. during a 7 day period. In a linear regression model, self-recorded daily time spent outdoors was associated with an increase of 8.2% (95% CI: 7.3-9.2%) in the personal UVR exposure with every hour spent outdoors. The amount of self-recorded total daily time spent outdoors was better correlated with the personal daily UVR dose for activities conducted near noon time compared to activities conducted in the morning or late afternoon, and for activities often performed in the sun (e.g. gardening or recreation activities) compared to other outdoor activities (e.g. driving) in which the participant is usually shaded from the sun. Our results demonstrated a significant correlation between diary records of time spent outdoors with objective personal UVR dose measurements. C1 [Chodick, Gabriel; Kleinerman, Ruth A.; Linet, Martha S.; Freedman, Daryl M.] NIH, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NCI,DHHS, Bethesda, MD 20892 USA. [Chodick, Gabriel] Maccabi Healthcare Serv, Tel Aviv, Israel. [Fears, Tom] NIH, Biostat Branch, Div Canc Epidemiol & Genet, NCI,DHHS, Bethesda, MD USA. [Kimlin, Michael G.] Queensland Univ Technol, Fac Hlth, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia. [Alexander, Bruce H.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN USA. RP Chodick, G (reprint author), NIH, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NCI,DHHS, Bethesda, MD 20892 USA. EM hodik_g@mac.org.il RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Kleinerman, Ruth/0000-0001-7415-2478; Kimlin, Michael/0000-0002-9536-8646 FU Intramural NIH HHS [ZIA CP010133-18] NR 30 TC 21 Z9 22 U1 0 U2 6 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAY-JUN PY 2008 VL 84 IS 3 BP 713 EP 718 DI 10.1111/j.1751-1097.2007.00236.x PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 296BL UT WOS:000255518400025 PM 18435619 ER PT J AU Akimov, SA Frolov, VAJ Kuzmin, PI Zimmerberg, J Chizmadzhev, YA Cohen, FS AF Akimov, Sergey A. Frolov, Vladimir A. J. Kuzmin, Peter I. Zimmerberg, Joshua Chizmadzhev, Yuri A. Cohen, Fredric S. TI Domain formation in membranes caused by lipid wetting of protein SO PHYSICAL REVIEW E LA English DT Article ID ATOMIC-FORCE MICROSCOPY; LINE TENSION; PHOSPHOLIPID-MEMBRANES; CAPILLARY CONDENSATION; CYLINDRICAL INCLUSIONS; BENDING ELASTICITIES; BIOLOGICAL-MEMBRANES; BILAYER-MEMBRANES; PHASE-TRANSITIONS; LATERAL DIFFUSION AB Formation of rafts and other domains in cell membranes is considered as wetting of proteins by lipids. The membrane is modeled as a continuous elastic medium. Thermodynamic functions of the lipid films that wet proteins are calculated using a mean-field theory of liquid crystals as adapted to biomembranes. This approach yields the conditions necessary for a macroscopic wetting film to form; its thickness could also be determined. It is shown that films of macroscopic thicknesses form around large (tens nanometers in diameter) lipid-protein aggregates; only thin adsorption films form around single proteins or small complexes. The means by which wetting films can facilitate the merger of these aggregates is considered. It is shown that a wetting film prevents a protein from leaving an aggregate. Using experimentally derived values of elastic moduli and spontaneous curvatures as well as height mismatch between aggregates and bulk membrane, we obtained numerical results, which can be compared with the experimental data. C1 [Akimov, Sergey A.; Frolov, Vladimir A. J.; Kuzmin, Peter I.; Chizmadzhev, Yuri A.] Russian Acad Sci, Frumkin Inst Phys Chem & Electrochem, Lab Bioelectrochem, Moscow 119991, Russia. [Akimov, Sergey A.; Frolov, Vladimir A. J.; Kuzmin, Peter I.; Zimmerberg, Joshua; Chizmadzhev, Yuri A.] NICHHD, Lab Cellular & Mol Biophys, Natl Inst Hlth, Bethesda, MD 20892 USA. [Cohen, Fredric S.] Rush Univ, Med Ctr, Dept Physiol & Mol Biophys, Chicago, IL 60612 USA. RP Akimov, SA (reprint author), Russian Acad Sci, Frumkin Inst Phys Chem & Electrochem, Lab Bioelectrochem, Moscow 119991, Russia. RI Chizmadzhev, Yuri/L-1984-2013; Akimov, Sergey/L-2001-2013; Akimov, Sergey/I-6432-2015 FU Intramural NIH HHS [Z01 HD001415-18]; NIGMS NIH HHS [R01 GM066837] NR 90 TC 8 Z9 9 U1 1 U2 5 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAY PY 2008 VL 77 IS 5 AR 051901 DI 10.1103/PhysRevE.77.051901 PN 1 PG 17 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 315MZ UT WOS:000256885400088 PM 18643096 ER PT J AU Kim, YC Fisher, ME AF Kim, Young C. Fisher, Michael E. TI Charge fluctuations and correlation lengths in finite electrolytes SO PHYSICAL REVIEW E LA English DT Article ID DEBYE-HUCKEL THEORY; IONIC FLUIDS; DENSITY-FLUCTUATIONS; COULOMB-SYSTEMS; CRITICALITY; LEBOWITZ; PHASE AB Fluctuations of the charge Q(Lambda) inside a subdomain Lambda embedded in an electrolyte contained in a finite cubical box of dimensions L X L X L with periodic boundary conditions are investigated. When A is an L X L "slab" of width W, asymptotically exact expressions for the mean-square fluctuation < Q(Lambda)(2)> are obtained in terms of the Lebowitz length xi(L)(T,rho) and of the "true" or asymptotic screening/decay length xi(Z,infinity)(T,rho) together, when the charge correlation decay is oscillatory, with the characteristic wavelength lambda(Z)(T,rho). In finite systems, the normalized charge fluctuations exhibit threefold scaling behavior in the ratios xi(Z,infinity)/W, W/lambda(Z), and W/L. This enables one to estimate all the correlation lengths away from criticality quite precisely from finite-size grand canonical Monte Carlo simulations. The results for xi(Z,infinity), lambda(Z), and xi(L) are presented for the restricted primitive model or hard-sphere 1:1 electrolyte for densities rho less than or similar to 1.3 rho(c), and T greater than or similar to 4T(c). The fitted values compare favorably with the expectations of generalized Debye-Hijckel theory [Lee and Fisher, Europhys. Lett. 39, 611 (1997)]; specifically, if xi(D)alpha(T/rho)(1/2) is the Debye length, we find xi(Z,infinity) < xi(D)< xi(L), although, since ion-pairing is neglected, the charge oscillations set in only for densities similar to 1.9 times larger than predicted. C1 [Kim, Young C.; Fisher, Michael E.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Kim, YC (reprint author), NIDDK, Chem Phys Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM xpectnil@umd.edu NR 36 TC 2 Z9 2 U1 1 U2 4 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAY PY 2008 VL 77 IS 5 AR 051502 DI 10.1103/PhysRevE.77.051502 PN 1 PG 7 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 315MZ UT WOS:000256885400061 PM 18643069 ER PT J AU Zhang, J Masciocchi, M Lewis, D Sun, W Liu, A Wang, Y AF Zhang, J. Masciocchi, M. Lewis, D. Sun, W. Liu, A. Wang, Y. TI Placental anti-oxidant gene polymorphisms, enzyme activity, and oxidative stress in preeclampsia SO PLACENTA LA English DT Article DE placenta; polymorphism; oxidative stress; preeclampsia ID MITOCHONDRIAL TARGETING SEQUENCE; POLYMERASE CHAIN-REACTION; MESSENGER-RNA EXPRESSION; SUPEROXIDE-DISMUTASE; BREAST-CANCER; IN-VIVO; GLUTATHIONE; RISK; ASSOCIATION; WOMEN AB The etiology and pathophysiology of preeclampsia are not fully understood. However, oxidative stress has been strongly linked to the occurrence of this multi-system disease. This has led to many theories of the pathogenesis of preeclampsia involving placental oxidative stress. In this study, we hypothesized that polymorphisms of anti-oxidant genes in the placental tissue contributed to susceptibility to preeclampsia. Polymorphisms in copper/zinc superoxide dismutase (CuZn-SOD), manganese superoxide dismutase (MnSOD), glutathione-S-transferase M1 (GSTM1), and glutathione-S-transferase T1 (GSTT1) in the umbilical cord tissue were assayed by polymerase chain reaction (PCR) in 23 nulliparous preeclampsia cases and 32 nulliparous normotensive controls. Corresponding enzyme activity levels and an oxidative stress biomarker (8-isoprostane) of the placental tissue were also measured. In addition, maternal plasma 8-isoprostane levels were also determined. Our results showed that no significant differences in polymorphism frequency of the tested genes, enzyme activity levels or 8-isoprostane levels in the placental tissue were detected between the cases and controls. However, maternal plasma 8-isoprostane level was significantly higher in the cases than in the controls (105.8 vs. 27.9 pg/ml, p = 0.03). In conclusion, our study showed that polymorphisms of CuZn-SOD, MnSOD, GSTM1 and GSTT1 in the placental tissue were not associated with preeclampsia. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Zhang, J.; Masciocchi, M.; Sun, W.; Liu, A.] NICHHD, NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Lewis, D.; Wang, Y.] Louisiana State Univ, Hlth Sci Ctr, Dept Obstet & Gynecol, Shreveport, LA 71130 USA. RP Zhang, J (reprint author), NICHHD, NIH, Div Epidemiol Stat & Prevent Res, Bldg 6100 Room 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov; mmasciocchi@hmc.psu.edu; dlewi1@lsuhsc.edu; sunw@mail.nih.gov; liua@mail.nih.gov; ywang1@lsuhsc.edu OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS [NIH0010199548]; PHS HHS [NIH0010199548] NR 35 TC 17 Z9 21 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD MAY PY 2008 VL 29 IS 5 BP 439 EP 443 DI 10.1016/j.placenta.2008.02.012 PG 5 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 299PN UT WOS:000255767600009 PM 18387669 ER PT J AU Sugase-Miyamoto, Y Liu, Z Wiener, MC Optican, LM Richmond, BJ AF Sugase-Miyamoto, Yasuko Liu, Zheng Wiener, Matthew C. Optican, Lance M. Richmond, Barry J. TI Short-term memory trace in rapidly adapting synapses of inferior temporal cortex SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID VISUAL WORKING-MEMORY; DORSOLATERAL PREFRONTAL CORTEX; CORTICAL NETWORK MODEL; PERIRHINAL CORTEX; RHESUS-MONKEYS; INFEROTEMPORAL CORTEX; STIMULUS ASSOCIATION; DELAYED ALTERNATION; RECOGNITION MEMORY; NEURONAL CORRELATE AB Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory. C1 [Sugase-Miyamoto, Yasuko; Liu, Zheng; Richmond, Barry J.] NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sugase-Miyamoto, Yasuko] Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki, Japan. [Wiener, Matthew C.] Merck Res Labs, Dept Comp Sci & Appl Math, Rahway, NJ USA. [Optican, Lance M.] NEI, Sensorimotor Res Lab, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sugase-Miyamoto, Y (reprint author), NIMH, Neuropsychol Lab, NIH, Dept Hlth & Human Serv, Bldg 9, Bethesda, MD 20892 USA. EM bjr@ln.nimh.nih.gov FU Intramural NIH HHS NR 60 TC 28 Z9 28 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAY PY 2008 VL 4 IS 5 AR e1000073 DI 10.1371/journal.pcbi.1000073 PG 16 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 315GM UT WOS:000256866400014 PM 18464917 ER PT J AU Han, JL Kraft, P Nan, H Guo, Q Chen, C Qureshi, A Hankinson, SE Hu, FB Duffy, DL Zhao, ZZ Martin, NG Montgomery, GW Hayward, NK Thomas, G Hoover, RN Chanock, S Hunter, DJ AF Han, Jiali Kraft, Peter Nan, Hongmei Guo, Qun Chen, Constance Qureshi, Abrar Hankinson, Susan E. Hu, Frank B. Duffy, David L. Zhao, Zhen Zhen Martin, Nicholas G. Montgomery, Grant W. Hayward, Nicholas K. Thomas, Gilles Hoover, Robert N. Chanock, Stephen Hunter, David J. TI A genome-wide association study identifies novel alleles associated with hair color and skin pigmentation SO PLOS GENETICS LA English DT Article ID POSTMENOPAUSAL BREAST-CANCER; REGULATORY FACTOR FAMILY; RISK; GENE; POLYMORPHISMS; HAPLOTYPE; HUMANS; STRATIFICATION; REFLECTANCE; POPULATION AB We conducted a multi-stage genome-wide association study of natural hair color in more than 10,000 men and women of European ancestry from the United States and Australia. An initial analysis of 528,173 single nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified IRF4 and SLC24A4 as loci highly associated with hair color, along with three other regions encompassing known pigmentation genes. We confirmed these associations in 7,028 individuals from three additional studies. Across these four studies, SLC24A4 rs12896399 and IRF4 rs12203592 showed strong associations with hair color, with p= 6.0 x 10(-62) and p= 7.46 x 10(-127), respectively. The IRF4 SNP was also associated with skin color (p = 6.2 x 10(-14)), eye color (p = 6.1 x 10(-13)), and skin tanning response to sunlight (p = 3.9 x 10(-89)). A multivariable analysis pooling data from the initial GWAS and an additional 1,440 individuals suggested that the association between rs12203592 and hair color was independent of rs1540771, a SNP between the IRF4 and EXOC2 genes previously found to be associated with hair color. After adjustment for rs12203592, the association between rs1540771 and hair color was not significant (p = 0.52). One variant in the MATP gene was associated with hair color. A variant in the HERC2 gene upstream of the OCA2 gene showed the strongest and independent association with hair color compared with other SNPs in this region, including three previously reported SNPs. The signals detected in a region around the MC1R gene were explained by MC1R red hair color alleles. Our results suggest that the IRF4 and SLC24A4 loci are associated with human hair color and skin pigmentation. C1 [Han, Jiali; Nan, Hongmei; Guo, Qun; Qureshi, Abrar; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Han, Jiali; Nan, Hongmei; Guo, Qun; Qureshi, Abrar; Hankinson, Susan E.; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Han, Jiali; Kraft, Peter; Nan, Hongmei; Guo, Qun; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Kraft, Peter; Nan, Hongmei; Hu, Frank B.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chen, Constance; Thomas, Gilles; Hoover, Robert N.; Chanock, Stephen; Hunter, David J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chen, Constance] BioInformed, Gaithersburg, MD USA. [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Duffy, David L.; Zhao, Zhen Zhen; Martin, Nicholas G.; Montgomery, Grant W.; Hayward, Nicholas K.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Hunter, David J.] Broad Inst Harvard, Cambridge, MA USA. [Hunter, David J.] MIT, Cambridge, MA 02139 USA. RP Han, JL (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 75 Francis St, Boston, MA 02115 USA. EM dhunter@hsph.harvard.edu RI hayward, nicholas/C-1367-2015; Montgomery, Grant/B-7148-2008; Duffy, David/B-7392-2013 OI hayward, nicholas/0000-0003-4760-1033; Montgomery, Grant/0000-0002-4140-8139; Martin, Nicholas/0000-0003-4069-8020; Duffy, David/0000-0001-7227-632X FU NCI NIH HHS [P01 CA087969, CA049449, CA087969, CA098233, CA128080, CA132175, CA88363, R01 CA049449, R01 CA088363, R03 CA128080, R03 CA132175, U01 CA049449, U01 CA098233] NR 31 TC 191 Z9 199 U1 7 U2 29 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2008 VL 4 IS 5 AR e1000074 DI 10.1371/journal.pgen.1000074 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 315HL UT WOS:000256869100014 PM 18483556 ER PT J AU Melzer, D Perry, JRB Hernandez, D Corsi, AM Stevens, K Rafferty, I Lauretani, F Murray, A Gibbs, JR Paolisso, G Rafiq, S Simon-Sanchez, J Lango, H Scholz, S Weedon, MN Arepalli, S Rice, N Washecka, N Hurst, A Britton, A Henley, W van de Leemput, J Li, RL Newman, AB Tranah, G Harris, T Panicker, V Dayan, C Bennett, A McCarthy, MI Ruokonen, A Jarvelin, MR Guralnik, J Bandinelli, S Frayling, TM Singleton, A Ferrucci, L AF Melzer, David Perry, John R. B. Hernandez, Dena Corsi, Anna-Maria Stevens, Kara Rafferty, Ian Lauretani, Fulvio Murray, Anna Gibbs, J. Raphael Paolisso, Giuseppe Rafiq, Sajjad Simon-Sanchez, Javier Lango, Hana Scholz, Sonja Weedon, Michael N. Arepalli, Sampath Rice, Neil Washecka, Nicole Hurst, Alison Britton, Angela Henley, William van de Leemput, Joyce Li, Rongling Newman, Anne B. Tranah, Greg Harris, Tamara Panicker, Vijay Dayan, Colin Bennett, Amanda McCarthy, Mark I. Ruokonen, Aimo Jarvelin, Marjo-Riitta Guralnik, Jack Bandinelli, Stefania Frayling, Timothy M. Singleton, Andrew Ferrucci, Luigi TI A genome-wide association study identifies protein quantitative trait loci (pQTLs) SO PLOS GENETICS LA English DT Article ID HUMAN GENE-EXPRESSION; MENDELIAN RANDOMIZATION; COMMON VARIANT; BIRTH COHORT; POLYMORPHISMS; RECEPTOR; DISEASE; CANCER; YEAST; RISK AB There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts-cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8 x 10(-57)), CCL4L1 (p = 3.9 x 10(-21)), IL18 (p = 6.8 x 10(-13)), LPA (p = 4.4 x 10(-10)), GGT1 (p = 1.5 x 10(-7)), SHBG (p = 3.1 x 10(-7)), CRP (p = 6.4 x 10(-6)) and IL1RN (p = 7.3 x 10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8 x 10(-40)), but this finding was not present when TNF-alpha was measured using a different assay, or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. C1 [Melzer, David; Stevens, Kara; Murray, Anna; Rafiq, Sajjad; Rice, Neil; Hurst, Alison] Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Dept Epidemiol & Publ Hlth, Exeter EX4 4QJ, Devon, England. [Hernandez, Dena; Rafferty, Ian; Gibbs, J. Raphael; Simon-Sanchez, Javier; Scholz, Sonja; Arepalli, Sampath; Washecka, Nicole; Britton, Angela; van de Leemput, Joyce] NIA, Neurogenet Lab, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Corsi, Anna-Maria; Lauretani, Fulvio] Univ Florence, IOT, Tuscany Reg Hlth Agcy, Florence, Italy. [Corsi, Anna-Maria; Lauretani, Fulvio] Univ Florence, Dept Med & Surg Crit Care, Florence, Italy. [Paolisso, Giuseppe] Univ Naples 2, Dept Geriatr Med & Metab Dis, Naples, Italy. [Henley, William] Univ Plymouth, Sch Math & Stat, Plymouth PL4 8AA, Devon, England. [Li, Rongling] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Li, Rongling] Univ Tennessee, Hlth Sci Ctr, Coll Med, Ctr Genom & Bioinformat, Memphis, TN USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Med, Pittsburgh, PA USA. [Tranah, Greg] Calif Pacific Med Ctr, Res Inst, San Francisco Coordinating Ctr, San Francisco, CA USA. [Harris, Tamara; Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Panicker, Vijay; Dayan, Colin] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol, Avon, England. [Bennett, Amanda; McCarthy, Mark I.] Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [McCarthy, Mark I.] Wellcome Trust Ctr Human Genet, Oxford, England. [Ruokonen, Aimo] Univ Oulu, Dept Clin Chem, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Dept Publ Hlth Sci & Gen Practice, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London, England. [Bandinelli, Stefania] Geriatr Unit, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Melzer, D (reprint author), Univ Exeter, Peninsula Coll Med & Dent, Inst Biomed & Clin Sci, Dept Epidemiol & Publ Hlth, Exeter EX4 4QJ, Devon, England. EM tim.frayling@pms.ac.uk RI Singleton, Andrew/C-3010-2009; Gibbs, J. Raphael/A-3984-2010; Perez , Claudio Alejandro/F-8310-2010; Lango Allen, Hana/G-9026-2012; Newman, Anne/C-6408-2013; Lauretani, Fulvio/K-5115-2016; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Lango Allen, Hana/0000-0002-7803-8688; Newman, Anne/0000-0002-0106-1150; Panicker, Vijay/0000-0003-1551-8411; Dayan, Colin/0000-0002-6557-3462; Murray, Anna/0000-0002-2351-2522; Rafiq, Sajjad/0000-0003-4873-4540; Paolisso, Giuseppe/0000-0002-2137-455X; Lauretani, Fulvio/0000-0002-5287-9972; Melzer, David/0000-0002-0170-3838; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Scholz, Sonja/0000-0002-6623-0429 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01 AG024233, R01 AG24233-01] NR 48 TC 213 Z9 219 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2008 VL 4 IS 5 AR e1000072 DI 10.1371/journal.pgen.1000072 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 315HL UT WOS:000256869100020 PM 18464913 ER PT J AU Taylor, KE Remmers, EF Lee, AT Ortmann, WA Plenge, RM Tian, C Chung, SA Nititham, J Hom, G Kao, AH Demirci, FY Kamboh, MI Petri, M Manzi, S Kastner, DL Seldin, MF Gregersen, PK Behrens, TW Criswell, LA AF Taylor, Kimberly E. Remmers, Elaine F. Lee, Annette T. Ortmann, Ward A. Plenge, Robert M. Tian, Chao Chung, Sharon A. Nititham, Joanne Hom, Geoffrey Kao, Amy H. Demirci, F. Yesim Kamboh, M. Ilyas Petri, Michelle Manzi, Susan Kastner, Daniel L. Seldin, Michael F. Gregersen, Peter K. Behrens, Timothy W. Criswell, Lindsey A. TI Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus SO PLOS GENETICS LA English DT Article ID RHEUMATOID-ARTHRITIS; PTPN22; POPULATION; COHORT; RISK AB Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-1 errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10 216). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p < 10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p < 10(-11)), and age at diagnosis <30 years (MAF = 33.8%, OR = 1.77, p < 10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p < 10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease. C1 [Taylor, Kimberly E.; Chung, Sharon A.; Nititham, Joanne; Criswell, Lindsey A.] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthritis, San Francisco, CA 94143 USA. [Remmers, Elaine F.; Kastner, Daniel L.] NIAMSD, Bethesda, MD 20892 USA. [Lee, Annette T.; Gregersen, Peter K.] N Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. [Ortmann, Ward A.; Hom, Geoffrey; Behrens, Timothy W.] Genentech Inc, San Francisco, CA 94080 USA. [Plenge, Robert M.] Broad Inst Harvard, Cambridge, MA USA. [Plenge, Robert M.] MIT, Cambridge, MA 02139 USA. [Plenge, Robert M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Cambridge, MA 02138 USA. [Tian, Chao; Seldin, Michael F.] Univ Calif Davis, Davis, CA 95616 USA. [Kao, Amy H.; Demirci, F. Yesim; Kamboh, M. Ilyas; Manzi, Susan] Univ Pittsburgh, Pittsburgh, PA USA. [Petri, Michelle] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Taylor, KE (reprint author), Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthritis, San Francisco, CA 94143 USA. EM lindsey.criswell@ucsf.edu OI Demirci, F. Yesim/0000-0001-6907-9843; Kamboh, M. Ilyas/0000-0002-3453-1438 FU Intramural NIH HHS; NCRR NIH HHS [5-M01-RR-00079, M01 RR000052, M01 RR000079, MOI-RR 00052]; NHLBI NIH HHS [HL54900, HL74165, HL88648, R01 HL054900, R01 HL074165, R01 HL088648]; NIAID NIH HHS [N01 AI95386, N01AI95386]; NIAMS NIH HHS [K23 AR051044, 2R01 AR046588 05A1, AR 43727, AR050267, K23 AR51044-01, K24 AR002175, K24 AR02175, R01 AR-44804, R01 AR043727, R01 AR046588, R01 AR050267, R01 AR052300] NR 24 TC 96 Z9 101 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2008 VL 4 IS 5 AR e1000084 DI 10.1371/journal.pgen.1000084 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 315HL UT WOS:000256869100005 PM 18516230 ER PT J AU Zeng, HK Horie, K Madisen, L Pavlova, MN Gragerova, G Rohde, AD Schimpf, BA Liang, YQ Ojala, E Kramer, F Roth, P Slobodskaya, O Dolka, I Southon, EA Tessarollo, L Bornfeldt, KE Gragerov, A Pavlakis, GN Gaitanaris, GA AF Zeng, Hongkui Horie, Kyoji Madisen, Linda Pavlova, Maria N. Gragerova, Galina Rohde, Alex D. Schimpf, Brian A. Liang, Yuqiong Ojala, Ethan Kramer, Farah Roth, Patricia Slobodskaya, Olga Dolka, Io Southon, Eileen A. Tessarollo, Lino Bornfeldt, Karin E. Gragerov, Alexander Pavlakis, George N. Gaitanaris, George A. TI An inducible and reversible mouse genetic rescue system SO PLOS GENETICS LA English DT Article ID APOE-DEFICIENT MICE; BONE-MARROW-TRANSPLANTATION; MAMMALIAN-CELLS; APOLIPOPROTEIN-E; TRANSGENIC MICE; SEVERE HYPERCHOLESTEROLEMIA; REGULATED EXPRESSION; RNA INTERFERENCE; ATHEROSCLEROSIS; REGRESSION AB Inducible and reversible regulation of gene expression is a powerful approach for uncovering gene function. We have established a general method to efficiently produce reversible and inducible gene knockout and rescue in mice. In this system, which we named iKO, the target gene can be turned on and off at will by treating the mice with doxycycline. This method combines two genetically modified mouse lines: a) a KO line with a tetracycline-dependent transactivator replacing the endogenous target gene, and b) a line with a tetracycline-inducible cDNA of the target gene inserted into a tightly regulated (TIGRE) genomic locus, which provides for low basal expression and high inducibility. Such a locus occurs infrequently in the genome and we have developed a method to easily introduce genes into the TIGRE site of mouse embryonic stem (ES) cells by recombinase-mediated insertion. Both KO and TIGRE lines have been engineered for high-throughput, large-scale and cost-effective production of iKO mice. As a proof of concept, we have created iKO mice in the apolipoprotein E (ApoE) gene, which allows for sensitive and quantitative phenotypic analyses. The results demonstrated reversible switching of ApoE transcription, plasma cholesterol levels, and atherosclerosis progression and regression. The iKO system shows stringent regulation and is a versatile genetic system that can easily incorporate other techniques and adapt to a wide range of applications. C1 [Zeng, Hongkui; Madisen, Linda; Pavlova, Maria N.; Gragerova, Galina; Rohde, Alex D.; Schimpf, Brian A.; Liang, Yuqiong; Ojala, Ethan; Gragerov, Alexander; Gaitanaris, George A.] Omeros Corp, Seattle, WA USA. [Horie, Kyoji; Roth, Patricia; Slobodskaya, Olga; Dolka, Io; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21701 USA. [Bornfeldt, Karin E.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Southon, Eileen A.; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Zeng, HK (reprint author), Allen Inst Brain Sci, Seattle, WA USA. EM pavlakis@ncifcrf.gov; ggaitanaris@omeros.com FU Intramural NIH HHS; NHLBI NIH HHS [HL076719, R01 HL076719] NR 40 TC 21 Z9 22 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD MAY PY 2008 VL 4 IS 5 AR e1000069 DI 10.1371/journal.pgen.1000069 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 315HL UT WOS:000256869100017 PM 18464897 ER PT J AU Shalowitz, DI Miller, FG AF Shalowitz, David I. Miller, Franklin G. TI Communicating the results of clinical research to participants: Attitudes, practices, and future directions SO PLOS MEDICINE LA English DT Review ID CHILDRENS ONCOLOGY GROUP; QUALITY-OF-LIFE; WORKER NOTIFICATION; PSYCHOLOGICAL IMPACT; FALSE REASSURANCE; GENETIC RESEARCH; EXPOSED WORKERS; RISK; TRIAL; CANCER C1 [Shalowitz, David I.] Univ Michigan, Sch Med, Bioeth Program, Ann Arbor, MI 48109 USA. [Miller, Franklin G.] Natl Inst Hlth, Dept Bioeth, Ctr Clin, Bethesda, MD USA. RP Shalowitz, DI (reprint author), Univ Michigan, Sch Med, Bioeth Program, Ann Arbor, MI 48109 USA. EM dshalowi@med.umich RI Shalowitz, David/A-7432-2009; OI Shalowitz, David/0000-0002-5189-4687 NR 59 TC 100 Z9 101 U1 3 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD MAY PY 2008 VL 5 IS 5 BP 714 EP 720 AR e91 DI 10.1371/journal.pmed.0050091 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 315AL UT WOS:000256850200011 PM 18479180 ER PT J AU Dugan, VG Chen, R Spiro, DJ Sengamalay, N Zaborsky, J Ghedin, E Nolting, J Swayne, DE Runstadler, JA Happ, GM Senne, DA Wang, RX Slemons, RD Holmes, EC Taubenberger, JK AF Dugan, Vivien G. Chen, Rubing Spiro, David J. Sengamalay, Naomi Zaborsky, Jennifer Ghedin, Elodie Nolting, Jacqueline Swayne, David E. Runstadler, Jonathan A. Happ, George M. Senne, Dennis A. Wang, Ruixue Slemons, Richard D. Holmes, Edward C. Taubenberger, Jeffery K. TI The evolutionary genetics and emergence of avian influenza viruses in wild birds SO PLOS PATHOGENS LA English DT Article ID A VIRUSES; H5N1 INFLUENZA; MIGRATORY WATERFOWL; INTERSPECIES TRANSMISSION; DOMESTIC POULTRY; NORTHERN EUROPE; AQUATIC BIRDS; HUMAN HEALTH; HOST-RANGE; DUCKS AB We surveyed the genetic diversity among avian influenza virus (AIV) in wild birds, comprising 167 complete viral genomes from 14 bird species sampled in four locations across the United States. These isolates represented 29 type A influenza virus hemagglutinin ( HA) and neuraminidase (NA) subtype combinations, with up to 26% of isolates showing evidence of mixed subtype infection. Through a phylogenetic analysis of the largest data set of AIV genomes compiled to date, we were able to document a remarkably high rate of genome reassortment, with no clear pattern of gene segment association and occasional inter-hemisphere gene segment migration and reassortment. From this, we propose that AIV in wild birds forms transient "genome constellations,'' continually reshuffled by reassortment, in contrast to the spread of a limited number of stable genome constellations that characterizes the evolution of mammalian-adapted influenza A viruses. C1 [Dugan, Vivien G.; Wang, Ruixue; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Chen, Rubing; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Spiro, David J.; Sengamalay, Naomi; Zaborsky, Jennifer] J Craig Venter Inst, Rockville, MD USA. [Ghedin, Elodie] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Nolting, Jacqueline; Slemons, Richard D.] Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43210 USA. [Swayne, David E.] USDA ARS, SE Poultry Res Lab, Athens, GA 30605 USA. [Runstadler, Jonathan A.; Happ, George M.] Univ Alaska Fairbanks, Inst Arctic Biol, Fairbanks, AK USA. [Senne, Dennis A.] Anim & Plant Hlth Inspect Serv, Natl Vet Serv Labs, USDA, Ames, IA USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Dugan, VG (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RI Chen, Rubing/A-2276-2010; Chen, Rubing/F-2314-2011; Nolting, Jacqueline/C-4464-2015; OI Holmes, Edward/0000-0001-9596-3552 FU Intramural NIH HHS NR 68 TC 196 Z9 205 U1 5 U2 34 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2008 VL 4 IS 5 AR e1000076 DI 10.1371/journal.ppat.1000076 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 312JY UT WOS:000256668900002 PM 18516303 ER PT J AU Nelson, S Jost, CA Xu, Q Ess, J Martin, JE Oliphant, T Whitehead, SS Durbin, AP Graham, BS Diamond, MS Pierson, TC AF Nelson, Steevenson Jost, Christiane A. Xu, Qinq Ess, Jessica Martin, Julie E. Oliphant, Theodore Whitehead, Stephen S. Durbin, Anna P. Graham, Barney S. Diamond, Michael S. Pierson, Theodore C. TI Maturation of west nile virus modulates sensitivity to antibody-mediated neutralization SO PLOS PATHOGENS LA English DT Article ID BORNE ENCEPHALITIS-VIRUS; MONOCLONAL-ANTIBODIES; ENVELOPE GLYCOPROTEIN; MEMBRANE-FUSION; DENGUE VIRUSES; ANIMAL VIRUSES; PROTEIN PRM; FLAVIVIRUS; INFECTION; EPITOPES AB West Nile virions incorporate 180 envelope (E) proteins that orchestrate the process of virus entry and are the primary target of neutralizing antibodies. The E proteins of newly synthesized West Nile virus (WNV) are organized into trimeric spikes composed of pre-membrane (prM) and E protein heterodimers. During egress, immature virions undergo a protease-mediated cleavage of prM that results in a reorganization of E protein into the pseudo-icosahedral arrangement characteristic of mature virions. While cleavage of prM is a required step in the virus life cycle, complete maturation is not required for infectivity and infectious virions may be heterogeneous with respect to the extent of prM cleavage. In this study, we demonstrate that virion maturation impacts the sensitivity of WNV to antibody-mediated neutralization. Complete maturation results in a significant reduction in sensitivity to neutralization by antibodies specific for poorly accessible epitopes that comprise a major component of the human antibody response following WNV infection or vaccination. This reduction in neutralization sensitivity reflects a decrease in the accessibility of epitopes on virions to levels that fall below a threshold required for neutralization. Thus, in addition to a role in facilitating viral entry, changes in E protein arrangement associated with maturation modulate neutralization sensitivity and introduce an additional layer of complexity into humoral immunity against WNV. C1 [Nelson, Steevenson; Jost, Christiane A.; Xu, Qinq; Ess, Jessica; Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Martin, Julie E.; Graham, Barney S.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Oliphant, Theodore; Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Oliphant, Theodore; Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Oliphant, Theodore; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Whitehead, Stephen S.] NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Durbin, Anna P.] Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Immunizat Res, Dept Int Hlth, Baltimore, MD USA. RP Nelson, S (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS; NIAID NIH HHS [U01 AI061373] NR 49 TC 96 Z9 96 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD MAY PY 2008 VL 4 IS 5 AR e1000060 DI 10.1371/journal.ppat.1000060 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 312JY UT WOS:000256668900019 PM 18464894 ER PT J AU Chow, L Rezmann, L Imamura, K Wang, L Catt, K Tikellis, C Louis, WJ Fraurnan, AG Louis, SNS AF Chow, L. Rezmann, L. Imamura, K. Wang, L. Catt, K. Tikellis, C. Louis, W. J. Fraurnan, A. G. Louis, S. N. S. TI Functional angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3 prostate cancer cell lines SO PROSTATE LA English DT Article DE angiotensin II; AT(2)-receptors; prostate cancer cell lines; cell growth ID SHP-1 TYROSINE PHOSPHATASE; ANTIPROLIFERATIVE ACTIVITY; EPITHELIAL-CELLS; EXPRESSION; PROTEIN; TRANSACTIVATION; HYPERPLASIA; RENIN; ASSOCIATION; ACTIVATION AB BACKGROUND. There is clear evidence of a tissue-based renin-angiotensin system in the prostate and studies to date suggest that AT(1)-receptor blocking drugs inhibit the growth of some prostate cancer cell lines and delay the development of prostate cancer. The present studies examine the action of Ang II in two prostate cancer cell lines and report the presence of functional AT(2)-receptors that regulate the actions of growth factors. METHODS. Immunohistochemistry was used to identify the presence of Ang II and QPCR techniques to examine AT(1)- and AT(2)-receptor mRNA expression in androgen-dependent (LNCaP) and independent (PC3) cell lines. The effects of AT(1)- and AT(2)-receptor activation upon EGF-induced DNA synthesis and ERK2 phosphorylation in these cells were also examined. RESULTS. Functional AT2-receptors together with Ang II were identified in both cell lines and stimulation of these receptors inhibited EGF-induced DNA synthesis and ERK2 phosphorylation. AT(1)-receptors, although present in both cell lines, were only functional in LNCaP cells where activation stimulated DNA synthesis. CONCLUSIONS. Functional AT2-receptors are present and have the capacity to inhibit EGF-induced prostate cancer cell growth in LNCaP and fast growing androgen-independent PC3 cell lines, whereas functional AT(1)-receptors are found only in LNCaP cells where their activation stimulates DNA synthesis. C1 [Chow, L.; Rezmann, L.; Imamura, K.; Wang, L.; Louis, W. J.; Fraurnan, A. G.] Univ Melbourne, Dept Med, Austin Hlth, Heidelberg, Vic, Australia. [Catt, K.; Louis, S. N. S.] NICHD, NIH, Endocrinol & Reprod Res Branch, Bethesda, MD USA. [Tikellis, C.] Baker Heart Res Inst, Melbourne, Vic, Australia. RP Louis, SNS (reprint author), Austin Hlth, Dept Clin Pharmacol & Therapeut, Heidelberg, Vic 3084, Australia. EM simonnsl@unimelb.edu.au NR 24 TC 23 Z9 24 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 EI 1097-0045 J9 PROSTATE JI Prostate PD MAY 1 PY 2008 VL 68 IS 6 BP 651 EP 660 DI 10.1002/pros.20738 PG 10 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 293DI UT WOS:000255314800008 PM 18288685 ER PT J AU Deflorian, F Engel, S Colson, AO Raaka, BM Gershengorn, MC Costanzi, S AF Deflorian, Francesca Engel, Stanislav Colson, Anny-Odile Raaka, Bruce M. Gershengorn, Marvin C. Costanzi, Stefano TI Understanding the structural and functional differences between mouse thyrotropin-releasing hormone receptors 1 and 2 SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE GPCR; TRH receptors; mutagenesis; TM5 rotation; conformational changes; activation; homology modeling; molecular dynamics; docking; Monte Carlo search ID THYROTROPIN-RELEASING-HORMONE; MOLECULAR-DYNAMICS SIMULATIONS; PROTEIN-COUPLED RECEPTORS; TRH-LIKE PEPTIDES; BINDING POCKET.; REFINED MODEL; BILAYER; GRAMICIDIN; CLONING; COMPLEX AB Multiple computational methods have been employed in a comparative study of thyrotropin-releasing hormone receptors I and 2 (TRH-R1 and TRH-R2) to explore the structural bases for the different functional properties of these G protein-coupled receptors. Three-dimensional models of both murine TRH receptors have been built and optimized by means of homology modeling based on the crystal structure of bovine rhodopsin, molecular dynamics simulations, and energy minimizations in a membrane-aqueous environment. The comparison between the two models showed a correlation between the higher flexibility and higher basal activity of TRH-R2 versus the lesser flexibility and lower basal activity of TRH-R1 and supported the involvement of the highly conserved W6.48 in the signaling process. A correlation between the level of basal activity and conformational changes of TM5 was detected also. Comparison between models of the wild type receptors and their W6.48A mutants, which have reversed basal activities compared with their respective wild types, further supported these correlations. A flexible molecular docking procedure revealed that TRH establishes a direct interaction with W6.48 in TRH-R2 but not in TRH-R1. We designed and performed new mutagenesis experiments that strongly supported these observations. C1 [Deflorian, Francesca; Colson, Anny-Odile; Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Engel, Stanislav; Raaka, Bruce M.; Gershengorn, Marvin C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov; stefanoc@mail.nih.gov RI Engel, Stanislav/G-2799-2013; Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS NR 46 TC 13 Z9 13 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAY 1 PY 2008 VL 71 IS 2 BP 783 EP 794 DI 10.1002/prot.21763 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 278DI UT WOS:000254263400024 PM 17979196 ER PT J AU Goonesekere, NCW Lee, B AF Goonesekere, Nalin C. W. Lee, Byungkook TI Context-specific amino acid substitution matrices and their use in the detection of protein homologs SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE CSSM; score matrix; homology detection; sequence alignment; environment polarity; fold recognition ID FOLD RECOGNITION; SEQUENCE ALIGNMENT; TWILIGHT ZONE; THREADING ALGORITHM; DATABASE SEARCHES; PSI-BLAST; INFORMATION; PROFILES; CLASSIFICATION; PREDICTION AB The sequence homology detection relies on score matrices, which reflect the frequency of amino acid substitutions observed in a dataset of homologous sequences. The substitution matrices in popular use today are usually constructed without consideration of the structural context in which the substitution takes place. Here, we present amino acid substitution matrices specific for particular polar-nonpolar environment of the amino acid. As expected, these matrices [context-specific substitution matrices (CSSMs)] show striking differences from the popular BLOSUM62 matrix, which does not include structural information. When incorporated into BLAST and PSI-BLAST, CSSM outperformed BLOSUM matrices as assessed by ROC curve analyses of the number of true and false hits and by the accuracy of the sequence alignments to the hit sequences. These findings are also of relevance to profile-profile-based methods of homology detection, since CSSMs may help build a better profile. Profiles generated for protein sequences in PDB using CSSM-PSI-BLAST will be made available for searching via RPSBLAST through our web site http://lmbbi.nci.nih.gov/. C1 [Goonesekere, Nalin C. W.; Lee, Byungkook] NIH, Natl Canc Inst, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. [Goonesekere, Nalin C. W.] Univ No Iowa, Dept Chem & Biochem, Cedar Falls, IA 50614 USA. RP Lee, B (reprint author), NIH, Natl Canc Inst, Ctr Canc Res, Mol Biol Lab, Rm 5120,Bldg 37,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM bk@nih.gov FU Intramural NIH HHS NR 43 TC 12 Z9 12 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD MAY 1 PY 2008 VL 71 IS 2 BP 910 EP 919 DI 10.1002/prot.21775 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 278DI UT WOS:000254263400034 PM 18004781 ER PT J AU Swartz, MS Stroup, TS McEvoy, JP Davis, SM Rosenheck, RA Keefe, RSE Hsiao, JK Lieberman, JA AF Swartz, Marvin S. Stroup, T. Scott McEvoy, Joseph P. Davis, Sonia M. Rosenheck, Robert A. Keefe, Richard S. E. Hsiao, John K. Lieberman, Jeffrey A. TI What CATIE found: Results from the schizophrenia trial SO PSYCHIATRIC SERVICES LA English DT Article ID INTERVENTION EFFECTIVENESS CATIE; CLINICAL ANTIPSYCHOTIC TRIALS; NEW-GENERATION ANTIPSYCHOTICS; RANDOMIZED CONTROLLED-TRIAL; 2ND-GENERATION ANTIPSYCHOTICS; CONVENTIONAL ANTIPSYCHOTICS; METAANALYSIS; OLANZAPINE; RISPERIDONE; QUETIAPINE AB The authors provide an overview of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sponsored by the National Institute of Mental Health. CATIE was designed to compare a proxy first-generation antipsychotic, perphenazine, to several newer drugs. In phase 1 of the trial, consenting patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months on a double-blind basis. Patients with tardive dyskinesia were excluded from being randomly assigned to perphenazine and were assigned to one of the four second-generation antipsychotics in phase 1A. Clozapine was included in phase 2 of the study. Overall, olanzapine had the longest time to discontinuation in phase 1, but it was associated with significant weight and metabolic concerns. Perphenazine was not significantly different in overall effectiveness, compared with quetiapine, risperidone, and ziprasidone. Also, perphenazine was found to be the most cost-effective drug. Clozapine was confirmed as the most effective drug for individuals with a poor symptom response to previous antipsychotic drug trials, although clozapine was also associated with troublesome adverse effects. There were no differences in neurocognitive or psychosocial functioning in response to medications. Subsequent randomizations suggest that a poor response to an initial medication may mean that a different medication will be more effective or better tolerated. Although the CATIE results are controversial, they are broadly consistent with most previous antipsychotic drug trials and meta-analyses; however, the results may not generalize well to patients at high risk of tardive dyskinesia. Patient characteristics and clinical circumstances affected drug effectiveness; these patient factors are important in making treatment choices. C1 [Swartz, Marvin S.; McEvoy, Joseph P.; Keefe, Richard S. E.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Davis, Sonia M.] Quintiles Inc, Res Triangle Pk, NC USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Hsiao, John K.] NIMH, Div Serv & Intervent Res, Rockville, MD 20857 USA. [Lieberman, Jeffrey A.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. RP Swartz, MS (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Box 3173, Durham, NC 27710 USA. EM swart001@mc.duke.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH NIH HHS [N01 MH90001, N01MH90001, N01 MH 90001] NR 30 TC 61 Z9 62 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD MAY PY 2008 VL 59 IS 5 BP 500 EP 506 DI 10.1176/appi.ps.59.5.500 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 296AQ UT WOS:000255516300007 PM 18451005 ER PT J AU Stewart, LQ Roper, JA Young, WS O'Carroll, AM Lolait, SJ AF Stewart, Lesley Q. Roper, James A. Young, W. Scott, III O'Carroll, Anne-Marie Lolait, Stephen J. TI The role of the arginine vasopressin Avp1b receptor in the acute neuroendocrine action of antidepressants SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE vasopressin; Avp1b receptor; ACTH; corticosterone; antidepressants ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; SEROTONIN-REUPTAKE INHIBITORS; CENTRAL-NERVOUS-SYSTEM; V1B RECEPTOR; MAJOR DEPRESSION; PARAVENTRICULAR NUCLEUS; RESTRAINT STRESS; FUNCTIONAL-CHARACTERIZATION; RAT PITUITARY AB In times of stress the hypothalamic-pituitary-adrenal (HPA) axis is activated and releases two neurohormones, corticotropin-releasing hormone (Crh) and arginine vasopressin (Avp), to synergistically stimulate the secretion of adrenocorticotropin hormone (ACTH) from the anterior pituitary, culminating in a rise in circulating glucocorticoids. Avp mediates its actions at the Avp V1b receptor (Avpr1b) present on pituitary corticotropes. Dysregulation of the stress response is associated with the pathophysiology of depression and a major treatment involves increasing the availability of monamines at the synaptic cleft. Acute administration of selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) has previously been shown to activate the HPA axis. The present study was undertaken to evaluate the involvement of the Avpr1b in the HPA axis response to acute SC administration of an SSRI (fluoxetine 10mg/kg) and a TCA (desipramine 10mg/kg). We measured plasma ACTH and corticosterone (CORT) levels and neuropeptide mRNA expression in the hypothalamic paraventricular nucleus (PVN) of Avpr1b knockout (KO) mice and wildtype controls. Fluoxetine and desipramine administration significantly attenuated plasma ACTH and CORT levels in mate and female Avpr1b KO mice when compared to their wild-type counterparts. Avp, oxytocin (Oxt) and Crh mRNA expression in the PVN did not change in fluoxetine-treated mate Avpr1b KO or wild-type mice. In contrast, fluoxetine treatment increased PVN Avp mRNA levels in female Avpr1b wild type but not KO animals. PVN Oxt mRNA levels increased in fluoxetine-treated female mice of both genotypes. The data suggests that the Avpr1b is required to drive the HPA axis response to acute antidepressant treatment and provides further evidence of a sexual dichotomy in the regulation of PVN Avp/Oxt gene expression following antidepressant administration. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Stewart, Lesley Q.; Roper, James A.; O'Carroll, Anne-Marie; Lolait, Stephen J.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Lolait, SJ (reprint author), Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM s.j.lolait@bristol.ac.uk RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU Intramural NIH HHS; NIMH NIH HHS [Z01-MH-002498-17]; Wellcome Trust NR 82 TC 26 Z9 27 U1 0 U2 2 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 MAY PY 2008 VL 33 IS 4 BP 405 EP 415 DI 10.1016/j.psyneuen.2007.12.009 PG 11 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 300TH UT WOS:000255847600001 PM 18243568 ER PT J AU Pascoe, JE Williams, KL Mukhopadhyay, P Rice, KC Woods, JH Ko, MC AF Pascoe, John E. Williams, Keith L. Mukhopadhyay, Partha Rice, Kenner C. Woods, James H. Ko, Mei-Chuan TI Effects of mu, kappa, and delta opioid receptor agonists on the function of hypothalamic-pituitary-adrenal axis in monkeys SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE HPA axis; opioid receptor agonists; opioid receptor antagonists; ACTH; cortisol; primates ID INTRACISTERNAL NOR-BINALTORPHIMINE; ADRENOCORTICAL HPA AXIS; MALE RHESUS-MONKEYS; THERMAL ANTINOCICEPTION; DIFFERENT DURATIONS; OPIATE; CORTISOL; ANTAGONIST; SECRETION; MORPHINE AB Opioids can modulate neuroendocrine function. Less is known about the involvement of opioid receptor subtypes in the stimulatory effects of opioids on the primate hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to investigate the stimulatory effects of opioids selective for each receptor subtype on plasma adrenocorticotropic hormone (ACTH) and cortisol. levels in both mate and female monkeys. The blood collection procedure was conducted in home-caged and unanesthetized rhesus monkeys that showed low and stable basal ACTH and cortisol levels. Three opioid receptor agonists, fentanyl, U-50488H, and SNC80, were used in behaviorally active doses; they are highly selective for mu, kappa, and delta opioid receptors, respectively. Plasma samples were collected at multiple time points before and after IV administration of each compound and were quantified by radioimmunoassay. Neither fentanyl (0.0003-0.02 mg/kg) nor SNC80 (0.03-0.3 mg/kg) changed either ACTH or cortisol. basal levels. In contrast, U-50488H (0.01-1 mg/kg) dose-dependently stimulated ACTH and cortisol release in both mate and female monkeys. Importantly, the stimulatory effects of U-50488H on the secretion of ACTH were Mocked by a selective kappa opioid receptor antagonist, nor-Binaltorphimine. The antagonist effect of nor-binaltorphimine lasted up to 20 weeks. These results indicate that only synthetic kappa, but not mu or delta opioid receptor agonists stimulate HPA axis activity after acute administration in primates. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Pascoe, John E.; Mukhopadhyay, Partha; Woods, James H.; Ko, Mei-Chuan] Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Williams, Keith L.] Oakland Univ, Dept Psychol, Rochester, MI 48309 USA. [Rice, Kenner C.] NIDA, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Rice, Kenner C.] NIAAA, NIH, Bethesda, MD 20892 USA. [Ko, Mei-Chuan] Natl Chengchi Univ, Dept Psychol, Taipei 116, Taiwan. [Ko, Mei-Chuan] Natl Chengchi Univ, Grad Inst Life Sci, Taipei 116, Taiwan. RP Ko, MC (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. EM mko@umich.edu RI Ko, Mei-Chuan/C-9468-2009; OI Ko, Mei-Chuan/0000-0003-2436-4506; Williams, Keith/0000-0003-2581-0491 FU NIDA NIH HHS [K21 DA000254, DA-013685, P01 DA000254, P01 DA000254-320004, P50 DA000254, R01 DA013685, R01 DA013685-03] NR 48 TC 24 Z9 24 U1 0 U2 5 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 MAY PY 2008 VL 33 IS 4 BP 478 EP 486 DI 10.1016/j.psyneuen.2008.01.006 PG 9 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 300TH UT WOS:000255847600009 PM 18325678 ER PT J AU Bhattacharjee, AK Chang, L White, L Bazinet, RP Rapoport, SI AF Bhattacharjee, Abesh Kumar Chang, Lisa White, Laura Bazinet, Richard P. Rapoport, Stanley I. TI Imaging apomorphine stimulation of brain arachidonic acid signaling via D-2-like receptors in unanesthetized rats SO PSYCHOPHARMACOLOGY LA English DT Article DE apomorphine; arachidonic acid; dopamine; brain; rat; raclopride; D-2 receptors; imaging; autoradiography ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; SUBTYPE-SPECIFIC ANTIBODIES; D2-LIKE DOPAMINE-RECEPTORS; PARKINSONS-DISEASE; PHOSPHOLIPASE A(2); D-2 RECEPTORS; IN-VIVO; SUBSTANTIA NIGRA; BLOOD-FLOW AB Rationale and objective Because of the important role of dopamine in neurotransmission, it would be useful to be able to image brain dopamine receptor-mediated signal transduction in animals and humans. Administering the D-1-D-2 receptor agonist apomorphine may allow us to do this, as the D-2-like receptor is reported to be coupled to cytosolic phospholipase A(2) activation and arachidonic acid (AA) release from membrane phospholipid. Methods Unanesthetized adult rats were given intraperitoneally apomorphine (0.5 mg/kg) or saline, with or without pretreatment with 6 mg/kg intravenous raclopride, a D-2/D-3 receptor antagonist. [1-C-14]AA was injected intravenously, then AA incorporation coefficients k*-brain radioactivity divided by integrated plasma radioactivity-markers of AA signaling, were measured using quantitative autoradiography in 62 brain regions. Results Apomorphine significantly elevated k* in 26 brain regions, including the frontal cortex, motor and somatosensory cortex, caudate-putamen, thalamic nuclei, and nucleus accumbens. Raclopride alone did not change baseline values of k*, but raclopride pretreatment prevented the apomorphine-induced increments in k*. Conclusions A mixed D-1-D-2 receptor agonist, apomorphine, increased the AA signal by activating only D-2-like receptors in brain circuits containing regions with high D-2-like receptor densities. Thus, apomorphine might be used with positron emission tomography to image brain D-2-like receptor-mediated AA signaling in humans in health and disease. C1 [Bhattacharjee, Abesh Kumar; Chang, Lisa; White, Laura; Bazinet, Richard P.; Rapoport, Stanley I.] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bhattacharjee, AK (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S126, Bethesda, MD 20892 USA. EM abeshb@mail.nih.gov FU Intramural NIH HHS NR 84 TC 13 Z9 14 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAY PY 2008 VL 197 IS 4 BP 557 EP 566 DI 10.1007/s00213-008-1073-3 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 285BK UT WOS:000254752100004 PM 18274730 ER PT J AU Mcneely, JD Windham, BG Anderson, DE AF Mcneely, Jessica D. Windham, B. Gwen Anderson, David E. TI Dietary sodium effects on heart rate variability in salt sensitivity of blood pressure SO PSYCHOPHYSIOLOGY LA English DT Article DE blood pressure; heart rate variability; sodium ID RESPIRATORY SINUS ARRHYTHMIA; POWER-SPECTRAL-ANALYSIS; NERVOUS-SYSTEM; HYPERTENSION; WOMEN; ACTIVATION; STRESS; BLACKS; RISK; AGE AB High dietary sodium intake is a risk factor for hypertension, and heart rate variability (HRV) is decreased in hypertension. Effects of dietary sodium intake on HRV of normotensive persons have not, however, been investigated to date. The present study examined effects of low and high sodium diets on blood pressure, heart rate, and HRV in 36 healthy, normotensive women, ages 40-70. Each was placed on a low sodium diet for 6 days followed by a high sodium diet for 6 days. The high salt diet increased mean systolic blood pressure, decreased heart rate, and increased high frequency HRV (HF). Cardiac vagal tone, estimated at baseline from heart period and a time domain estimate of respiratory sinus arrhythmia, was higher in salt-sensitive than salt-insensitive subjects. The finding of increased vagal tone in normotensive persons on high salt intake indicates that dietary sodium status should be considered in behavioral studies of HRV. C1 [Mcneely, Jessica D.; Anderson, David E.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Windham, B. Gwen] NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Anderson, DE (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Andersod@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000600-19] NR 27 TC 10 Z9 10 U1 1 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0048-5772 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD MAY PY 2008 VL 45 IS 3 BP 405 EP 411 DI 10.1111/j.1469-8986.2007.00629.x PG 7 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 285QU UT WOS:000254792100009 PM 18047481 ER PT J AU Cappellacci, L Franchetti, P Petrelli, R Vita, P Jacobson, KA Maddileti, S Harden, TK Grifantini, M AF Cappellacci, Loredana Franchetti, Palmarisa Petrelli, Riccardo Vita, Patrizia Jacobson, Kenneth A. Maddileti, Savitry Harden, T. Kendall Grifantini, Mario TI ATP-mimetics derived from 2 '(3 ')-C-methyladenosine as human P2Y2 agonists SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Cappellacci, Loredana; Franchetti, Palmarisa; Petrelli, Riccardo; Vita, Patrizia; Grifantini, Mario] Univ Camerino, Dept Chem Sci, I-62032 Camerino, Italy. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Maddileti, Savitry; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S14 EP S14 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900029 ER PT J AU Gao, ZG Jacobson, KA AF Gao, Zhan-Guo Jacobson, Kenneth A. TI Translocation of arrestin induced by human A3 adenosine receptor ligands in an engineered cell line: comparison with G Protein-dependent pathways SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S78 EP S79 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900152 ER PT J AU Jindrichova, M Vavra, V Obsil, T Stojilkovic, SS Zemkova, H AF Jindrichova, Marie Vavra, Vojtech Obsil, Tomas Stojilkovic, Stanko S. Zemkova, Hana TI A role of conserved tyrosine in the first transmembrane domain in purinergic P2X receptor function SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Jindrichova, Marie; Vavra, Vojtech; Zemkova, Hana] Inst Physiol ASCR VVI, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. [Obsil, Tomas] Charles Univ Prague, Dept Phys & Macromol Chem, Fac Sci, Prague, Czech Republic. [Stojilkovic, Stanko S.] NICHD, Sect Cellular Signaling, PDN, NIH, Bethesda, MD USA. RI Vavra, Vojtech/C-1857-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S199 EP S200 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900384 ER PT J AU Jourdain, M Hechler, B Zerr-Fouineau, M Cazenave, JP Freund, M Jacobson, K Gachet, C AF Jourdain, Marie Hechler, Beatrice Zerr-Fouineau, Murielle Cazenave, Jean-Pierre Freund, Monique Jacobson, Ken Gachet, Christian TI Inverse sensitivity to P2Y1 and P2Y12 receptor inhibition in ApoE-/- as compared to WT mice in a model of FeCl3-induced thrombosis SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Jourdain, Marie; Hechler, Beatrice; Zerr-Fouineau, Murielle; Cazenave, Jean-Pierre; Freund, Monique; Gachet, Christian] Inst Natl Sante & Rech Med, U311, Strasbourg, France. [Jourdain, Marie; Hechler, Beatrice; Zerr-Fouineau, Murielle; Cazenave, Jean-Pierre; Freund, Monique; Gachet, Christian] Etab Francais Sang Alsace, Strasbourg, France. [Jourdain, Marie; Hechler, Beatrice; Zerr-Fouineau, Murielle; Cazenave, Jean-Pierre; Freund, Monique; Gachet, Christian] Univ Strasbourg 1, Strasbourg, France. [Jacobson, Ken] NIDDK, Natl Inst Hlth, Bethesda, MD USA. RI Hechler, Beatrice/D-4227-2017 NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S9 EP S10 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900022 ER PT J AU Kim, Y Hechler, B Klutz, AM Ivanov, AA Zhan-Guo, G Gachet, C Jacobson, KA AF Kim, Yoonkyung Hechler, Beatrice Klutz, Athena M. Ivanov, Andrei A. Gao, Zhan-Guo Gachet, Christian Jacobson, Kenneth A. TI Macromolecular ligands for G protein-coupled receptors: Poly(amidoamine) dendrimer conjugates of A2A adenosine receptor agonists SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Kim, Yoonkyung; Klutz, Athena M.; Ivanov, Andrei A.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Hechler, Beatrice; Gachet, Christian] EFS Alsace, INSERM, U 311, Strasbourg, France. [Hechler, Beatrice; Gachet, Christian] Univ Strasbourg 1, Strasbourg, France. RI Hechler, Beatrice/D-4227-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S22 EP S22 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900044 ER PT J AU Ko, H Fricks, I Melman, A Carter, R Ivanov, AA Harden, TK Jacobson, KA AF Ko, Hyojin Fricks, Ingrid Melman, Artem Carter, Rhonda Ivanov, Andrei A. Harden, T. Kendall Jacobson, Kenneth A. TI The glucose moiety of uridine 5 '-diphosphoglucose is structurally permissive in activation of the human P2Y14 receptor SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Ko, Hyojin; Melman, Artem; Ivanov, Andrei A.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, Bethesda, MD USA. [Fricks, Ingrid; Carter, Rhonda; Harden, T. Kendall] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S22 EP S23 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900045 ER PT J AU Ochaion, A Bar-Yehuda, S Jacobson, KA Joshi, BV Gao, ZG Cohen, S Patoka, R Barer, F Del Valle, L Perez-Liz, G Fishman, P AF Ochaion, A. Bar-Yehuda, S. Jacobson, K. A. Joshi, B. V. Gao, Z. G. Cohen, S. Patoka, R. Barer, F. Del Valle, L. Perez-Liz, G. Fishman, P. TI CF502 targets the A(3) adenosine receptor to induce anti-inflammatory effect via down-regulation of the NF-kappa B signaling pathway SO PURINERGIC SIGNALLING LA English DT Meeting Abstract C1 [Ochaion, A.; Bar-Yehuda, S.; Cohen, S.; Patoka, R.; Barer, F.; Fishman, P.] Can Fite BioPharma Ltd, IL-49170 Petah Tiqwa, Israel. [Jacobson, K. A.; Joshi, B. V.; Gao, Z. G.] NIDDK, NIH, Bethesda, MD USA. [Del Valle, L.; Perez-Liz, G.] Temple Univ, Sch Med, Dept Neurosci Neuropathol Core, Philadelphia, PA 19122 USA. [Del Valle, L.; Perez-Liz, G.] Temple Univ, Sch Med, Ctr NeuroVirol, Philadelphia, PA 19122 USA. Meir Med Ctr, Internal Dept D, Kefar Sava, Israel. RI Jacobson, Kenneth/A-1530-2009; Del Valle, Luis/J-4085-2015 OI Jacobson, Kenneth/0000-0001-8104-1493; Del Valle, Luis/0000-0003-3894-9206 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD MAY PY 2008 VL 4 SU 1 BP S66 EP S66 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 347QU UT WOS:000259156900129 ER PT J AU Ott, DE AF Ott, David E. TI Cellular proteins detected in HIV-1 SO REVIEWS IN MEDICAL VIROLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-LYMPHOCYTES; MONOCYTE-DERIVED MACROPHAGES; URACIL DNA GLYCOSYLASE; HLA CLASS-II; PLASMA-MEMBRANE; CYCLOPHILIN-A; HOST PROTEINS; LIPID RAFTS; LIFE-CYCLE AB It has been known for some time that HIV-1 virions contain cellular proteins in addition to proteins encoded by the viral genome. Recent studies have vastly increased the number of host proteins detected in HIV-1. This review summarises the current findings on several cellular proteins present in these virions, including some functional studies on their potential roles in the viral replication cycle and pathogenesis. Because retroviruses require extensive assistance from host proteins and pathways, the data from biochemical characterisations of HIV-1 serve as an important starting point for understanding the role of cellular proteins that act in or influence the biology of HIV-1. Additionally, a better understanding of the interactions between cellular proteins and viral components might provide more targets for anti-HIV therapeutic intervention and provide for a better understanding of how HIV-1 alters the immune system. The extensive study of HIV-1 has already brought new insights to the fields of immunology and vaccine science. In the same way, knowledge of viral-cellular protein interactions might assist our understanding of important cellular pathways. Copyright (c) 2008 John Wiley & Sons, Ltd. C1 Natl Canc Inst, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. RP Ott, DE (reprint author), Natl Canc Inst, SAIC Frederick Inc, AIDS Vaccine Program, Bldg 535,Room 415-433, Frederick, MD 21702 USA. EM ott@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 143 TC 64 Z9 66 U1 2 U2 5 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1052-9276 J9 REV MED VIROL JI Rev. Med. Virol. PD MAY-JUN PY 2008 VL 18 IS 3 BP 159 EP 175 DI 10.1002/rmv.570 PG 17 WC Virology SC Virology GA 304OP UT WOS:000256119100003 PM 18265424 ER PT J AU Porras, C Safaeian, M Gonzalez, P Hildesheim, A Silva, S Schiffman, M Rodriguez, AC Wacholder, S Freer, E Quint, K Bratti, C Espinoza, A Cortes, B Herrero, R AF Porras, Carolina Safaeian, Mahboohbeh Gonzalez, Paula Hildesheim, Allan Silva, Sandra Schiffman, Mark Rodriguez, Ana Cecilia Wacholder, Sholom Freer, Enrique Quint, Koen Bratti, Concepcion Espinoza, Albert Cortes, Bernal Herrero, Rolando CA Costa Rica HPV Vaccine Trial CVT G TI Epidemiology of genital Chlamydia trachomatis infection among young women in Costa Rica SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; PELVIC-INFLAMMATORY-DISEASE; NEISSERIA-GONORRHOEAE; INTRAUTERINE-DEVICES; BACTERIAL VAGINOSIS; HORMONAL CONTRACEPTION; CERVICAL ECTOPY; RISK; PREVALENCE; SMOKING AB Objective: To investigate Chlamydia trachomatis (Ct) epidemiology among 5829 women 18 to 25 years old, in Costa Rica. Methods: Data are from a community-based human papillomavirus 16/18 vaccine trial. Before randomization, eligible women who reported previous sexual activity were interviewed and tested for Ct DNA by Hybrid Capture 2 and polymerase chain reaction-based genotyping. Multivariate models were developed. Results: Overall prevalence was 14.2% (95% confidence interval, 13.3-15.1). Among Ct genotypes, serovar E was the most common (4.3%), followed by serovar F (3.0%), serovar D/Da (2.9%), and serovar I/Ia (2.1%). Ct increased with lifetime sexual partners of the women, and among women with 1 lifetime partner, with sexual partners of the partner. Current intrauterine device users had an increase in Ct detection [odds ratio (OR) 1.6, 1.1-2.5] but hormonal contraceptives or condom users did not. Miscarriages were associated with a reduction in Ct detection (OR 0.7, 0.5-1.0) while current regular smoking increased it (OR 1.7, 1.2-2.5). Vaginal discharge, reactive changes, ASCUS or LSIL and moderate to severe inflammation in the cytology were significantly more common among Ct positive women (P <0.001). Gonorrhea prevalence was 0.8%, and it was, as other STIs, highly correlated with Ct detection. Conclusions: This is a high-prevalence population where we confirmed the strong link between Ct and sexual behavior of women and their partners. The establishment of a screening program in the age group included in this study should be considered. More studies are needed in developing countries to further investigate the role of intrauterine devices and the lack of protection by condoms, in addition to the interplay between Ct and other STIs, ectopy, inflammation, and epithelial abnormalities. C1 [Porras, Carolina; Gonzalez, Paula; Bratti, Concepcion; Espinoza, Albert; Cortes, Bernal; Herrero, Rolando] Fdn INCIENSA, San Jose, Costa Rica. [Safaeian, Mahboohbeh; Hildesheim, Allan; Schiffman, Mark; Rodriguez, Ana Cecilia; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Silva, Sandra; Freer, Enrique] Univ Costa Rica, Ctr Invest Estructuras Microscopicas, San Jose, Costa Rica. RP Porras, C (reprint author), 300 Oeste ICE,Piso 7, San Jose, Costa Rica. EM cporras@proyectoguanacaste.org RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI NIH HHS [N01-CP-11005] NR 37 TC 14 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD MAY PY 2008 VL 35 IS 5 BP 461 EP 468 DI 10.1097/OLQ.0b013e3181644b4c PG 8 WC Infectious Diseases SC Infectious Diseases GA 295SG UT WOS:000255493600007 PM 18446086 ER PT J AU Goldman, SE Hall, M Boudreau, R Matthews, KA Cauley, JA Ancoli-Israel, S Stone, KL Rubin, SM Satterfield, S Simonsick, EM Newman, AB AF Goldman, Suzanne E. Hall, Martica Boudreau, Robert Matthews, Karen A. Cauley, Jane A. Ancoli-Israel, Sonia Stone, Katie L. Rubin, Susan M. Satterfield, Suzanne Simonsick, Eleanor M. Newman, Anne B. TI Association between nighttime sleep and napping in older adults SO SLEEP LA English DT Article DE napping; sleep duration; sleep fragmentation; diabetes; elderly ID EXCESSIVE DAYTIME SLEEPINESS; GENERAL-POPULATION; RISK-FACTOR; SIESTA; FRAGMENTATION; COMPLAINTS; MORTALITY; DURATION; AGE; DEPRESSION AB Study Objectives: Napping might indicate deficiencies in nighttime sleep, but the relationship is not well defined. We assessed the association of nighttime sleep duration and fragmentation with subsequent daytime sleep. Design: Cross-sectional study. Participants: 235 individuals (47.5% men, 29.7% black), age 80.1 (2.9) years. Measurements and Results: Nighttime and daytime sleep were measured with wrist actigraphy and sleep diaries for an average of 6.8 (SD 0.7) nights. Sleep parameters included total nighttime sleep (h), movement and fragmentation index (fragmentation), and total daytime sleep (h). The relationship of total nighttime sleep and fragmentation to napping (yes/no) was assessed using logistic regression. In individuals who napped, mixed random effects models were used to determine the association between the previous night sleep duration and fragmentation and nap duration, and nap duration and subsequent night sleep duration. All models were adjusted for age, race, gender, BMI, cognitive status, depression, cardiovascular disease, respiratory symptoms, diabetes, pain, fatigue, and sleep medication use. Naps were recorded in sleep diaries by 178 (75.7%) participants. The odds ratios (95% CI) for napping were higher for individuals with higher levels of nighttime fragmentation (2.1 [0.8, 5.7]), respiratory symptoms (2.4 [1.1, 5.4]), diabetes (6.1 [1.2, 30.7]), and pain (2.2 [1.0, 4.7]). Among rappers, neither sleep duration nor fragmentation the preceding night was associated with nap duration the next day. Conclusion: More sleep fragmentation was associated with higher odds of napping although not with nap duration. Further research is needed to determine the causal association between sleep fragmentation and daytime napping. C1 [Goldman, Suzanne E.] Vanderbilt Univ, Med Ctr, Dept Neurol, Sleep Disorders Program, Nashville, TN 37232 USA. [Hall, Martica; Matthews, Karen A.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Boudreau, Robert; Cauley, Jane A.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ancoli-Israel, Sonia] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Stone, Katie L.] Calif Pacific Med Ctr, Res Inst, San Francisco, CA USA. [Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. [Simonsick, Eleanor M.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Goldman, SE (reprint author), Vanderbilt Univ, Med Ctr, Dept Neurol, Sleep Disorders Program, 1301 Med Ctr Dr,Room B-727, Nashville, TN 37232 USA. EM Suzanne.e.goldman@vanderbilt.edu RI Hall, Martica/D-2809-2012; Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015; OI Hall, Martica/0000-0003-0642-2098; Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408; Boudreau, Robert/0000-0003-0162-5187 FU Intramural NIH HHS; NCI NIH HHS [CA112035, CA85264, R01 CA085264, R01 CA112035]; NIA NIH HHS [2 T32 AG000181-16, AG08415, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01 AG008415, R01 AG026720, T32 AG000181] NR 41 TC 30 Z9 32 U1 1 U2 3 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD MAY 1 PY 2008 VL 31 IS 5 BP 733 EP 740 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 295CC UT WOS:000255451600017 PM 18517043 ER PT J AU Yan, Z Wang, Z Sharova, L Sharov, AA Ling, C Piao, Y Aiba, K Matoba, R Wang, W Ko, MSH AF Yan, Zhijiang Wang, Zhong Sharova, Lioudmila Sharov, Alexei A. Ling, Chen Piao, Yulan Aiba, Kazuhiro Matoba, Ryo Wang, Weidong Ko, Minoru S. H. TI BAF250B-associated SWI/SNF chromatin-remodeling complex is required to maintain undifferentiated mouse embryonic stem cells SO STEM CELLS LA English DT Article DE chromatin remodeling; gene targeting; SWI/SNF; embryonic stem cells; DNA microarray; BAF250B; ARID1B ID EXPRESSION; DIFFERENTIATION; MICROARRAY; REVEALS; SUBUNIT; FAMILY; PURIFICATION; SPECIFICITY; DISRUPTION; MUTATION AB Whether SWI/SNF chromatin remodeling complexes play roles in embryonic stem (ES) cells remains unknown. Here we show that SWI/SNF complexes are present in mouse ES cells, and their composition is dynamically regulated upon induction of ES cell differentiation. For example, the SWI/SNF purified from undifferentiated ES cells contains a high level of BAF155 and a low level of BAF170 (both of which are homologs of yeast SWI3 protein), whereas that from differentiated cells contains nearly equal amounts of both. Moreover, the levels of BAF250A and BAF250B decrease during the differentiation of ES cells, whereas that of BRM increases. The altered expression of SWI/SNF components hinted that these complexes could play roles in ES cell maintenance or differentiation. We therefore generated ES cells with biallelic inactivation of BAF250B and found that these cells display a reduced proliferation rate and an abnormal cell cycle. Importantly, these cells are deficient in the self-renewal capacity of undifferentiated ES cells and exhibit certain phenotypes of differentiated cells, including reduced expression of several pluripotency-related genes and increased expression of some differentiation-related genes. These data suggest that the BAF250B-associated SWI/SNF is essential for mouse ES cells to maintain their normal proliferation and pluripotency. The work presented here underscores the importance of SWI/SNF chromatin remodeling complexes in pluripotent stem cells. C1 [Yan, Zhijiang; Ling, Chen; Wang, Weidong] NIA, Genome Instabil & Chromatin Remodeling Sect, Genet Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. [Sharova, Lioudmila; Sharov, Alexei A.; Piao, Yulan; Aiba, Kazuhiro; Matoba, Ryo; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. [Wang, Zhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Richard B Simches Res Ctr, Boston, MA USA. RP Wang, W (reprint author), NIA, Genome Instabil & Chromatin Remodeling Sect, Genet Lab, Natl Inst Hlth, Baltimore, MD 21224 USA. EM wangw@grc.nia.nih.gov; kom@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS [Z01 AG000662-07, Z01 AG000650-09] NR 43 TC 87 Z9 89 U1 0 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2008 VL 26 IS 5 BP 1155 EP 1165 DI 10.1634/stemcells.2007-0846 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 305SB UT WOS:000256197000008 PM 18323406 ER PT J AU Pawelczyk, E Arbab, AS Chaudhry, A Balakumaran, A Robey, PG Frank, JA AF Pawelczyk, Edyta Arbab, Ali S. Chaudhry, Aneeka Balakumaran, Arun Robey, Pamela G. Frank, Joseph A. TI In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: Implications for cellular therapy SO STEM CELLS LA English DT Article DE human bone marrow stromal cells; activated macrophages; cell labeling; superparamagnetic iron oxide nanoparticles; bromodeoxyuridine; ferumoxides; protamine sulfate ID ENDOTHELIAL PROGENITOR CELLS; INFLAMMATORY RESPONSE; STROMAL CELLS; GLIOMA MODEL; SPINAL-CORD; RAT-BRAIN; TRANSPLANTATION; VIVO; MRI; DIFFERENTIATION AB There is increasing interest in using exogenous labels such as bromodeoxyuridine (BrdU) or superparamagnetic iron oxide nanoparticles (SPION) to label cells to identify transplanted cells and monitor their migration by fluorescent microscopy or in vivo magnetic resonance imaging (MRI), respectively. Direct implantation of cells into target tissue can result in >80% cell death due to trauma or apoptosis. Bystander uptake of labeled cells by activated macrophages (AM) can confound the interpretation of results. This study investigated the frequency of BrdU or SPION uptake by AM using the Boyden chamber model of inflammation. SPION/BrdU-Iabeled bone marrow stromal cells or HeLa cells, AM, and mouse fibroblasts (MF) or human fibroblasts (HF) were mixed in various ratios in Matrigel in the upper chamber and incubated for up to 96 hours. The AM were chemotactically induced to migrate to the lower chamber. Fluorescence-activated cell sorting analysis of AM from lower and upper chambers, in the presence of either MF or HF using anti-CD68, anti-BrdU, anti-dextran antibodies, revealed 10%-20% dextran-positive or 10% BrdU-positive AM after 96 hours of incubation. Transfer of iron to AM accounted for <10% of the total iron in labeled cells. The uptake of BrdU and SPION was dependent on the ratio of labeled cells to inflammatory cells and microenvironmental conditions. Direct implantation of BrdU/SPION-labeled cells into target tissue can result in uptake of label by AM; therefore, care should be taken to validate by histology transplanted cells for bystander cell markers and correlation with MRI results. C1 [Pawelczyk, Edyta; Chaudhry, Aneeka; Frank, Joseph A.] Henry Ford Hlth Syst, Expt Neuroimaging Sect Lab Diagnost Radiol Res, Ctr Clin, Detroit, MI USA. [Arbab, Ali S.] Henry Ford Hlth Syst, Dept Radiol, Detroit, MI USA. [Balakumaran, Arun; Robey, Pamela G.] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Bethesda, MD USA. RP Pawelczyk, E (reprint author), Bldg 10,Room B1N256,10 Ctr Dr, Bethesda, MD 20892 USA. EM pawelczyke@cc.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Intramural NIH HHS NR 36 TC 75 Z9 78 U1 1 U2 12 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD MAY PY 2008 VL 26 IS 5 BP 1366 EP 1375 DI 10.1634/stemcells.2007-0707 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 305SB UT WOS:000256197000028 PM 18276802 ER PT J AU Seidel, C Wondrak, M Grade, M Ried, T Claes, E Kunz-Schughart, LA AF Seidel, C. Wondrak, M. Grade, M. Ried, T. Claes, E. Kunz-Schughart, L. A. TI Exploring expression and therapeutic relevance of CD133 positive subpopulations of colorectal cancer cell lines SO STRAHLENTHERAPIE UND ONKOLOGIE LA English DT Meeting Abstract CT 14th Annual Congress of the Deutschen-Gesellschaft-fur-Radioonkologie/25th Annual Conference of the Osterreichischen-Gesellschaft-fur-Radioonkologie-Radiobiologie-und-Mediz inische-Radiophysik CY NOV 15-19, 2006 CL Vienna, AUSTRIA SP Desche Gesell Radioonkol, Osterreich Gesell Radioonkol Radiobiol & Med Radiophys C1 [Seidel, C.; Wondrak, M.; Claes, E.; Kunz-Schughart, L. A.] Fac Med Carl Gustav Carus, Ctr Radiat Res Oncol, OncoRay, Dresden, Germany. [Grade, M.; Ried, T.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD MAY PY 2008 VL 184 SU 1 BP 122 EP 122 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 289DH UT WOS:000255034700330 ER PT J AU Ay, H Arsava, EM Rosand, J Furie, KL Singhal, AB Schaefer, PW Wu, O Gonzalez, RG Koroshetz, WJ Sorensen, AG AF Ay, Hakan Arsava, E. Murat Rosand, Jonathan Furie, Karen L. Singhal, Aneesh B. Schaefer, Pamela W. Wu, Ona Gonzalez, R. Gilberto Koroshetz, Walter J. Sorensen, A. Gregory TI Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke SO STROKE LA English DT Article DE acute stroke; cerebral infarct; diffusion-weighted imaging; leukoaraiosis; MRI ID WHITE-MATTER LESIONS; APOLIPOPROTEIN-E POLYMORPHISM; CEREBRAL-ARTERY OCCLUSION; ACUTE ISCHEMIC-STROKE; HYPERINTENSITY VOLUME; BINSWANGERS-DISEASE; INTRACRANIAL VOLUME; KNOCKOUT MICE; FOLLOW-UP; MRI AB Background and Purpose-Leukoaraiosis (LA) is associated with structural and functional vascular changes that may compromise tissue perfusion at the microvascular level. We hypothesized that the volume of LA correlated with the proportion of initially ischemic but eventually infarcted tissue in acute human stroke. Methods-We studied 61 consecutive patients with diffusion-weighted imaging-mean transit time mismatch. All patients were scanned twice within 12 hours of symptom onset and between days 4 and 30. We explored the relationship between the volume of white matter regions with LA on acute images and the proportion of diffusion-weighted imaging-mean transit time mismatch tissue that progressed to infarction (percentage mismatch lost). Results-Bivariate analyses showed a statistically significant correlation between percentage mismatch lost and LA volume (r = 0.33, P<0.01). A linear regression model with percentage mismatch lost as response and LA volume, acute diffusion-weighted imaging and mean transit time volumes, age, admission blood glucose level, admission mean arterial blood pressure, etiologic stroke subtype, time to acute MRI, and time between acute and follow-up imaging as covariates revealed that LA volume was an independent predictor of infarct growth (P = 0.04). The adjusted percentage mismatch lost in the highest quartile of LA volume was 1.9-fold (95% CI: 1.2 to 3.1) greater than the percentage mismatch lost in the lowest quartile. Conclusion-LA volume at the time of acute ischemic stroke is a predictor infarct growth. Because LA is associated with factors that modulate tissue perfusion as well as tissue capacity for handling of ischemia, LA volume appears to be a composite predictive marker for the fate of acutely ischemic tissue. C1 [Ay, Hakan; Arsava, E. Murat; Schaefer, Pamela W.; Wu, Ona; Gonzalez, R. Gilberto; Sorensen, A. Gregory] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,AA Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ay, Hakan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Stroke Serv, Charlestown, MA 02129 USA. [Ay, Hakan; Rosand, Jonathan; Furie, Karen L.; Singhal, Aneesh B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Stroke Serv, Charlestown, MA 02129 USA. [Rosand, Jonathan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02129 USA. [Rosand, Jonathan] Broad Inst MIT, Program Med & Populat Genet, Cambridge, MA USA. [Rosand, Jonathan] Harvard Univ, Cambridge, MA 02138 USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD 20892 USA. RP Ay, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,AA Martinos Ctr Biomed Imaging, 149 13th St,Room 2301, Charlestown, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013 OI Arsava, Ethem Murat/0000-0002-6527-4139 FU AHRQ HHS [R01-HS11392-02]; NCRR NIH HHS [P41-RR14075]; NINDS NIH HHS [R01-NS38477-04] NR 40 TC 75 Z9 82 U1 1 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 MAY PY 2008 VL 39 IS 5 BP 1409 EP 1413 DI 10.1161/STROKEAHA.107.501932 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 294GG UT WOS:000255393100004 PM 18340093 ER PT J AU Foroud, T Sauerbeck, L Brown, R Anderson, C Woo, D Kleindorfer, D Flaherty, ML Deka, R Hornung, R Meissner, I Bailey-Wilson, JE Rouleau, G Connolly, ES Lai, DB Koller, DL Huston, J Broderick, JP AF Foroud, Tatiana Sauerbeck, Laura Brown, Robert Anderson, Craig Woo, Daniel Kleindorfer, Dawn Flaherty, Matthew L. Deka, Ranjan Hornung, Richard Meissner, Irene Bailey-Wilson, Joan E. Rouleau, Guy Connolly, E. Sander Lai, Dongbing Koller, Daniel L. Huston, John, III Broderick, Joseph P. CA FIA Study Investigators TI Genome screen to detect linkage to intracranial aneurysm susceptibility genes - The Familial Intracranial Aneurysm (FIA) study SO STROKE LA English DT Article DE intracranial aneurysm; linkage; single nucleotide polymorphism; gene x environment interaction; smoking ID SUBARACHNOID HEMORRHAGE; CEREBRAL ANEURYSMS; CHROMOSOME 19Q13.3; ELASTIN GENE; HAPLOTYPE; HISTORY; LOCUS; ASSOCIATION; MAPS; 7Q11 AB Background and Purpose-Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods-Multiplex families having at least 2 individuals with "definite" or "probable" IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene X smoking (pack- years) interaction. Results-The greatest evidence of linkage was found on chromosomes 4 (LOD = 2.5; 156 cM), 7 (LOD = 1.7; 183 cM), 8 (LOD = 1.9; 70 cM), and 12 (LOD = 1.6; 102 cM) using the broad disease definition. Using the average pack- years for the affected individuals in each family, the genes on chromosomes 4 (LOD = 3.5; P = 0.03), 7 (LOD = 4.1; P = 0.01) and 12 (LOD = 3.6; P = 0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions - We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene X smoking interaction with 3 of the loci. C1 [Foroud, Tatiana; Lai, Dongbing; Koller, Daniel L.] Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. [Sauerbeck, Laura; Woo, Daniel; Kleindorfer, Dawn; Flaherty, Matthew L.; Deka, Ranjan; Broderick, Joseph P.] Univ Cincinnati, Sch Med, Cincinnati, OH 45221 USA. [Brown, Robert; Meissner, Irene; Huston, John, III] Mayo Clin, Rochester, MN USA. [Anderson, Craig] Univ Sydney, George Inst Int Hlth, Sydney, NSW 2006, Australia. [Hornung, Richard] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. [Bailey-Wilson, Joan E.] NHGRI, Baltimore, MD USA. [Rouleau, Guy] Univ Montreal, Notre Dame Hosp, Montreal, PQ H3C 3J7, Canada. [Connolly, E. Sander] Columbia Univ, New York, NY USA. RP Foroud, T (reprint author), Indiana Univ, Sch Med, Hlth Informat & Translat Sci Bldg HS 4000,410 W 1, Indianapolis, IN 46202 USA. EM tforoud@iupui.edu RI Hankey, Graeme /H-4968-2014; OI Hankey, Graeme /0000-0002-6044-7328; Bailey-Wilson, Joan/0000-0002-9153-2920 FU NHGRI NIH HHS [N01HG65403]; NINDS NIH HHS [R01 NS039512, R01 NS039512-05, R01 NS39512, T32 NS047996] NR 37 TC 27 Z9 28 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 MAY PY 2008 VL 39 IS 5 BP 1434 EP 1440 DI 10.1161/STROKEAHA.107.502930 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 294GG UT WOS:000255393100008 PM 18323491 ER PT J AU Matarin, M Brown, WM Singleton, A Hardy, JA Meschia, JF AF Matarin, Mar Brown, W. Mark Singleton, Andrew Hardy, John A. Meschia, James F. CA ISGS Investigators TI Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21 SO STROKE LA English DT Article DE ischemic stroke; genetics; heart disease; diabetes ID WIDE ASSOCIATION; VARIANTS; RISK; LOCI AB Background and Purpose - Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near CDKN2A and CDKN2B genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population. Methods - We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using > 400 000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block. Results - In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65). Conclusions - These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery. C1 [Matarin, Mar; Singleton, Andrew] NIA, Mol Genet Unit, Neurogenet Lab, Natl Inst Hlth,Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Brown, W. Mark] Wake Forest Univ Hlth Sci, Biostat Sect, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. [Hardy, John A.] UCL, Reta Lila Weston Inst Neurol Studies, Neurol Inst, London WC1E 6BT, England. [Meschia, James F.] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. RP Matarin, M (reprint author), NIA, Mol Genet Unit, Neurogenet Lab, Natl Inst Hlth,Porter Neurosci Res Ctr, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM delmarm@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Matarin, Mar/F-1771-2016 OI Matarin, Mar/0000-0002-4717-5735 FU Intramural NIH HHS; Medical Research Council [G0701075]; NINDS NIH HHS [R01 NS042733, R01 NS42733] NR 12 TC 95 Z9 97 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 MAY PY 2008 VL 39 IS 5 BP 1586 EP 1589 DI 10.1161/STROKEAHA.107.502963 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 294GG UT WOS:000255393100032 PM 18340101 ER PT J AU Wintermark, M Albers, GW Alexandrov, AV Alger, JR Bammer, R Baron, JC Davis, S Demaerschalk, BM Derdeyn, CP Donnan, GA Eastwood, JD Fiebach, JB Fisher, M Furie, KL Goldmakher, GV Hacke, W Kidwell, CS Kloska, SP Kohrmann, M Koroshetz, W Lee, TY Lees, KR Lev, MH Liebeskind, DS Ostergaard, L Powers, WJ Provenzale, J Schellinger, P Silbergleit, R Sorensen, AG Wardlaw, J Warach, S AF Wintermark, Max Albers, Gregory W. Alexandrov, Andrei V. Alger, Jeffry R. Bammer, Roland Baron, Jean-Claude Davis, Stephen Demaerschalk, Bart M. Derdeyn, Colin P. Donnan, Geoffrey A. Eastwood, James D. Fiebach, Jochen B. Fisher, Marc Furie, Karen L. Goldmakher, Gregory V. Hacke, Werner Kidwell, Chelsea S. Kloska, Stephan P. Koehrmann, Martin Koroshetz, Walter Lee, Ting-Yim Lees, Kennedy R. Lev, Michael H. Liebeskind, David S. Ostergaard, Leif Powers, William J. Provenzale, James Schellinger, Peter Silbergleit, Robert Sorensen, Alma Gregory Wardlaw, Joanna Warach, Steven TI Acute stroke imaging research roadmap SO STROKE LA English DT Article DE acute stroke; CT; magnetic resonance; outcomes; thrombolysis; perfusion imaging AB The recent "Advanced Neuroimaging for Acute Stroke Treatment" meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them. C1 [Wintermark, Max] Univ Calif San Francisco, Dept Radiol, Neuroradiol Sect, San Francisco, CA 94143 USA. [Albers, Gregory W.; Bammer, Roland] Stanford Univ, Palo Alto, CA USA. [Alexandrov, Andrei V.] Univ Alabama, Comprehens Stroke Ctr, Birmingham, AL USA. [Alger, Jeffry R.] Univ Calif Los Angeles, Los Angeles, CA USA. [Baron, Jean-Claude] Addenbrookes Hosp, Dept Neurol, Cambridge, England. [Davis, Stephen] Univ Melbourne, Royal Melbourne Hosp, Dept Neurol, Parkville, Vic 3052, Australia. [Demaerschalk, Bart M.] Mayo Clin, Phoenix, AZ USA. [Derdeyn, Colin P.] Washington Univ, St Louis, MO USA. [Donnan, Geoffrey A.] Univ Melbourne, Natl Stroke Res Inst, Parkville, Vic 3052, Australia. [Eastwood, James D.; Provenzale, James] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Fiebach, Jochen B.] Charite Univ Hosp & Berlin, NeuroImaging Ctr BNIC, Berlin, Germany. [Fisher, Marc] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Furie, Karen L.; Goldmakher, Gregory V.; Lev, Michael H.; Sorensen, Alma Gregory] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hacke, Werner] Univ Heidelberg, D-6900 Heidelberg, Germany. [Kidwell, Chelsea S.] Georgetown Univ, Washington Hosp Ctr, Washington, DC USA. [Kloska, Stephan P.] Univ Munster, Dept Clin Radiol, Munster, Germany. [Koehrmann, Martin] Univ Clin, Dept Neurol, Erlangen, Germany. [Koroshetz, Walter; Warach, Steven] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. [Lees, Kennedy R.] Univ Glasgow, Western Infirm, Univ Dept Med & Therapeut, Glasgow G12 8QQ, Lanark, Scotland. [Liebeskind, David S.] Univ Calif Los Angeles, Los Angeles Stroke Ctr, Los Angeles, CA 90024 USA. [Ostergaard, Leif] Ctr Funct Integrat Neurosci, Dept Neuroradiol, Aarhus, Denmark. [Powers, William J.] Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. [Schellinger, Peter] Univ Clin, Dept Neurol, Erlangen, Germany. [Silbergleit, Robert] Univ Michigan, Ann Arbor, MI 48109 USA. [Wardlaw, Joanna] Western Gen Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. RP Wintermark, M (reprint author), Univ Calif San Francisco, Dept Radiol, Neuroradiol Sect, 505 Parnassus Ave,Box 0628, San Francisco, CA 94143 USA. EM Max.Wintermark@radiology.ucsf.edu RI Bonefeld, Birgit/B-7936-2010; Ostergaard, Leif/A-9281-2008; Lee, Ting-Yim/M-1721-2013; Davis, Stephen/L-5260-2013; OI Ostergaard, Leif/0000-0003-2930-6997; Kaste, Markku/0000-0001-6557-6412; baron, jean-claude/0000-0002-5264-2588; Davis, Stephen/0000-0003-0962-2300; Alexandrov, Andrei V/0000-0001-8871-1023; Fiebach, Jochen B./0000-0002-7936-6958; Wintermark, Max/0000-0002-6726-3951; Derdeyn, Colin/0000-0002-5932-2683; Donnan, Geoffrey/0000-0001-6324-3403 FU NINDS NIH HHS [1R13NS061371-01] NR 0 TC 134 Z9 135 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAY PY 2008 VL 39 IS 5 BP 1621 EP 1628 DI 10.1161/STROKEAHA.107.512319 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 294GG UT WOS:000255393100043 PM 18403743 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI Telling bacteria: Do not LytTR SO STRUCTURE LA English DT Editorial Material ID RESPONSE REGULATORS; DOMAIN AB Transcriptional regulators containing the LytTR-type DNA-binding domain control production of virulence factors in several bacterial pathogens. In this issue of Structure, Sidote et al. report the crystal structure of this elusive domain in complex with its DNA target (Sidote et al., 2008). C1 [Galperin, Michael Y.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z01 LM000061-14, Z01 LM000073-12, Z99 LM999999] NR 8 TC 21 Z9 21 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAY PY 2008 VL 16 IS 5 BP 657 EP 659 DI 10.1016/j.str.2008.04.003 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 299AR UT WOS:000255728700003 PM 18462668 ER PT J AU Levy-Clarke, GA Greenman, D Sieving, PC Byrnes, G Shen, D Nussenblatt, R Chan, CC AF Levy-Clarke, Grace A. Greenman, David Sieving, Pamela C. Byrnes, Gordon Shen, Defen Nussenblatt, Robert Chan, Chi-Chao TI Ophthalmic manifestations, cytology, immunohistochemistry, and molecular analysis of intraocular metastatic T-cell lymphoma: Report of a case and review of the literature SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE metastatic; primary cutaneous peripheral T-cell lymphoma; primary intraocular lymphoma; T-cell lymphoma ID POLYMERASE-CHAIN-REACTION; NERVOUS-SYSTEM LYMPHOMA; VIRUS TYPE-I; MYCOSIS-FUNGOIDES; OCULAR INVOLVEMENT; CUTANEOUS LYMPHOMAS; TREATMENT OUTCOMES; DIAGNOSIS; LEUKEMIA/LYMPHOMA; MICRODISSECTION AB We report a case of T-cell lymphoma metastatic to the eye, with an accompanying review of the literature. A 78-year-old white male with bilateral vitritis was diagnosed with primary cutaneous peripheral T-cell lymphoma unspecified, via vitreous biopsy. The tumor was found to be clonally related to the prior cutaneous malignancy using cytology, immunophenotyping, and molecular analysis. The vast majority of primary intraocular lymphomas are malignant B-cells, whereas intraocular T-cell lymphomas are uncommon. This case demonstrates the utility of immunophenotyping and molecular analysis with microdissection and polymerase chain reaction, as critical adjunctive studies, in patients presenting with a masquerade syndrome, and later diagnosed with T-cell intraocular lymphomas. Vitreo-retinal without uveal involvement in this case, similar to many ocular metastatic T-cell lymphomas reported in the literature, is particularly intriguing becuase the uvea, not retina, is the typical ocular tissue involvement in the majority of metastatic B-cell lymphomas. C1 [Levy-Clarke, Grace A.; Greenman, David; Shen, Defen; Nussenblatt, Robert; Chan, Chi-Chao] NEI, NIH, Bethesda, MD 20892 USA. [Sieving, Pamela C.] Natl Inst Hlth Lib, NIH, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Byrnes, Gordon] Retina Grp Washington, Chevy Chase, MA USA. RP Levy-Clarke, GA (reprint author), 9400 9th St N, St Petersburg, FL 33702 USA. OI Sieving, Pamela/0000-0003-3794-5000 FU Intramural NIH HHS [Z01 EY000222-22] NR 52 TC 23 Z9 23 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD MAY-JUN PY 2008 VL 53 IS 3 BP 285 EP 295 DI 10.1016/j.survophthal.2008.02.004 PG 11 WC Ophthalmology SC Ophthalmology GA 307QO UT WOS:000256333600007 PM 18501272 ER PT J AU Thanos, PK Michaelides, M Benveniste, H Wang, GJ Volkow, ND AF Thanos, Panayotis K. Michaelides, Michael Benveniste, Helene Wang, Gene Jack Volkow, Nora D. TI The effects of cocaine on regional brain glucose metabolism is attenuated in dopamine transporter knockout mice SO SYNAPSE LA English DT Article DE PET; drug abuse; ADHD; DAT; insulin ID ENERGY-METABOLISM; NUCLEUS-ACCUMBENS; PLACE PREFERENCE; RAT; LACKING; REWARD; GENE; TIME; AMPHETAMINE; PHENOTYPE AB Cocaine's ability to block the dopamine transporter (DAT) is crucial for its reinforcing effects. However the brain functional consequences of DAT blockade by cocaine are less clear since they are confounded by its concomitant blockade of norepinephrine and serotonin transporters. To separate the dopaminergic from the non-dopaminergic effects of cocaine on brain function we compared the regional brain metabolic responses to cocaine between dopamine transporter deficient (DAT(-/-)) mice with that of their DAT(+/+) littermates. We measured regional brain metabolism (marker of brain function) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and microPET (mu PET) before and after acute cocaine administration (i.p. 10 mg/kg). Scans were conducted 2 weeks apart. At baseline DAT-/- mice had significantly greater metabolism in thalamus and cerebellum than DAT(+/+). Acute cocaine decreased whole brain metabolism and this effect was greater in DAT(+/+) (15%) than in DAT(-/-) mice (5%). DAT(+/+) mice showed regional decreases in the olfactory bulb, motor cortex, striatum, hippocampus, thalamus and cerebellum whereas DAT(-/-) mice showed decreases only in thalamus. The differential pattern of regional responses to cocaine in DAT(-/-) and DAT(+/+) suggests that most of the brain metabolic changes from acute cocaine are due to DAT blockade. Cocaine-induced decreases in metabolism in thalamus (region with dense noradrenergic innervation) in DAT(-/-) suggest that these were mediated by cocaine's blockade of norepinephrine transporters. The greater baseline metabolism in DAT(-/-) than DAT(+/+) mice in cerebellum (brain region mostly devoid of DAT) suggests that dopamine indirectly regulates activity of these brain regions. C1 [Thanos, Panayotis K.; Michaelides, Michael; Benveniste, Helene; Wang, Gene Jack] Brookhaven Natl Lab, Behav Neuropharmacol Lab, Dept Med, Upton, NY 11973 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, NIH, Dept Hlth & Human Serv, Lab Neuroimaging, Bethesda, MD 20892 USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Behav Neuropharmacol Lab, Dept Med, Upton, NY 11973 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU Intramural NIH HHS [Z01 AA000551-04]; NIAAA NIH HHS [R01 AA011034, T32 AA007574, AA07574, AA 11034, AA07611, P50 AA007611]; NIDA NIH HHS [R01 DA013511, DA-013511]; NINDS NIH HHS [R01 NS019576, NS-019576] NR 38 TC 26 Z9 26 U1 0 U2 3 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 MAY PY 2008 VL 62 IS 5 BP 319 EP 324 DI 10.1002/syn.20503 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 284CA UT WOS:000254681600001 PM 18286542 ER PT J AU De Zorzi, M Caggiari, L Ahlenstiel, G Rehermann, B De Re, V AF De Zorzi, M. Caggiari, L. Ahlenstiel, G. Rehermann, B. De Re, V. TI Description of two new major histocompatibility complex (MHC) class II DRB1 [Pan troglodytes (Patr)-DRB1] alleles SO TISSUE ANTIGENS LA English DT Editorial Material DE DRB1; MHC class II; Pan troglodytes; polymerase chain reaction-sequence; based typing ID IDENTIFICATION; VIRUS C1 [De Zorzi, M.; Caggiari, L.; De Re, V.] Natl Canc Inst, IRCCS, Ctr Riferimento Oncol, Dipartimento Oncol Mol & Ric Traslaz, I-33081 Aviano, Italy. [Ahlenstiel, G.; Rehermann, B.] NIDDKD, Immunol Sect, Liver Dis Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP De Re, V (reprint author), Natl Canc Inst, IRCCS, Ctr Riferimento Oncol, Dipartimento Oncol Mol & Ric Traslaz, Via Franco Gallini 2, I-33081 Aviano, Italy. EM vdere@cro.it OI Ahlenstiel, Golo/0000-0003-0026-1457 FU Associazione Italiana per la Ricerca sul Cancro NR 6 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD MAY PY 2008 VL 71 IS 5 BP 490 EP U6 DI 10.1111/j.1399-0039.2008.01027.x PG 3 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 288PL UT WOS:000254998200021 PM 18346032 ER PT J AU Li, WJ Jiang, YJ Tuan, RS AF Li, Wan-Ju Jiang, Yi Jen Tuan, Rocky S. TI Cell-nanofiber-based cartilage tissue engineering using improved cell seeding, growth factor, and bioreactor technologies SO TISSUE ENGINEERING PART A LA English DT Article ID ARTICULAR-CARTILAGE; MECHANICAL-PROPERTIES; DENSITY CULTURES; STEM-CELLS; CHONDROGENESIS; CHONDROCYTES; SCAFFOLDS; MODULATE; SYSTEM AB Biodegradable nanofibrous scaffolds serving as an extracellular matrix substitute have been shown to be applicable for cartilage tissue engineering. However, a key challenge in using nanofibrous scaffolds for tissue engineering is that the small pore size limits the infiltration of cells, which may result in uneven cell distribution throughout the scaffold. This study describes an effective method of chondrocyte loading into nanofibrous scaffolds, which combines cell seeding, mixing, and centrifugation to form homogeneous, packed cell-nanofiber composites (CNCs). When the effects of different growth factors are compared, CNCs cultured in medium containing a combination of insulin-like growth factor-1 and transforming growth factor-beta 1 express the highest mRNA levels of collagen type II and aggrecan. Radiolabeling analyses confirm the effect on collagen and sulfated-glycosaminoglycans (sGAG) production. Histology reveals chondrocytes with typical morphology embedded in lacuna-like space throughout the entire structure of the CNC. Upon culturing using a rotary wall vessel bioreactor, CNCs develop into a smooth, glossy cartilage-like tissue, compared to a rough-surface tissue when maintained in a static environment. Bioreactor-grown cartilage constructs produce more total collagen and sGAG, resulting in greater gain in net tissue weight, as well as express cartilage-associated genes, including collagen types II and IX, cartilage oligomeric matrix protein, and aggrecan. In addition, dynamic culture enhances the mechanical property of the engineered cartilage. Taken together, these results indicate the applicability of nanofibrous scaffolds, combined with efficient cell loading and bioreactor technology, for cell-based cartilage tissue engineering. C1 [Li, Wan-Ju; Jiang, Yi Jen; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1523,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural NIH HHS [ZIA AR041178-02]; NIAMS NIH HHS [Z01 AR041131] NR 35 TC 25 Z9 28 U1 1 U2 10 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD MAY PY 2008 VL 14 IS 5 BP 639 EP 648 DI 10.1089/tea.2007.0136 PG 10 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 306HV UT WOS:000256239800007 PM 18419231 ER PT J AU Rosen, MB Lee, JS Ren, H Vallanat, B Liu, J Waalkes, MP Abbott, BD Lau, C Corton, C AF Rosen, Mitchell B. Lee, Janice S. Ren, Hongzu Vallanat, Beena Liu, Jie Waalkes, Michael P. Abbott, Barbara D. Lau, Christopher Corton, Christopher TI Toxicogenomic dissection of the perfluorooctanoic acid transcript profile in mouse liver: Evidence for the involvement of nuclear receptors PPAR alpha and CAR SO TOXICOLOGICAL SCIENCES LA English DT Article DE peroxisome proliferator; perfluorinated alkyl acid; perfluorooctanoic acid; liver cancer ID CONSTITUTIVE ANDROSTANE RECEPTOR; PROLIFERATOR-ACTIVATED RECEPTORS; RETINOID-X-RECEPTOR; PEROXISOME PROLIFERATORS; NONGENOTOXIC CARCINOGEN; GENE-EXPRESSION; FEMALE RATS; MICE; GAMMA; TOXICITY AB A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects linked to liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). To determine the role of PPAR alpha in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPAR alpha-null mice exposed to PFOA or the PPAR alpha agonist WY-14,643 (WY). After 7 days of exposure, 85% or 99.7% of the genes altered by PFOA or WY exposure, respectively were dependent on PPAR alpha. The PPAR alpha-independent genes regulated by PFOA included those involved in lipid homeostasis and xenobiotic metabolism. Many of the lipid homeostasis genes including acyl-CoA oxidase (Acox1) were also regulated by WY in a PPAR alpha-dependent manner. The increased expression of these genes in PPAR alpha-null mice may be partly due to increases in PPAR gamma expression upon PFOA exposure. Many of the identified xenobiotic metabolism genes are known to be under control of the nuclear receptor CAR (constitutive activated/androstane receptor) and the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). There was excellent correlation between the transcript profile of PPAR alpha-independent PFOA genes and those of activators of CAR including phenobarbital and 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) but not those regulated by the Nrf2 activator, dithiol-3-thione. These results indicate that PFOA alters most genes in wild-type mouse liver through PPAR alpha, but that a subset of genes are regulated by CAR and possibly PPAR gamma in the PPAR alpha-null mouse. C1 [Rosen, Mitchell B.; Lee, Janice S.; Ren, Hongzu; Vallanat, Beena; Abbott, Barbara D.; Lau, Christopher; Corton, Christopher] US EPA, NHEERL, ORD, Res Triangle Pk, NC 27711 USA. [Ren, Hongzu; Vallanat, Beena; Corton, Christopher] US EPA, NHEERL Toxicogenom Core, Res Triangle Pk, NC 27711 USA. [Liu, Jie; Waalkes, Michael P.] Natl Canc Inst, Res Triangle Pk, NC 27711 USA. RP Corton, C (reprint author), US EPA, Natl Hlth & Environm Effects, Div Environm Carcinogenesis, 109 TW Alexander Dr,MD-B143-06, Res Triangle Pk, NC 27711 USA. EM corton.chris@epa.gov FU Intramural NIH HHS NR 44 TC 81 Z9 82 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2008 VL 103 IS 1 BP 46 EP 56 DI 10.1093/toxsci/kfn025 PG 11 WC Toxicology SC Toxicology GA 287ZH UT WOS:000254955500006 PM 18281256 ER PT J AU Morgan, DL Flake, GP Kirby, PJ Palmer, SM AF Morgan, Daniel L. Flake, Gordon P. Kirby, Patrick J. Palmer, Scott M. TI Respiratory toxicity of diacetyl in C57Bl/6 mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE diacetyl; inhalation; mice; lymphocytic bronchitis; obliterative bronchiolitis; microwave popcorn; artificial butter flavoring ID ALPHA,BETA-UNSATURATED KETONES; BRONCHIOLITIS OBLITERANS; INHALATION TOXICITY; REPEATED EXPOSURE; NASAL PASSAGES; RATS; HAMSTERS; WORKERS; VAPOR; RISK AB Diacetyl, a component of artificial butter flavoring, is a potential etiological agent of obliterative bronchiolitis (OB); however, the toxic dose and mechanisms of toxicity remain controversial. We evaluated the respiratory toxicity of diacetyl in a murine model using several exposure profiles relevant to workplace conditions at microwave popcorn packaging plants. Male C57Bl/6 mice were exposed to inhaled diacetyl across several concentrations and duration profiles, or by direct oropharyngeal aspiration. Effects of diacetyl on the respiratory tract were evaluated by histopathology and BALF analyses. Subacute exposure to 200 or 400 ppm diacetyl for 5 days caused deaths, necrotizing rhinitis, necrotizing laryngitis and bronchitis. Reducing the exposure to 1 h/day (100, 200, 400 ppm) for 4 weeks resulted in less nasal and laryngeal toxicity, but led to peribronchial and peribronchiolar lymphocytic inflammation. A similar pattern was observed with intermittent high-dose exposures at 1200 ppm (15 min, twice a day, 4 weeks). Subchronic exposures to 100 ppm (6 h/day, 12 weeks) caused moderate nasal injury, and peribronchial lymphocytic inflammation accompanied by epithelial atrophy, denudation, and regeneration. Treatment with 400 mg/kg by oropharyngeal aspiration to bypass the nose caused foci of fibrohistiocytic proliferation with little or no inflammation at the junction of the terminal bronchiole and alveolar duct. Depending on the route and duration of exposure, diacetyl causes significant epithelial injury, peribronchial lymphocytic inflammation, or fibrohistiocytic lesions in the terminal bronchioles. Collectively these results indicate that clinically relevant diacetyl exposures result in a pattern of injury that replicates features of human OB. C1 [Morgan, Daniel L.; Kirby, Patrick J.] NIEHS, Mol Toxicol Lab, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Flake, Gordon P.] NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. [Palmer, Scott M.] Duke Univ, Med Ctr, Dept Med, Div Pulm & Crit Care, Durham, NC 27710 USA. RP Morgan, DL (reprint author), NIEHS, Mol Toxicol Lab, Natl Toxicol Program, MD IF-00, Res Triangle Pk, NC 27709 USA. EM morgan3@niehs.nih.gov FU Intramural NIH HHS [Z01 ES101865-03] NR 28 TC 39 Z9 42 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD MAY PY 2008 VL 103 IS 1 BP 169 EP 180 DI 10.1093/toxsci/kfn016 PG 12 WC Toxicology SC Toxicology GA 287ZH UT WOS:000254955500018 PM 18227102 ER PT J AU Kang, JS Wanibuchi, H Morimura, K Wongpoomchai, R Chusiri, Y Gonzalez, FJ Fukushima, S AF Kang, Jin Seok Wanibuchi, Hideki Morimura, Keiichirou Wongpoomchai, Rawiwan Chusiri, Yaowares Gonzalez, Frank J. Fukushima, Shoji TI Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE thioacetamide (TAA); hepatotoxicity; CYP2E1; Cyp2e1-null mice; oxidative stress ID INDUCED HEPATIC-NECROSIS; CYTOCHROME-P450 2E1; OXIDATIVE STRESS; LIVER-CIRRHOSIS; RATS; EXPRESSION; MICE; INDUCTION; TOXICITY; INJURY AB Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. However, there is no direct evidence on the role of CYP2E1 in TAA-mediated hepatotoxicity. To clarify this, TAA-induced hepatotoxicity was investigated using Cyp2e1-null mice. Male wild-type and Cyp2e1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and hepatotoxicity examined 24 and 48 h after TAA treatment. Relative liver weights of Cyp2e1-null mice were significantly different at 24 h compared to wild-type mice (p < 0.01). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in Cyp2e1-null mice were significantly different at both time points compared to wildtype mice (p < 0.01). Histopathological examination showed Cyp2e1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was also only limited to wild-type mice (p < 0.01). Similarly, TNF-alpha, IL-6 and glutathione peroxidase mRNA expression in Cyp2e1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (p < 0.01). Western blot analysis further revealed no increase in iNOS expression in Cyp2e1-null mice. These results reveal that CYP2E1 mediates TAA-induced hepatotoxicity in wild-type mice as a result of increased oxidative stress. (c) 2008 Published by Elsevier Inc. C1 [Kang, Jin Seok; Wanibuchi, Hideki; Morimura, Keiichirou; Wongpoomchai, Rawiwan; Chusiri, Yaowares; Fukushima, Shoji] Osaka City Univ, Sch Med, Dept Pathol, Abeno Ku, Osaka 5458585, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Fukushima, S (reprint author), Osaka City Univ, Sch Med, Dept Pathol, Abeno Ku, 1-4-3 Asahi Machi, Osaka 5458585, Japan. EM s-fukushima@jisha.or.jp NR 28 TC 41 Z9 41 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 1 PY 2008 VL 228 IS 3 BP 295 EP 300 DI 10.1016/j.taap.2007.11.010 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 298SL UT WOS:000255707300004 PM 18374380 ER PT J AU Song, CC Xiao, Z Nagashima, K Li, CCH Lockett, SJ Dai, RM Cho, EH Conrads, TP Veenstra, TD Colburn, NH Wang, Q Wang, JM AF Song, Changcheng Xiao, Zhen Nagashima, Kunio Li, Chou-Chi H. Lockett, Stephen J. Dai, Ren-Ming Cho, Edward H. Conrads, Thomas P. Veenstra, Timothy D. Colburn, Nancy H. Wang, Qing Wang, Ji Ming TI The heavy metal cadmium induces valosin-containing protein (VCP)-mediated aggresome formation SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE cadmium; aggresome; ubiquitin proteasome system; HDAC6 ID HISTONE DEACETYLASE; CELLS; PROTEASOME; UBIQUITIN; ATPASE; AGGREGATION; IDENTIFICATION; DEGRADATION; PROTEOLYSIS; RESISTANCE AB Cadmium (Cd2+) is a heavy metal ion known to have a long biological half-life in humans. Accumulating evidence shows that exposure to Cd2+ is associated with neurodegenerative diseases characterized by the retention of ubiquitinated and misfolded proteins in the lesions. Here, we report that Cd2+ directly induces the formation of protein inclusion bodies in cells. The protein inclusion body is an aggresome, a major organelle for collecting ubiquitinated or misfolded proteins. Our results show that aggresomes are enriched in the detergent-insoluble fraction of Cd2+-treated cell lysates. Proteomic analysis identified 145 proteins in the aggresome-enriched fractions. One of the proteins is the highly conserved valosin-containing protein (VCP), which has been shown to colocalize with aggresomes and bind ubiquitinated proteins through its N domain (#1-200). Our subsequent examination of VCP's role in the formation of aggresomes induced by Cd2+ indicates that the C-terminal tail (#780-806) of VCP interacts with histone deacetylase HDAC6, a mediator for aggresome formation, suggesting that VCP participates in transporting ubiquitinated proteins to aggresomes. This function of VCP is impaired by inhibition of the deacetylase activity of HDAC6 or by over-expression of VCP mutants that do not bind ubiquitinated proteins or HDAC6. Our results indicate that Cd2+ induces the formation of protein inclusion bodies by promoting the accumulation of ubiquitinated proteins in aggresomes through VCP and HDAC6. Our delineation of the role of VCP in regulating cell responses to ubiquitinated proteins has important implications for understanding Cd2+ toxicity and associated diseases. (c) 2007 Elsevier Inc. All rights reserved. C1 [Song, Changcheng; Li, Chou-Chi H.; Dai, Ren-Ming; Colburn, Nancy H.; Wang, Qing] NCI, Lab Canc Prevent, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Xiao, Zhen; Conrads, Thomas P.; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. [Nagashima, Kunio; Lockett, Stephen J.; Cho, Edward H.] NCI, Image Anal Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Song, Changcheng; Wang, Ji Ming] NCI, Lab Mol Immunoregulat, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Song, Changcheng] Biogratech Inc, Gaithersburg, MD 20878 USA. RP Song, CC (reprint author), NCI, Lab Canc Prevent, Basic Res Program, SAIC Frederick Inc, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM songc@ncifcrf.gov RI Cho, Edward/B-3727-2012 OI Cho, Edward/0000-0002-0278-334X FU NCI NIH HHS [N01CO12400, N01-CO-12400, N01 CO012400] NR 48 TC 21 Z9 21 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAY 1 PY 2008 VL 228 IS 3 BP 351 EP 363 DI 10.1016/j.taap.2007.12.026 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 298SL UT WOS:000255707300010 PM 18261755 ER PT J AU Starr, T Ng, TW Wehrly, TD Knodler, LA Celli, J AF Starr, Tregei Ng, Tony W. Wehrly, Tara D. Knodler, Leigh A. Celli, Jean TI Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment SO TRAFFIC LA English DT Article DE Brucella; endocytic pathway; live cell imaging; pathogenesis; phagosome maturation; Rab7; vacuole acidification ID ENDOPLASMIC-RETICULUM; MURINE MACROPHAGES; LYSOSOME FUSION; HUMAN MONOCYTES; PROTEIN RILP; VIRB OPERON; ABORTUS; SURVIVAL; SUIS; PHAGOSOMES AB Upon entry into mammalian cells, the intracellular pathogen Brucella abortus resides within a membrane-bound compartment, the Brucella-containing vacuole (BCV), the maturation of which is controlled by the bacterium to generate a replicative organelle derived from the endoplasmic reticulum (ER). Prior to reaching the ER, Brucella is believed to ensure its intracellular survival by inhibiting fusion of the intermediate BCV with late endosomes and lysosomes, although such BCVs are acidic and accumulate the lysosomal-associated membrane protein (LAMP-1). Here, we have further examined the nature of intermediate BCVs using confocal microscopy and live cell imaging. We show that BCVs rapidly acquire several late endocytic markers, including the guanosine triphosphatase Rab7 and its effector Rab-interacting lysosomal protein (RILP), and are accessible to fluid-phase markers either delivered to the whole endocytic pathway or preloaded to lysosomes, indicating that BCVs interact with late endosomes and lysosomes. Consistently, intermediate BCVs are acidic and display proteolytic activity up to 12 h post-infection. Expression of dominant-negative Rab7 or overexpression of RILP significantly impaired the ability of bacteria to convert their vacuole into an ER-derived organelle and replicate, indicating that BCV maturation requires interactions with functional late endosomal/lysosomal compartments. In cells expressing dominant-negative Rab7[T22N], BCVs remained acidic, yet displayed decreased fusion with lysosomes. Taken together, these results demonstrate that BCVs traffic along the endocytic pathway and fuse with lysosomes, and such fusion events are required for further maturation of BCVs into an ER-derived replicative organelle. C1 [Starr, Tregei; Ng, Tony W.; Wehrly, Tara D.; Knodler, Leigh A.; Celli, Jean] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Celli, J (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov FU Intramural NIH HHS NR 27 TC 117 Z9 122 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD MAY PY 2008 VL 9 IS 5 BP 678 EP 694 DI 10.1111/j.1600-0854.2008.00718.x PG 17 WC Cell Biology SC Cell Biology GA 285RD UT WOS:000254793000007 PM 18266913 ER PT J AU Lee-Stroka, H Slezak, SL Adams, S Martin, J Robbins, FM Caruccio, L Byrne, KM Stroncek, DF AF Lee-Stroka, Hallie Slezak, Stefanie L. Adams, Sharon Martin, Joshua Robbins, Fu-Meei Caruccio, Lorraine Byrne, Karen M. Stroncek, David F. TI Another example of a KEL1 variant red cell phenotype due to a threonine to serine change at position 193 of Kell glycoprotein SO TRANSFUSION LA English DT Article ID BLOOD-GROUP PROTEIN; MOLECULAR-BASIS; GROUP SYSTEM; K1 ANTIGEN; EXPRESSION; XK AB Background: Healthy subjects whose red blood cells (RBCs) react variably with anti-KEL1, but strongly express other Kell blood group antigens, have been described and called KEL1 variant. A 53-year-old Caucasian blood donor was identified whose RBCs reacted with three monoclonal and two polyclonal anti-KEL1 and did not react with two monoclonal and one polyclonal anti-KEL1. The molecular basis of this phenotype was investigated. Study design and methods: Genomic white blood cell DNA was analyzed for KEL*1/2 genotype by utilizing sequence-specific primers and polymerase chain reaction. In addition, the region of the KEL*1/2 polymorphism at position 578 of KEL was analyzed by DNA sequencing. Results: Genotyping of the donor with the KEL1 variant phenotype revealed that he was KEL*2 homozygous. Sequencing revealed one typical KEL*2 allele and a KEL*2 allele with an adenosine (A) to thymidine (T) substitution at position 577 that predicted a threonine to serine change at position 193. Conclusion: It is not known if this phenotype is clinically relevant, but for at least some genotyping applications probes that identify this polymorphism should be used and anti-KEL1 should be tested for reactivity to this allele. C1 [Lee-Stroka, Hallie; Slezak, Stefanie L.; Adams, Sharon; Martin, Joshua; Robbins, Fu-Meei; Caruccio, Lorraine; Byrne, Karen M.; Stroncek, David F.] NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C711,10 Ctr Dr MSC 1184, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov FU Intramural NIH HHS [Z01 CL002095-11] NR 16 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD MAY PY 2008 VL 48 IS 5 BP 925 EP 929 DI 10.1111/j.1537-2995.2007.01623.x PG 5 WC Hematology SC Hematology GA 295TU UT WOS:000255497600019 PM 18248571 ER PT J AU Harbison, CE Chiorini, JA Parrish, CR AF Harbison, Carole E. Chiorini, John A. Parrish, Colin R. TI The parvovirus capsid odyssey: from the cell sur face to the nucleus SO TRENDS IN MICROBIOLOGY LA English DT Review ID ADENOASSOCIATED VIRUS TYPE-2; CLATHRIN-MEDIATED ENDOCYTOSIS; VP1 N-TERMINUS; CANINE PARVOVIRUS; MINUTE-VIRUS; TRANSFERRIN RECEPTORS; FELINE PARVOVIRUSES; HOST-RANGE; INTRACELLULAR TRAFFICKING; CYTOPLASMIC TRAFFICKING AB During cellular entry and infection, the parvovirus capsid follows a complex path from the cell surface to the nucleus, where the DNA is replicated. Various receptors have been characterized that bind to different parvoviruses and mediate their entry into cells. However, the subsequent trafficking pathways within the endosomal system, cytoplasm and into the nucleus are still not well defined. Studies of viruses entering various cell types under different conditions show particles located in many different endosomal compartments, within the cytoplasm and in the nucleus with significant variations in timing and distribution. Here, we define the previously unresolved issues that are now better understood for the infection pathways of these viruses, and outline some of the areas that remain to be clarified in future studies. C1 [Harbison, Carole E.; Parrish, Colin R.] Cornell Univ, Coll Vet Med, Baker Inst Anim Hlth, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. [Chiorini, John A.] Natl Inst Dent & Craniofacial Res, AAV Biol Sect, Gene Therapy & Therapeut Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Parrish, CR (reprint author), Cornell Univ, Coll Vet Med, Baker Inst Anim Hlth, Dept Microbiol & Immunol, Ithaca, NY 14853 USA. EM crp3@cornell.edu NR 61 TC 40 Z9 40 U1 0 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD MAY PY 2008 VL 16 IS 5 BP 208 EP 214 DI 10.1016/j.tim.2008.01.012 PG 7 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 305LL UT WOS:000256179800006 PM 18406140 ER PT J AU Yu, Q Leatherbury, L Tian, X Lo, CW AF Yu, Qing Leatherbury, Linda Tian, Xin Lo, C. W. TI Cardiovascular assessment of fetal mice by in utero echocardiography SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article DE fetal ultrasound; image comparison; mouse fetus; development; cardiovascular system ID VELOCITY WAVE-FORMS; ULTRASOUND BIOMICROSCOPY; DEVELOPMENTAL-CHANGES; 1ST TRIMESTER; HEART; DOPPLER; PREGNANCY; GESTATION; FLOW; HEMODYNAMICS AB To establish a developmental profile of fetal mouse cardiovascular parameters, we analyzed a large body of ultrasound measurements obtained by in utero echocardiography of C57BL/6J fetal mice from embryonic day 12.5 to 19.5 (term). Measurements were obtained using two-dimensional (2D), spectral Doppler and M-mode imaging with standard clinical cardiac ultrasound imaging planes. As these studies were conducted as part of a large scale mouse mutagenesis screen, stringent filtering criteria were used to eliminate potentially abnormal fetuses. Our analysis showed heart rate increased from 190 to 245 beats per minute as the mouse fetus grew from 8 mm at embryonic day 12.5 to 18.7 mm at term. This was accompanied by increases in peak outflow velocity, E-wave, E/A ratio and ventricular dimensions. In contrast, the A-wave, myocardial performance index and isovolemic contraction time decreased gradually. Systolic function remained remarkably stable at 80% ejection fraction. Analysis of intra- and interobserver variabilities showed these parameters were reproducible, with most comparing favorably to clinical ultrasound measurements in human fetuses. A comprehensive database was generated comprising 23 echocardiographic parameters delineating fetal mouse cardiovascular function from embryonic day 12.5 to term. This database can serve as a standard for evaluating cardiovascular pathophysiology in genetically altered and mutant mouse models. C1 [Yu, Qing; Leatherbury, Linda; Lo, C. W.] NHLBI, NIH, LDB, Bethesda, MD 20814 USA. [Tian, Xin] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Leatherbury, Linda] Childrens Natl Med Ctr, Childrens Natl Heart Inst, Washington, DC 20010 USA. RP Lo, CW (reprint author), NHLBI, NIH, LDB, 9000 Rockville Pike,Bldg 10-Room 6C103A, Bethesda, MD 20814 USA. EM loc@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL005701-06, NIH0011060326]; NHLBI NIH HHS [Z01 HL005701] NR 31 TC 31 Z9 32 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-5629 J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD MAY PY 2008 VL 34 IS 5 BP 741 EP 752 DI 10.1016/j.ultrasmedbio.2007.11.001 PG 12 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 297KN UT WOS:000255615700005 PM 18328616 ER PT J AU Lee, W Deter, RL Sameera, S Espinoza, J Goncalves, LF Romero, R AF Lee, W. Deter, R. L. Sameera, S. Espinoza, J. Goncalves, L. F. Romero, R. TI Individualized growth assessment of fetal thigh circumference using three-dimensional ultrasonography SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE fetal growth; Rossavik growth model; soft tissue; thigh circumference; three-dimensional ultrasonography ID MENSTRUAL AGE; CURVE STANDARDS; BIRTH-WEIGHT; ASSESSMENT SCORE; NORMAL FETUSES; ULTRASOUND; NUTRITION; REEVALUATION; PREGNANCIES; PREDICTION AB Objectives To develop individualized growth assessment (IGA) standards for upper (ThC(u)) and middle (ThC(m)) fetal thigh circumferences using three-dimensional ultrasonography. Methods A prospective, longitudinal sonographic study of 30 fetuses was performed beginning at 18 weeks' menstrual age. Second-trimester sonographic parameters were measured from three-dimensional volume data to establish IGA standards. Normal infant growth outcomes were confirmed using modified Neonatal Growth Assessment Scores (m(3)NGAS(51)). ThC(u) and ThC(m) were studied in more detail. Rossavik growth model specification procedures, based on the slopes of the second-trimester growth curves, were developed for both ThC(u) and ThC(m). Third-trimester growth trajectories and birth measurements were subsequently predicted for these parameters. Percentage deviations during the third trimester and percentage differences at actual birth age were used to compare observed and predicted measurements. The 95% ranges for Growth Potential Realization Index (GPRI) values for both types of thigh circumference were determined. Values for m(3)NGAS(51) using GPRI(ThC(u)), GPRI(ThC(m)) and GPRI(ThC(o)) (original method) were compared. Results The 30 newborns had no postnatal evidence of abnormal growth. Two examiners demonstrated a satisfactory measurement bias of mean +/- SD 2.1 +/- 3.6 (95% limits of agreement, -4.9 to 9.1)% for ThC(m) and 3.3 +/- 4.1 (95% limits of agreement, -4.8 to 11.4)% for ThC(u). Rossavik functions fitted parameter trajectories well, with mean R-2 values of 99.5 +/- 0.4% for ThC(u) and 99.6 +/- 0.3% for ThC(m). By fixing coefficients k at their mean values, their respective fits did not change, and the variabilities of coefficients c and s were significantly reduced. For ThC(u), coefficient c was significantly related to the second-trimester slope (R-2 = 98.6%), as was s to c (R-2 = 91.0%). For ThC(m), coefficient c was significantly related to the second-trimester slope (R2 = 98.6%), as was s to c (R-2 = 85.6%). Third-trimester growth trajectories, derived from second-trimester slopes for individual fetuses, had third-trimester deviations of 0.07 +/- 3.7% for ThC(u) and -0.04 +/- 3.7% for ThC(m). Percentage differences at birth age were 16.8 +/- 10.2% for ThC(u) and 8.9 +/- 9.5% for ThC(m). With correction for systematic overestimations, the mean GPRI values were 103.7 (95% range, 90-121)% for ThC(u) and 101.6 (95% range, 88-118)% for ThC(m). Corresponding mean +/- SD m(3)NGAS(51) values, using GPRI(ThC(u)), GPRI(ThC(m)) and GPRI(ThC(o)), were 203 +/- 11%, 201 +/- 10% and 200 +/- 9%, respectively. Conclusions Fetal thigh circumference can be measured reliably and evaluated using standard IGA methods. Both ThC(u) and ThC(m) give similar results in the third trimester but neonatal thigh circumference predictions are improved by using ThC(m). Corresponding GPRI(ThC(m)) values are closer to the ideal value of 100% and can be used in m(3)NGAS(51) calculations for assessment of neonatal growth outcome. Copyright (C) 2008 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Lee, W.; Sameera, S.] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. [Lee, W.; Espinoza, J.; Goncalves, L. F.; Romero, R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. [Deter, R. L.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, W.; Espinoza, J.; Romero, R.] NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu FU Intramural NIH HHS NR 34 TC 8 Z9 8 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD MAY PY 2008 VL 31 IS 5 BP 520 EP 528 DI 10.1002/uog.5302 PG 9 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 304KH UT WOS:000256107900008 PM 18389488 ER PT J AU Thompson, IM Tangen, CM Parnes, HL Lippman, SM Coltman, CA AF Thompson, Ian M. Tangen, Catherine M. Parnes, Howard L. Lippman, Scott M. Coltman, Charles A., Jr. TI Does the level of prostate cancer risk affect cancer prevention with finasteride? SO UROLOGY LA English DT Article ID DIGITAL RECTAL EXAMINATION; FLUTAMIDE; CARCINOMA; THERAPY; TRIAL; SENSITIVITY; COMBINATION; INHIBITOR; ANTIGEN; MEN AB OBJECTIVES Finasteride reduced the risk of prostate cancer by 24.8% in the Prostate Cancer Prevention Trial (PCPT). Whether this represents treatment or prevention and who is most likely to benefit are unknown. We sought to clarify these issues by this investigation. METHODS We fit a logistic regression model to men in the placebo group of the PCPT using risk factors for prostate cancer at entry to predict prostate cancer during the subsequent 7 years of study. Men in the two treatment groups were categorized into quintiles of risk of prostate cancer based on the predictive logistic model. A second model was fit evaluating finasteride's effect on prostate cancer for each subgroup defined by quartiles of baseline prostate-specific antigen (PSA). The magnitude of the prevention effect of finasteride on prostate cancer was then evaluated across risk and PSA strata. RESULTS Finasteride significantly reduced prostate cancer risk for all risk quintiles. For quintiles 1 through 5, odds ratios were 0.72, 0.52, 0.64, 0.66, and 0.71, respectively (all P <= 0.05). For quartiles of risk of entry PSA (less than 0.7 ng/mL, 0.7 to 1.1 ng/mL, 1.1 to 1.7 ng/mL, and 1.8 to 3.0 ng/mL, odds ratios increased (smaller treatment effect) as PSA increased: 0.60, 0.62, 0.66, and 0.69, respectively, but remained significant for all strata (each P < 0.001). CONCLUSIONS Finasteride significantly reduced prostate cancer risk regardless of the level of this risk, estimated either by multivariable risk or by PSA stratum; this suggests that finasteride exerts both treatment and preventive effects. All men undergoing PSA screening should be informed of the potential for finasteride to reduce their risk of prostate cancer. C1 [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Canc Prevent Div, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA. SW Oncol Grp, San Antonio, TX USA. RP Thompson, IM (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM thompsoni@uthscsa.edu FU NCI NIH HHS [U10 CA037429, U10 CA037429-24S1] NR 17 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD MAY PY 2008 VL 71 IS 5 BP 854 EP 857 DI 10.1016/j.urology.2008.01.025 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 302TJ UT WOS:000255992000035 PM 18455628 ER PT J AU Hoque, A Goodman, P Ambrosone, CB Figg, WD Price, DK Kopp, W Wu, X Conroy, J Lehman, TA Santella, RM AF Hoque, Ashraful Goodman, Phyllis Ambrosone, Christine B. Figg, William D. Price, Douglas K. Kopp, William Wu, Xlfeng Conroy, Jeffrey Lehman, Teresa A. Santella, Regina M. TI Extraction of DNA from serum for high-throughput genotyping: Findings from pilot studies within the prostate cancer prevention trial SO UROLOGY LA English DT Article ID SELENIUM AB OBJECTIVES Deoxyribonucleic acid (DNA) extraction from blood and genotyping for candidate single nucleotide polymorphisms (SNP) is now an important part of almost all molecular epidemiologic studies. However, in many studies the amount of blood sample is limited or only serum is available. We conducted several pilot studies to identify methods for DNA extraction and high-throughput SNP genotyping of both white blood cell (WBC) and serum DNA that can be done centrally and reliably for large numbers of samples. METHODS We used biospecimens from the Prostate Cancer Prevention Trial (PCPT), a phase III, double-blind, placebo-controlled trial that tested the efficacy of finasteride for the primary prevention of prostate cancer. DNA was extracted from WBCs, from serum, and also from serum after organic solvent extraction for analysis of hormones. We also conducted blinded high-throughput genotyping in three laboratories to assess feasibility and reliability of results with differing methodologies using DNA from WBCs and from serum. RESULTS Genotyping of DNA extracted from WBCs resulted in highly reliable, reproducible results across laboratories using different genotyping platforms. However, genotyping with DNA extracted from serum did not provide reliable data using high-throughput multiplex approaches such as Sequenom (hME and iPLEX) and Applied Biosystems SNPlex, but was successful using Taqman. CONCLUSIONS Based on the results of these pilot studies, we conclude that DNA obtained from serum must be used judiciously, and that genotyping using multiplex methods is not suitable for serum DNA. C1 [Santella, Regina M.] Columbia Univ, Sch Publ Hlth, New York, NY 10032 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. NCI, Clin Support Lab, SAIC Frederick Inc, Frederick, MD 21701 USA. NCI, Bethesda, MD 20892 USA. BioServe Biotechnol Ltd, Beltsville, MD USA. RP Santella, RM (reprint author), Columbia Univ, Sch Publ Hlth, 630 W 168th St,Room 19-418, New York, NY 10032 USA. EM rpsl@columbia.edu RI Figg Sr, William/M-2411-2016 FU NCI NIH HHS [U10 CA037429, CA37429, N01-CO-12400, P01 CA108964]; NIEHS NIH HHS [ES09089, P30 ES009089, P30 ES009089-096522] NR 5 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD MAY PY 2008 VL 71 IS 5 BP 967 EP 970 DI 10.1016/j.urology.2007.11.042 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 302TJ UT WOS:000255992000060 PM 18267333 ER PT J AU Quezado, M Ronchetti, R Pacak, K Linehan, WM Merino, M AF Quezado, Martha Ronchetti, Ruben Pacak, Karel Linehan, W. Marston Merino, Maria TI Pheochromocytoma with divergente differentiation (composite pheochromocytoma) in von Hippel-Landau (VHL) disease SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 [Quezado, Martha; Ronchetti, Ruben; Pacak, Karel; Linehan, W. Marston; Merino, Maria] Natl Canc Inst, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD MAY PY 2008 VL 452 SU 1 BP S75 EP S75 PG 1 WC Pathology SC Pathology GA 305QJ UT WOS:000256192600170 ER PT J AU Tsokos, M Galli, S AF Tsokos, Maria Galli, Susana TI Caspase 8, survivin and XIAP expression in Ewing Sarcoma Family Tumors (ESFT) SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 [Tsokos, Maria; Galli, Susana] NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD MAY PY 2008 VL 452 SU 1 BP S16 EP S17 PG 2 WC Pathology SC Pathology GA 305QJ UT WOS:000256192600037 ER PT J AU Karnik, NS Popma, A Blair, J Khanzode, L Miller, SP Steiner, H AF Karnik, Niranjan S. Popma, Arne Blair, James Khanzode, Leena Miller, Samantha P. Steiner, Hans TI Personality correlates of physiological response to stress among incarcerated juveniles SO ZEITSCHRIFT FUR KINDER-UND JUGENDPSYCHIATRIE UND PSYCHOTHERAPIE LA English DT Article DE psychophysiology; delinquency; stress response; personality ID HEART-RATE; AGGRESSION; BEHAVIOR; VIOLENCE; BOYS AB Background: To examine the relationship between personality type and physiological response to stress among juvenile delinquents. Methods: Delinquent males (N = 42, mean age 16.5, SD = 1) recruited from a convenience sample at local juvenile detention facility were compared to a male control sample from a local high school (N = 79; mean age 16.1, SD = 0.8). All participants completed the WeinbergerAdjustment Inventory and a Stress-Inducing Speech Task during both of which heart rate was measured. Results: Compared to controls, delinquent youths showed significantly lower heart rates under both free association and stress conditions (p < 0.05) and a lower rate of increase during stressful stimuli (p < 0.05). Among delinquents, those with a non-reactive personality type appeared to show consistently lower levels of physiological arousal as measured by heart rate. Conclusions: Delinquents consistently had lower overall levels of arousal as measured by heart rate. In delinquent boys, we also found a persistently low arousal group with a non-reactive psychological pattern. This combination may be a forerunner of future psychopathy or a product of the developmental trajectory that leads to and results from psychopathic behavior. C1 [Karnik, Niranjan S.] Univ Calif San Francisco, Sch Med Anthropol Hist & Social Med, San Francisco, CA 94143 USA. [Popma, Arne] VU Med Ctr, Amsterdam, Netherlands. [Blair, James] NIMH, Bethesda, MD USA. [Khanzode, Leena; Miller, Samantha P.; Steiner, Hans] Stanford Univ, Stanford, CA 94305 USA. RP Karnik, NS (reprint author), Univ Calif San Francisco, Sch Med Anthropol Hist & Social Med, 222 Calif St,Suite 485, San Francisco, CA 94143 USA. EM karnikn@dahsm.ucsf.edu OI Karnik, Niranjan/0000-0001-7650-3008 FU Intramural NIH HHS [Z01 MH002860-03] NR 16 TC 3 Z9 3 U1 0 U2 4 PU VERLAG HANS HUBER PI BERN 9 PA LANGGASS-STRASSE 76, CH-3000 BERN 9, SWITZERLAND SN 1422-4917 J9 Z KINDER JUG-PSYCH JI Z. Kinder-und Jugendpsy. Psychother. PD MAY PY 2008 VL 36 IS 3 BP 185 EP 190 DI 10.1024/1422-4917.36.3.185 PG 6 WC Psychiatry SC Psychiatry GA 308RF UT WOS:000256407000005 PM 18622978 ER PT J AU Mueller, CM Mai, PL Bucher, J Peters, JA Loud, JT Greene, MH AF Mueller, Christine M. Mai, Phuong L. Bucher, Jaime Peters, June A. Loud, Jennifer T. Greene, Mark H. TI Complementary and alternative medicine use among women at increased genetic risk of breast and ovarian cancer SO BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE LA English DT Article ID PROPHYLACTIC OOPHORECTOMY; ATTITUDES; SURVIVORS; POPULATIONS; DEPRESSION; PREVALENCE; THERAPIES; SYMPTOMS; SURGERY AB Background: Complementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer. Methods: A pre-visit telephone interview was conducted to ascertain CAM use among the BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study. Logistic regression was used to evaluate the association between various factors and CAM use in this population. Results: Among the 164 BRCA1 or BRCA2 mutation-positive (BRCA+) women in this analysis, 78% reported CAM use, with prayer and lifestyle diet being the two most commonly reported modalities. Many subjects used multiple CAM therapies, with 34% reporting use of three or more modalities. The most commonly used modalities were mind-body therapies and biologically-based practices, 61.6% and 51.8%, respectively. High-risk women were more likely to use CAM if they were older, more educated, more worried about ovarian cancer risk, or had a previous cancer diagnosis. Conclusion: This study suggests that the prevalence of CAM use is high among BRCA mutation carriers, with frequency of use comparable to that of breast cancer patients and survivors. Given the high prevalence of CAM use in our subjects, especially biologically-based therapies including herbal supplements, whose safety and efficacy in relation to cancer risk are unknown, our study suggests that future research is necessary to clarify these risks, and that it is important for providers to inquire about and to discuss the pros and cons of CAM use with their BRCA+ patients. C1 [Mueller, Christine M.; Mai, Phuong L.; Peters, June A.; Loud, Jennifer T.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Bucher, Jaime] Univ Toledo, Coll Med, Toledo, OH 43606 USA. RP Mueller, CM (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM muellerc@mail.nih.gov; maip@mail.nih.gov; jaime.bucher@utoledo.edu; petersju@mail.nih.gov; loudj@mail.nih.gov; greenem@mail.nih.gov FU NCI [NO2-CP-11019-50, N02-CP65504-50]; [01-C-0009] FX This work was supported by funding from the National Cancer Institute Intramural Research Program. The protocol patients described herein were consented participants in NCI Protocol 01-C-0009, which was supported by support services contracts NO2-CP-11019-50 and N02-CP65504-50 with Westat, Rockville, MD. We remain deeply grateful to the ongoing participation of the women who contributed their time and efforts to support this study. NR 31 TC 16 Z9 16 U1 3 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6882 J9 BMC COMPLEM ALTERN M JI BMC Complement. Altern. Med. PD APR 30 PY 2008 VL 8 AR 17 DI 10.1186/1472-6882-8-17 PG 9 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA 398PI UT WOS:000262743600001 PM 18447953 ER PT J AU Nishiyama, A Mochizuki, K Mueller, F Karpova, T McNally, JG Ozato, K AF Nishiyama, Akira Mochizuki, Kazuki Mueller, Florian Karpova, Tatiana McNally, James G. Ozato, Keiko TI Intracellular delivery of acetyl-histone peptides inhibits native bromodomain-chromatin interactions and impairs mitotic progression SO FEBS LETTERS LA English DT Article DE peptide transduction; acetyl-histone tail; bromodomain; Brd4; FRAP ID IN-VIVO; BRD4; TRANSCRIPTION; PROTEINS; CELLS AB Bromodomains present in Brd4 and other chromatin proteins interact with acetylated histones to regulate transcription and cell growth. To study Brd4-chromatin interactions in vivo, histone H4 tail peptides were fused to a synthetic protein transduction domain (PTD) derived from the human immunodeficiency virus Tat and delivered into cultured cells. Acetyl-H4 peptides, but not unacetylated H4 peptides inhibited real time Brd4-chromatin interactions in living cells as assessed by fluorescence recovery after photobleaching assays. The acetyl-H4 peptides also inhibited an interaction of Brd4 with chromosomes during mitosis and reduced cell growth potential. Together, PTD-based delivery of histone tail peptides offers a novel means to study the mechanism and biological significance of bromodomain-chromatin interactions in vivo. Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. C1 [Nishiyama, Akira; Mochizuki, Kazuki; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, Genom & Differentiat Program, NIH, Bethesda, MD 20892 USA. [Mueller, Florian; Karpova, Tatiana; McNally, James G.] Natl Canc Inst, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, Genom & Differentiat Program, NIH, Bldg 6,Room 2A01,6 Ctr Dr, Bethesda, MD 20892 USA. EM ozatok@nih.gov RI Mueller, Florian/C-9075-2012 OI Mueller, Florian/0000-0002-9622-4396 FU Intramural NIH HHS [Z01 HD008815-01, Z99 HD999999] NR 15 TC 12 Z9 12 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 APR 30 PY 2008 VL 582 IS 10 BP 1501 EP 1507 DI 10.1016/j.febslet.2008.03.044 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 331IF UT WOS:000258005200018 PM 18396160 ER PT J AU Gilman, JM Ramchandani, VA Davis, MB Bjork, JM Hommer, DW AF Gilman, Jodi M. Ramchandani, Vijay A. Davis, Megan B. Bjork, James M. Hommer, Daniel W. TI Why we like to drink: A functional magnetic resonance imaging study of the rewarding and anxiolytic effects of alcohol SO JOURNAL OF NEUROSCIENCE LA English DT Article DE striatum; nucleus accumbens; alcohol; addiction; reward; amygdala ID NUCLEUS-ACCUMBENS; FAMILY HISTORY; YOUNG-ADULTS; HUMAN BRAIN; INDIVIDUAL-DIFFERENCES; NEURAL BASIS; MG-PERCENT; ETHANOL; ACTIVATION; ADDICTION AB People typically drink alcohol to induce euphoria or reduce anxiety, and they frequently drink in social settings, yet the effect of alcohol on human brain circuits involved in reward and emotion has been explored only sparingly. We administered alcohol intravenously to social drinkers while brain response to visual threatening and nonthreatening facial stimuli was measured using functional magnetic resonance imaging (fMRI). Alcohol robustly activated striatal reward circuits while attenuating response to fearful stimuli in visual and limbic regions. Self-ratings of intoxication correlated with striatal activation, suggesting that activation in this area may contribute to subjective experience of pleasure and reward during intoxication. These results show that the acute pharmacological rewarding and anxiolytic effects of alcohol can be measured with fMRI. C1 [Gilman, Jodi M.; Ramchandani, Vijay A.; Davis, Megan B.; Bjork, James M.; Hommer, Daniel W.] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP Gilman, JM (reprint author), NIH, Hartfield Clin Res Ctr, Bldg 10 CRC,Room 1-5330 10 Ctr Dr, Bethesda, MD 20892 USA. EM gilmanj@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU Intramural NIH HHS [Z99 AA999999] NR 62 TC 90 Z9 92 U1 1 U2 8 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 APR 30 PY 2008 VL 28 IS 18 BP 4583 EP 4591 DI 10.1523/JNEUROSCI.0086-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 294MG UT WOS:000255409500003 PM 18448634 ER PT J AU Fries, P Womelsdorf, T Oostenveld, R Desimone, R AF Fries, Pascal Womelsdorf, Thilo Oostenveld, Robert Desimone, Robert TI The effects of visual stimulation and selective visual attention on rhythmic neuronal synchronization in macaque area v4 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE synchronization; oscillation; coherence; gamma; alpha; attention ID GAMMA-OSCILLATIONS; NEURAL MECHANISMS; OCCIPITAL CORTEX; CORTICAL-NEURONS; TEMPORAL CORTEX; PARIETAL CORTEX; MODULATION; SEARCH; IMPACT AB Selective attention lends relevant sensory input priority access to higher-level brain areas and ultimately to behavior. Recent studies have suggested that those neurons in visual areas that are activated by an attended stimulus engage in enhanced gamma-band (30-70 Hz) synchronization compared with neurons activated by a distracter. Such precise synchronization could enhance the postsynaptic impact of cells carrying behaviorally relevant information. Previous studies have used the local field potential (LFP) power spectrum or spike-LFP coherence (SFC) to indirectly estimate spike synchronization. Here, we directly demonstrate zero-phase gamma-band coherence among spike trains of V4 neurons. This synchronization was particularly evident during visual stimulation and enhanced by selective attention, thus confirming the pattern inferred from LFP power and SFC. We therefore investigated the time course of LFP gamma-band power and found rapid dynamics consistent with interactions of top-down spatial and feature attention with bottom-up saliency. In addition to the modulation of synchronization during visual stimulation, selective attention significantly changed the prestimulus pattern of synchronization. Attention inside the receptive field of the recorded neuronal population enhanced gamma-band synchronization and strongly reduced alpha-band (9-11 Hz) synchronization in the prestimulus period. These results lend further support for a functional role of rhythmic neuronal synchronization in attentional stimulus selection. C1 [Fries, Pascal; Womelsdorf, Thilo; Oostenveld, Robert] Radboud Univ Nijmegen, FC Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands. [Fries, Pascal] Radboud Univ Nijmegen, Dept Biophys, NL-6525 EZ Nijmegen, Netherlands. [Desimone, Robert] NIMH, Neuropsychol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Desimone, Robert] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Fries, P (reprint author), Radboud Univ Nijmegen, FC Donders Ctr Cognit Neuroimaging, NL-6525 EN Nijmegen, Netherlands. EM pascal.fries@fcdonders.ru.nl RI Oostenveld, Robert/D-3259-2009; Fries, Pascal/E-3196-2010; OI Oostenveld, Robert/0000-0002-1974-1293; Fries, Pascal/0000-0002-4270-1468; Womelsdorf, Thilo/0000-0001-6921-4187 FU Intramural NIH HHS; NEI NIH HHS [R01 EY017292, R01-EY017292] NR 37 TC 206 Z9 207 U1 0 U2 13 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 APR 30 PY 2008 VL 28 IS 18 BP 4823 EP 4835 DI 10.1523/JNEUROSCI.4499-07.2008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 294MG UT WOS:000255409500028 PM 18448659 ER PT J AU Stewart, CV Plenz, D AF Stewart, Craig V. Plenz, Dietmar TI Homeostasis of neuronal avalanches during postnatal cortex development in vitro SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE cortex; development; spontaneous activity; neuronal avalanches; organotypic culture; multielectrode array; self-organized criticality ID RAT CEREBRAL-CORTEX; NEOCORTICAL EXPLANT CULTURES; CORTICAL SLICE CULTURES; FOREST-FIRE MODEL; ELECTRICAL-ACTIVITY; DEVELOPING NETWORKS; VISUAL-CORTEX; MULTIELECTRODE ARRAYS; SOMATOSENSORY CORTEX; ORGANOTYPIC CULTURES AB Cortical networks in vivo and in vitro are spontaneously active in the absence of inputs, generating highly variable bursts of neuronal activity separated by up to seconds of quiescence. Previous measurements in adult rat cortex revealed an intriguing underlying organization of these dynamics, termed neuronal avalanches, which is indicative of a critical network state. Here we demonstrate that neuronal avalanches persist throughout development in cortical slice cultures from newborn rats. More specifically, we find that in spite of large variations of average rate in activity, spontaneous bursts occur with power-law distributed sizes (exponent - 1.5) and a critical branching parameter close to 1. Our findings suggest that cortical networks homeostatically regulate a critical state during postnatal maturation. Published by Elsevier B.V. C1 [Stewart, Craig V.; Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Plenz, D (reprint author), NIMH, Sect Crit Brain Dynam, Porter Neurosci Res Ctr, Bldg 35,Room 3A-100,MSC 3735,35 Convent Dr,9000 R, Bethesda, MD 20892 USA. EM plenzd@mail.nih.gov FU Intramural NIH HHS [Z01 MH002797-06, Z99 MH999999] NR 78 TC 42 Z9 42 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 EI 1872-678X J9 J NEUROSCI METH JI J. Neurosci. Methods PD APR 30 PY 2008 VL 169 IS 2 BP 405 EP 416 DI 10.1016/j.jneumeth.2007.10.021 PG 12 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 297LY UT WOS:000255619400010 PM 18082894 ER PT J AU Abbatiello, SE Pan, YX Zhou, M Wayne, AS Veenstra, TD Hunger, SP Kilberg, MS Eyler, JR Richards, NGJ Conrads, TP AF Abbatiello, Susan E. Pan, Yuan-Xiang Zhou, Mi Wayne, Alan S. Veenstra, Timothy D. Hunger, Stephen P. Kilberg, Michael S. Eyler, John R. Richards, Nigel G. J. Conrads, Thomas P. TI Mass spectrometric quantification of asparagine synthetase in circulating leukemia cells from acute lymphoblastic leukemia patients SO JOURNAL OF PROTEOMICS LA English DT Article DE Mass spectrometry; Isotope-dilution; Biomarker; Asparagine synthetase; Leukemia ID ABSOLUTE QUANTIFICATION; EXPRESSION PATTERNS; PEPTIDE STANDARDS; UP-REGULATION; CYCLE ARREST; RESISTANCE; CHILDHOOD; PROTEINS; APOPTOSIS; LYMPHOMA AB The appearance of asparaginase-resistant acute lymphoblastic leukemia (ALL) in transformed cell lines has been correlated with increased expression of asparagine synthetase (ASNS). Recent measurements using mRNA-based assays have raised doubts, however, as to the importance of ASNS protein in the cellular mechanisms that confer drug resistance upon the leukemic cells. Studies aimed at determining the concentration of ASNS protein in human leukemias are therefore needed to resolve this issue. A mass spectrometry (MS)-based procedure is presented for the direct quantification of ASNS protein concentration in complex sample mixtures. This assay is able to distinguish samples from transformed cell lines that express ASNS over a wide dynamic range of concentration. Importantly, this method directly detects ASNS protein, the functional entity that may be synthesizing sufficient asparagine to render leukemia cells resistant to asparaginase-treatment. We also report the successful use of this MS method, which has lower limits of detection and quantification of 30 and 100 attomoles, respectively, for the first direct measurements of ASNS protein concentrations in four patient blast samples. (C) 2007 Elsevier B.V. All rights reserved. C1 [Eyler, John R.; Richards, Nigel G. J.] Univ Florida, Dept Chem, Gainesville, FL 32611 USA. [Abbatiello, Susan E.; Conrads, Thomas P.] Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. [Pan, Yuan-Xiang; Kilberg, Michael S.] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32611 USA. [Zhou, Mi; Hunger, Stephen P.] Univ Florida, Coll Med, Dept Pediat, Gainesville, FL 32611 USA. [Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Veenstra, Timothy D.] SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD USA. [Hunger, Stephen P.; Kilberg, Michael S.; Richards, Nigel G. J.] Univ Florida, Shands Canc Ctr, Gainesville, FL 32611 USA. [Conrads, Thomas P.] Univ Pittsburgh, Pittsburgh Canc Inst, Hillman Canc Ctr, Pittsburgh, PA USA. RP Richards, NGJ (reprint author), Univ Florida, Dept Chem, POB 117200, Gainesville, FL 32611 USA. EM richards@qtp.ufl.edu; conradstp@upmc.edu FU NIH [CA107437, DK52064, DK70647, T32 CA09126]; Chiles Endowment Biomedical Research Program of the Florida Department of Health; Hillman Foundation; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This work was supported by the NIH (CA107437) to S.P.H, (DK52064, DK70647) to M.S.K., the Chiles Endowment Biomedical Research Program of the Florida Department of Health (N.G.J.R) an NIH pre-doctoral training fellowship (T32 CA09126) to S.E.A and the Hillman Foundation (T.P.C.). This project was also supported, in part, with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 44 TC 12 Z9 13 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD APR 30 PY 2008 VL 71 IS 1 BP 61 EP 70 DI 10.1016/j.jprot.2007.11.009 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 370EA UT WOS:000260744300005 PM 18541474 ER PT J AU Sigurdson, AJ Ha, M Hauptmann, M Bhatti, P Sram, RJ Beskid, O Tawn, EJ Whitehouse, CA Lindholm, C Nakano, M Kodama, Y Nakamura, N Vorobtsova, I Oestreicher, U Stephan, G Yong, LC Bauchinger, M Schmid, E Chung, HW Darroudi, F Roy, L Voisin, P Barquinero, JF Livingston, G Blakey, D Hayata, I Zhang, W Wang, CY Bennett, LM Littlefield, LG Edwards, AA Kleinerman, RA Tucker, JD AF Sigurdson, Alice J. Ha, Mina Hauptmann, Michael Bhatti, Parveen Sram, Radim J. Beskid, Olena Tawn, E. Janet Whitehouse, Caroline A. Lindholm, Carita Nakano, Mimako Kodama, Yoshiaki Nakamura, Nori Vorobtsova, Irena Oestreicher, Ursula Stephan, Guenther Yong, Lee C. Bauchinger, Manfred Schmid, Ernst Chung, Hai Won Darroudi, Firouz Roy, Laurence Voisin, Phillipe Barquinero, Joan F. Livingston, Gordon Blakey, David Hayata, Isamu Zhang, Wei Wang, Chunyan Bennett, L. Michelle Littlefield, L. Gayle Edwards, Alan A. Kleinerman, Ruth A. Tucker, James D. TI International study of factors affecting human chromosome translocations SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE chromosome translocations; background frequency; controls; fluorescence in situ hybridization ID PERIPHERAL-BLOOD LYMPHOCYTES; RADIATION-INDUCED TRANSLOCATIONS; REPAIR GENE POLYMORPHISMS; CONTROL POPULATION; IONIZING-RADIATION; ABERRATION FREQUENCIES; CYTOGENETIC BIOMARKERS; BIOLOGICAL DOSIMETRY; SMOKING-HABITS; FISH AB Chromosome translocations in peripheral blood lymphocytes of normal, healthy humans increase with age, but the effects of gender, race, and cigarette smoking on background translocation yields have not been examined systematically. Further, the shape of the relationship between age and translocation frequency (TF) has not been definitively determined. We collected existing data from 16 laboratories in North America, Europe, and Asia on TFs measured in peripheral blood lymphocytes by fluorescence in situ hybridization whole chromosome painting among 1933 individuals. In Poisson regression models, age, ranging from newborns (cord blood) to 85 years, was strongly associated with TF and this relationship showed significant upward curvature at older ages versus a linear relationship (p < 0.001). Ever smokers had significantly higher TFs than non-smokers (rate ratio (RR) = 1.19, 95% confidence interval (CI), 1.09-1.30) and smoking modified the effect of age on TFs with a steeper age-related increase among ever smokers compared to non-smokers (p < 0.00 1). TFs did not differ by gender. Interpreting an independent effect of race was difficult owing to laboratory variation. Our study is three times larger than any pooled effort to date, confirming a suspected curvilinear relationship of TF with age. The significant effect of cigarette smoking has not been observed with previous pooled studies of TF in humans. Our data provide stable estimates of background TF by age, gender, race, and smoking status and suggest an acceleration of chromosome damage above age 60 and among those with a history of smoking cigarettes. (C) 2008 Elsevier B.V. All rights reserved. C1 [Tucker, James D.] Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. [Sigurdson, Alice J.; Ha, Mina; Bhatti, Parveen; Kleinerman, Ruth A.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Ha, Mina] Dankook Univ, Coll Med, Dept Prevent Med, Cheonan, South Korea. [Hauptmann, Michael] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Hauptmann, Michael] Netherlands Canc Inst, Amsterdam, Netherlands. [Sram, Radim J.; Beskid, Olena] Inst Cent Bohemia, Lab Genet Ecotoxicol, Inst Expt Med & Hlth, Prague, Czech Republic. [Tawn, E. Janet] Univ Cent Lancashire, Fac Hlth, Preston PR1 2HE, Lancs, England. [Lindholm, Carita] Radiat & Nucl Safety Author STUK, Helsinki, Finland. [Nakano, Mimako; Kodama, Yoshiaki; Nakamura, Nori] Radiat Effects Res Fdn, Hiroshima, Japan. [Oestreicher, Ursula; Stephan, Guenther] Fed Off Radiat Protect BfS, Oberschleissheim, Germany. [Stephan, Guenther; Yong, Lee C.; Bauchinger, Manfred; Littlefield, L. Gayle; Edwards, Alan A.] NIOSH, Cincinnati, OH 45226 USA. [Bauchinger, Manfred; Schmid, Ernst] GSF Natl Res Ctr Environm & Hlth, Inst Radiobiol, Neuherberg, Germany. [Chung, Hai Won] Seoul Natl Univ, Dept Mol Epidemiol, Sch Publ Hlth, Seoul, South Korea. [Darroudi, Firouz] Leiden Univ, Med Ctr, Dept Toxicogenet, Leiden, Netherlands. [Roy, Laurence; Voisin, Phillipe] IRSN, Fontenay Aux Roses, France. [Barquinero, Joan F.] UAB, Bellaterra, Spain. [Livingston, Gordon] Oak Ridge Inst Sci & Educ, Radiat Emergency Assistance Ctr Training Site, Oak Ridge, TN USA. [Blakey, David] Dept Hlth & Welf, Ottawa, ON K1A 0L2, Canada. [Hayata, Isamu] Natl Inst Radiol Sci, Chiba 260, Japan. [Zhang, Wei; Wang, Chunyan] Chinese Ctr Dis Control & Prevent, Natl Inst Radiol Protect, Beijing, Peoples R China. [Littlefield, L. Gayle] Oak Ridge Associated Univ, Oak Ridge, TN USA. [Edwards, Alan A.] Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. [Bennett, L. Michelle] NCI, Ctr Canc Res, NIH, DHHS, Bethesda, MD 20892 USA. RP Tucker, JD (reprint author), Wayne State Univ, Dept Biol Sci, 1370 Biol Sci Bldg,5047 Gullen Mall, Detroit, MI 48202 USA. EM jtucker@biology.biosci.wayne.edu RI Sram, Radim/H-2455-2014; Barquinero, Joan Francesc/L-6487-2014; OI Sram, Radim/0000-0003-4256-3816; Barquinero, Joan Francesc/0000-0003-0084-5268; Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS; NCI NIH HHS [Y1 CP 9012, P01 CA059431-060001, P01 CA059431-070001, P01 CA059431-08, P01 CA059431-080001, P01 CA059431-08S10001, Y03 CO5117, Y3 CO 5117]; NIAID NIH HHS [Y2 AI 5077] NR 47 TC 58 Z9 61 U1 3 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD APR 30 PY 2008 VL 652 IS 2 BP 112 EP 121 DI 10.1016/j.mrgentox.2008.01.005 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 311BZ UT WOS:000256576400002 PM 18337160 ER PT J AU Delmas, O Holmes, EC Talbi, C Larrous, F Dacheux, L Bouchier, C Bourhy, H AF Delmas, Olivier Holmes, Edward C. Talbi, Chiraz Larrous, Florence Dacheux, Laurent Bouchier, Christiane Bourhy, Herve TI Genomic Diversity and Evolution of the Lyssaviruses SO PLOS ONE LA English DT Article AB Lyssaviruses are RNA viruses with single-strand, negative-sense genomes responsible for rabies-like diseases in mammals. To date, genomic and evolutionary studies have most often utilized partial genome sequences, particularly of the nucleoprotein and glycoprotein genes, with little consideration of genome-scale evolution. Herein, we report the first genomic and evolutionary analysis using complete genome sequences of all recognised lyssavirus genotypes, including 14 new complete genomes of field isolates from 6 genotypes and one genotype that is completely sequenced for the first time. In doing so we significantly increase the extent of genome sequence data available for these important viruses. Our analysis of these genome sequence data reveals that all lyssaviruses have the same genomic organization. A phylogenetic analysis reveals strong geographical structuring, with the greatest genetic diversity in Africa, and an independent origin for the two known genotypes that infect European bats. We also suggest that multiple genotypes may exist within the diversity of viruses currently classified as 'Lagos Bat'. In sum, we show that rigorous phylogenetic techniques based on full length genome sequence provide the best discriminatory power for genotype classification within the lyssaviruses. C1 [Delmas, Olivier; Talbi, Chiraz; Larrous, Florence; Dacheux, Laurent; Bourhy, Herve] WHO, Collaborating Ctr Reference & Res Rabies, UPRE Lyssavirus Dynam & Host Adaptat, Inst Pasteur, Paris, France. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA USA. [Bouchier, Christiane] Pasteur Genopole Ile France, Plate forme Genom, Inst Pasteur, Paris, France. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Delmas, O (reprint author), WHO, Collaborating Ctr Reference & Res Rabies, UPRE Lyssavirus Dynam & Host Adaptat, Inst Pasteur, Paris, France. EM hbourhy@pasteur.fr RI Bourhy, Herve/F-5272-2010; OI Holmes, Edward/0000-0001-9596-3552 FU European commission through the VIZIER Integrated project [LSHG-CT-2004-511966]; Genomic Platform Ile de France Analyse de la Diversite Genetique des Rhabdoviridae; NIH [GM080533-01] FX O. Delmas was supported by the European commission through the VIZIER Integrated project (LSHG-CT-2004-511966). This work was also funded by the VIZIER program, and by the grant of Genomic Platform Ile de France Analyse de la Diversite Genetique des Rhabdoviridae 2005 to 2006, and in part by NIH grant number GM080533-01. NR 38 TC 73 Z9 89 U1 0 U2 14 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 APR 30 PY 2008 VL 3 IS 4 AR e2057 DI 10.1371/journal.pone.0002057 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 381YR UT WOS:000261572300026 PM 18446239 ER PT J AU Hong, SK Tsang, M Dawid, IB AF Hong, Sung-Kook Tsang, Michael Dawid, Igor B. TI The Mych Gene Is Required for Neural Crest Survival during Zebrafish Development SO PLOS ONE LA English DT Article AB Background: Among Myc family genes, c-Myc is known to have a role in neural crest specification in Xenopus and in craniofacial development in the mouse. There is no information on the function of other Myc genes in neural crest development, or about any developmental role of zebrafish Myc genes. Principal Findings: We isolated the zebrafish mych (myc homologue) gene. Knockdown of mych leads to severe defects in craniofacial development and in certain other tissues including the eye. These phenotypes appear to be caused by cell death in the neural crest and in the eye field in the anterior brain. Significance: Mych is a novel factor required for neural crest cell survival in zebrafish. C1 [Hong, Sung-Kook; Tsang, Michael; Dawid, Igor B.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Tsang, Michael] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. RP Hong, SK (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM hongsk@mail.nih.gov RI TSANG, Michael/E-2758-2013; Tsang, Michael/I-9305-2014 OI TSANG, Michael/0000-0001-6384-2422; Tsang, Michael/0000-0001-7123-0063 FU National Institute of Child Health and Human Development, National Institutes of Health FX Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health NR 32 TC 12 Z9 12 U1 0 U2 0 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 APR 30 PY 2008 VL 3 IS 4 AR e2029 DI 10.1371/journal.pone.0002029 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 381YR UT WOS:000261572300003 PM 18446220 ER PT J AU Yao, K Gagnon, S Akhyani, N Williams, E Fotheringham, J Frohman, E Stuve, O Monson, N Racke, MK Jacobson, S AF Yao, Karen Gagnon, Susan Akhyani, Nahid Williams, Elizabeth Fotheringham, Julie Frohman, Elliot Stuve, Olaf Monson, Nancy Racke, Michael K. Jacobson, Steven TI Reactivation of Human Herpesvirus-6 in Natalizumab Treated Multiple Sclerosis Patients SO PLOS ONE LA English DT Article AB The alpha(4) integrin antagonist natalizumab was shown to be effective in patients with immune-mediated disorders but was unexpectedly associated with JC polyomavirus associated progressive multifocal leukoencephalopathy (PML) in two multiple sclerosis (MS) and one Crohn's disease patients. Impaired immune surveillance due to natalizumab treatment may have contributed to the JCV reactivation. As HHV-6 has been suggested to play a role in MS, we asked whether this virus could also have been reactivated during natalizumab therapy. Matched sera and CSF from a limited set of MS patients treated with and without natalizumab were examined for evidence of HHV-6. In addition, we also superinfected a persistent JC virus infected glial cell with HHV-6A to determine if JC virus can be increased. Elevated serum HHV6 IgG and HHV-6A DNA was detected in the CSF of a subset of patients but not controls. We confirmed that superinfection with HHV-6 of a JC virus infected glial cells increased expression of JCV. These results support the hypothesis that treatment with natalizumab may be associated with reduced immune surveillance resulting in reactivation of viruses associated with MS pathogenesis. C1 [Yao, Karen; Gagnon, Susan; Akhyani, Nahid; Williams, Elizabeth; Fotheringham, Julie; Jacobson, Steven] NIH, Viral Immunol Sect, Bethesda, MD 20892 USA. [Frohman, Elliot; Stuve, Olaf; Monson, Nancy; Racke, Michael K.] Univ Texas, SW Med Ctr, Ctr Immunol, Dept Neurol, Dallas, TX USA. [Yao, Karen] Johns Hopkins Univ, Dept Biol, Baltimore, MD USA. RP Yao, K (reprint author), NIH, Viral Immunol Sect, Bldg 10, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU National Institutes of Health, National Institute of Neurological Disorders and Stroke FX This study was funded by the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 55 TC 35 Z9 37 U1 0 U2 0 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 APR 30 PY 2008 VL 3 IS 4 AR e2028 DI 10.1371/journal.pone.0002028 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 381YR UT WOS:000261572300002 PM 18446218 ER PT J AU Bolton, DL Barnitz, RA Sakai, K Lenardo, MJ AF Bolton, Diane L. Barnitz, Robert A. Sakai, Keiko Lenardo, Michael J. TI 14-3-3 theta binding to cell cycle regulatory factors is enhanced by HIV-1 Vpr SO BIOLOGY DIRECT LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL-PROTEIN-R; XENOPUS EGG EXTRACTS; TYPE-1 VPR; NUCLEAR-LOCALIZATION; DNA-DAMAGE; KINASE 1; T-CELLS; IN-VIVO; UBIQUITIN LIGASE AB Background: Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G(2), M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade. Results: We found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 theta during Vpr(v)-induced G2, M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3. association with Cdk1 and CyclinB1. Moreover, G2, M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3. binding to centrosomal proteins, PIk-1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, PIk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin beta. Conclusion: Thus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins. C1 [Bolton, Diane L.; Barnitz, Robert A.; Sakai, Keiko; Lenardo, Michael J.] NIAID, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Bolton, Diane L.] NIAID, Immunotechnol Sect, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sakai, Keiko] Kumamoto Univ, Ctr AIDS Res, Div Viral Immunol, Kumamoto, Japan. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM dbolton@nih.gov; tbarnitz@nih.gov; sakai001@kumamoto-u.ac.jp; lenardo@nih.gov RI sakai, Keiko/F-5807-2013 FU Intramural NIH HHS NR 67 TC 13 Z9 13 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD APR 29 PY 2008 VL 3 AR 17 DI 10.1186/1745-6150-3-17 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 303KR UT WOS:000256039900001 PM 18445273 ER PT J AU Fleg, JL AF Fleg, Jerome L. TI Improving exercise tolerance in chronic heart failure - A tale of inspiration? SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material ID RESPIRATORY MUSCLE WORK; AMBULATORY PATIENTS; CONTROLLED-TRIAL; SKELETAL-MUSCLE; BLOOD-FLOW; RATIONALE C1 NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Dis, 6701 Rockledge Dr,Room 8150, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov NR 24 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD APR 29 PY 2008 VL 51 IS 17 BP 1672 EP 1674 DI 10.1016/j.jacc.2008.01.027 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 292XU UT WOS:000255300200007 PM 18436119 ER PT J AU Kaila, VRI Verkhovsky, MI Hummer, G Wikstrom, M AF Kaila, Ville R. I. Verkhovsky, Michael I. Hummer, Gerhard Wikstrom, Marten TI Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell respiration; gating mechanism; proton leak; proton translocation ID HEME-COPPER OXIDASES; ATR-FTIR SPECTROSCOPY; PARACOCCUS-DENITRIFICANS; ELECTRON-TRANSFER; MOLECULAR-DYNAMICS; RHODOBACTER-SPHAEROIDES; CATALYTIC CYCLE; COUPLED PROTON; D-PATHWAY; ESCHERICHIA-COLI AB Aerobic life is based on a molecular machinery that utilizes oxygen as a terminal electron sink. The membrane-bound cytochrome c oxiclase (CcO) catalyzes the reduction of oxygen to water in mitochondria and many bacteria. The energy released in this reaction is conserved by pumping protons across the mitochondrial or bacterial membrane, creating an electrochemical proton gradient that drives production of ATP. A crucial question is how the protons pumped by CcO are prevented from flowing backwards during the process. Here, we show by molecular dynamics simulations that the conserved glutamic acid 242 near the active site of CcO undergoes a protonation state-dependent conformational change, which provides a valve in the pumping mechanism. The valve ensures that at any point in time, the proton pathway across the membrane is effectively discontinuous, thereby preventing thermodynamically favorable proton back-leakage while maintaining an overall high efficiency of proton translocation. Suppression of proton leakage is particularly important in mitochondria under physiological conditions, where production of ATP takes place in the presence of a high electrochemical proton gradient. C1 [Kaila, Ville R. I.; Verkhovsky, Michael I.; Wikstrom, Marten] Univ Helsinki, Inst Biotechnol, Struct Biol & Biophys Program, Helsinki Bioenerget Grp, Helsinki 00014, Finland. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Wikstrom, M (reprint author), Univ Helsinki, Inst Biotechnol, Struct Biol & Biophys Program, Helsinki Bioenerget Grp, Viikinkaari 1,POB 65, Helsinki 00014, Finland. EM marten.wikstrom@helsinki.fi RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 65 TC 83 Z9 83 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 29 PY 2008 VL 105 IS 17 BP 6255 EP 6259 DI 10.1073/pnas.0800770105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 296HM UT WOS:000255534100010 PM 18430799 ER PT J AU Jiao, D Golubkov, PA Darden, TA Ren, P AF Jiao, Dian Golubkov, Pavel A. Darden, Thomas A. Ren, Pengyu TI Calculation of protein-ligand binding free energy by using a polarizable potential SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE simulation; molecular dynamics; trypsin; benzamidine; force field ID MOLECULAR-DYNAMICS SIMULATIONS; FORCE-FIELDS; ION CHANNELS; WATER MODEL; T4 LYSOZYME; MECHANICS; TRYPSIN; LIE; ELECTROSTATICS; REPRESENTATION AB The binding of charged ligands benzamidine and diazamidine to trypsin was investigated by using a polarizable potential energy function and explicit-water molecular dynamics simulations. The binding free energies were computed from the difference between the free energies of decoupling the ligand from water and protein environments. Both the absolute and the relative free energies from the perturbation simulations agree with experimental measurements to within 0.5 kcal(.)mol(-1). Comparison of free-energy components sampled from different thermodynamic paths indicates that electrostatics is the main driving force behind benzamidine recognition of trypsin. The contribution of electronic polarization to binding appears to be crucial. By computing the free-energy contribution caused by the polarization between the ligand and its surroundings, we found that polarization has the opposite effect in dissimilar environments. Although polarization favors ligand solvation in water, it weakens the protein-ligand attraction by screening the electrostatic interaction between trypsin and benzamidine. We also examined the relative binding free energies of a benzamidine analog diazamidine to trypsin. The changes in free energy on benzamidine-diazamidine substitution were tens of kilocalories in both water and trypsin environments; however, the change in the total binding free energy is <2 kcal(.)mol(-1) because of cancellation, consistent with the experimental results. Overall, our results suggest that the use of a polarizable force field, given adequate sampling, is capable of achieving chemical accuracy in molecular simulations of protein-ligand recognition. C1 [Jiao, Dian; Golubkov, Pavel A.; Ren, Pengyu] Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. [Darden, Thomas A.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Ren, P (reprint author), Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA. EM pren@mail.utexas.edu RI Jiao, Dian/E-5814-2011; Jiao, Dian/F-4337-2011 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM079686, R01 GM079686-02, R01GM079686] NR 53 TC 127 Z9 130 U1 1 U2 20 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 APR 29 PY 2008 VL 105 IS 17 BP 6290 EP 6295 DI 10.1073/pnas.0711686105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 296HM UT WOS:000255534100016 PM 18427113 ER PT J AU Crawford, NPS Alsarraj, J Lukes, L Walker, RC Officewala, JS Yang, HH Lee, MP Ozato, K Hunter, KW AF Crawford, Nigel P. S. Alsarraj, Jude Lukes, Luanne Walker, Renard C. Officewala, Jennifer S. Yang, Howard H. Lee, Maxwell P. Ozato, Keiko Hunter, Kent W. TI Bromodomain 4 activation predicts breast cancer survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene expression signatures; metastasis; mouse models ID PROTEIN BRD4; METASTATIC PROGRESSION; SIGNATURE; MODIFIERS; PROFILES; TUMORS; SIPA1; MICE AB Previous work identified the Rap1 GTPase-activating protein Sipal as a germ-line-encoded metastasis modifier. The bromodomain protein Brd4 physically interacts with and modulates the enzymatic activity of Sipal. In vitro analysis of a highly metastatic mouse mammary tumor cell line ectopically expressing Brd4 demonstrates significant reduction of invasiveness without altering intrinsic growth rate. However, a dramatic reduction of tumor growth and pulmonary metastasis was observed after s.c. implantation into mice, implying that activation of Brd4 may somehow be manipulating response to tumor microenvironment in the in vivo setting. Further in vitro analysis shows that Brd4 modulates extracellular matrix gene expression, a class of genes frequently present in metastasis-predictive gene signatures. Microarray analysis of the mammary tumor cell lines identified a Brd4 activation signature that robustly predicted progression and/or survival in multiple human breast cancer datasets analyzed on different microarray platforms. Intriguingly, the Brd4 signature also almost perfectly matches a molecular classifier of low-grade tumors. Taken together, these data suggest that dysregulation of Brd4-associated pathways may play an important role in breast cancer progression and underlies multiple common prognostic signatures. C1 [Crawford, Nigel P. S.; Alsarraj, Jude; Lukes, Luanne; Walker, Renard C.; Officewala, Jennifer S.; Hunter, Kent W.] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Yang, Howard H.; Lee, Maxwell P.] NIH, Lab Populat Genet, Natl Canc Inst, Bethesda, MD 20892 USA. [Ozato, Keiko] NIH, Lab Mol Growth Regulat, Natl Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Hunter, KW (reprint author), NIH, Lab Canc Biol & Genet, Bldg 10, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov FU Intramural NIH HHS NR 28 TC 97 Z9 98 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 APR 29 PY 2008 VL 105 IS 17 BP 6380 EP 6385 DI 10.1073/pnas.0710331105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 296HM UT WOS:000255534100031 PM 18427120 ER PT J AU Appel, LJ Wright, JT Greene, T Kusek, JW Lewis, JB Wang, X Lipkowitz, MS Norris, KC Bakris, GL Rahman, M Contreras, G Rostand, SG Kopple, JD Gabbai, FB Schulman, GI Gassman, JJ Charleston, J Agodoa, LY AF Appel, Lawrence J. Wright, Jackson T., Jr. Greene, Tom Kusek, John W. Lewis, Julia B. Wang, Xuelei Lipkowitz, Michael S. Norris, Keith C. Bakris, George L. Rahman, Mahboob Contreras, Gabriel Rostand, Stephen G. Kopple, Joel D. Gabbai, Francis B. Schulman, Gerald I. Gassman, Jennifer J. Charleston, Jeanne Agodoa, Lawrence Y. CA African Amer Study Kidney Dis Hypertension Colloborative Res Grp TI Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID STAGE RENAL-DISEASE; SALT-SENSITIVE HYPERTENSION; RANDOMIZED CONTROLLED TRIAL; GLOMERULAR-FILTRATION-RATE; UNITED-STATES; RACIAL-DIFFERENCES; AASK; INSUFFICIENCY; LEVEL; RISK AB Background: Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD. Methods: Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20-65 mL/min/1.73 m(2)). Following a 3X2 factorial trial (1995-2001) that tested 3 drugs used as initial antibypertensive therapy (ACEIs, calcium channel blockers, and beta-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002-2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death. Results: During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean. BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, < 1 mL/min/1.73 m(2)). Conclusion: Despite the benefits of renin-angiotensin system-blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term. C1 [Appel, Lawrence J.; Charleston, Jeanne] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [Kusek, John W.; Agodoa, Lawrence Y.] NIDDK, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD USA. [Wright, Jackson T., Jr.; Rahman, Mahboob] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [Wang, Xuelei; Gassman, Jennifer J.] Cleveland Clin Fdn, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Greene, Tom] Univ Utah, Sch Med, Div Epidemiol, Salt Lake City, UT USA. [Lewis, Julia B.; Schulman, Gerald I.] Vanderbilt Univ Sch Med, Div Nephrol, Nashville, TN USA. [Lipkowitz, Michael S.] Mt Sinai Sch Med, Dept Med, Div Nephrol, New York, NY USA. [Kopple, Joel D.] Harbor UCLA Med Ctr, Biomed Res Inst, Los Angeles, CA USA. [Gabbai, Francis B.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Bakris, George L.] Univ Chicago, Sch Med, Dept Med, Chicago, IL 60637 USA. [Contreras, Gabriel] Univ Miami, Dept Med, Miami, FL USA. [Rostand, Stephen G.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. RP Appel, LJ (reprint author), Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Ste 2-618, Baltimore, MD 21205 USA. EM lappel@jhmi.edu RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [K24 DK062234, U01 DK048643]; NIMHD NIH HHS [P60 MD002265] NR 37 TC 87 Z9 90 U1 1 U2 1 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 APR 28 PY 2008 VL 168 IS 8 BP 832 EP 839 DI 10.1001/archinte.168.8.832 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 292EI UT WOS:000255248900009 PM 18443258 ER PT J AU Kim, KY Kawamoto, S Bao, JJ Sellers, JR Adelstein, RS AF Kim, Kye-Young Kawamoto, Sachlyo Bao, Jianjun Sellers, James R. Adelstein, Robert S. TI The B2 alternatively spliced isoform of nonmuscle myosin II-B lacks actin-activated MgATPase activity and in vitro motility SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE nonmuscle myosin II-B; alternative splicing; loop 2 insert; chimeric myosin ID SMOOTH-MUSCLE MYOSIN; HEAVY-CHAIN; ADENOSINE-TRIPHOSPHATASE; CHIMERIC SUBSTITUTIONS; IMAGE-RECONSTRUCTION; CELL-ADHESION; MOTOR DOMAIN; BINDING LOOP; SUBFRAGMENT-1; MEROMYOSIN AB We report the initial biochemical characterization of an alternatively spliced isoform of nonmuscle heavy meromyosin (HMM)-II-B2 and compare it with HMM II-B0, the nonspliced isoform. HMM II-B2 is the HMM derivative of an alternatively spliced isoform of endogenous nonmuscle myosin (NM) II-B, which has 21-amino acids inserted into loop 2, near the actin-binding region. NM II-B2 is expressed in the Purkinje cells of the cerebellum as well as in other neuronal cells [X. Ma, S. Kawamoto, J. Uribe, R.S. Adelstein, Function of the neuron-specific alternatively spliced isoforms of nonmuscle myosin II-B during mouse brain development, Mol. Biol. Cell 15 (2006) 2138-2149]. In contrast to any of the previously described isoforms of NM II (II-A, II-B0, II-B1, II-CO and II-Cl) or to smooth muscle myosin, the actin-activated MgATPase activity of HMM II-B2 is not significantly increased from a low, basal level by phosphorylation of the 20 kDa myosin light chain (MLC-20). Moreover, although HMM II-B2 can bind to actin in the absence of ATP and is released in its presence, it cannot propel actin in the sliding actin filament assay following MLC-20 phosphorylation. Unlike HMM II-B2, the actin-activated MgATPase activity of a chimeric HMM with the 21-amino acid II-B2 sequence inserted into the homologous location in the heavy chain of HMM II-C is increased following MLC-20 phosphorylation. This indicates that the effect of the II-B2 insert is myosin heavy chain specific. Published by Elsevier Inc. C1 [Kim, Kye-Young; Kawamoto, Sachlyo; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Bao, Jianjun] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM AdelsteR@NHLBL.NIH.GOV OI Adelstein, Robert/0000-0002-8683-2144 FU Intramural NIH HHS [Z01 HL004223-15] NR 34 TC 12 Z9 12 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 APR 25 PY 2008 VL 369 IS 1 BP 124 EP 134 DI 10.1016/j.bbrc.2007.11.108 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 281DV UT WOS:000254478000018 PM 18060863 ER PT J AU Sellers, JR Thirumurugan, K Sakamoto, T Hammer, JA Knight, PJ AF Sellers, James R. Thirumurugan, Kavitha Sakamoto, Takeshi Hammer, John A., III Knight, Peter J. TI Calcium and cargoes as regulators of myosin 5a activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE myosin; calmodulin; regulation; calcium ID TAIL DOMAIN; MELANOSOME TRANSPORT; ATPASE ACTIVITY; LINKS RAB27A; IQ-MOTIFS; VA; MELANOPHILIN; CALMODULIN; MOTOR; BINDING AB Myosin 5a is a two-headed actin-dependent motor that transports various cargoes in cells. Its enzymology and mechanochemistry have been extensively studied in vitro. It is a processive motor that takes multiple 36 nm steps on actin. The enzymatic activity of myosin 5 is regulated by an intramolecular folding mechanism whereby its lever arms fold back against the coiled-coil tail such that the motor domains directly bind the globular tail domains. We show that the structure seen in individual folded molecules is consistent with electron density map of two-dimensional crystals of the molecule. In this compact state, the actin-activated MgATPase activity of the molecule is markedly inhibited and the molecule cannot move processively on surface bound actin filaments. The actin-activated MgATPase activity of myosin 5a is activated by increasing the calcium concentration or by binding of a cargo-receptor molecule, melanophilin, in vitro. However, calcium binding to the calmodulin light chains results in dissociation of some of the calmodulin which disrupts the ability of myosin 5a to move on actin filaments in vitro. Thus we propose that. the physiologically relevant activation pathway in vivo involves binding of cargo-receptor proteins. (c) 2008 Published by Elsevier Inc. C1 [Sellers, James R.; Sakamoto, Takeshi] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Thirumurugan, Kavitha; Knight, Peter J.] Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Thirumurugan, Kavitha; Knight, Peter J.] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Hammer, John A., III] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov OI Hammer, John/0000-0002-2496-5179; Thirumurugan, Kavitha/0000-0002-4673-4099 FU Wellcome Trust [076057] NR 35 TC 17 Z9 17 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 25 PY 2008 VL 369 IS 1 BP 176 EP 181 DI 10.1016/j.bbrc.2007.11.109 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 281DV UT WOS:000254478000024 PM 18060865 ER PT J AU Chavakis, E Carmona, G Urbich, C Gottig, S Henschler, R Penninger, JM Zeiher, AM Chavakis, T Dimmeler, S AF Chavakis, Emmanouil Carmona, Guillaume Urbich, Carmen Goettig, Stephan Henschler, Reinhard Penninger, Josef M. Zeiher, Andreas M. Chavakis, Triantafyllos Dimmeler, Stefanie TI Phosphatidylinositol-3-kinase-gamma is integral to homing functions of progenitor cells SO CIRCULATION RESEARCH LA English DT Article DE progenitor cells; homing; integrins; adhesion; migration; PI3K gamma; neovascularization ID ACUTE MYOCARDIAL-INFARCTION; NITRIC-OXIDE SYNTHASE; NEOVASCULARIZATION CAPACITY; ENDOTHELIAL-CELLS; IN-VIVO; AVIDITY REGULATION; LYMPHOCYTE ARREST; B-CELL; T-CELL; RECRUITMENT AB Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. beta 1 and beta 2 integrins play a crucial role for progenitor cell homing to ischemic tissues. Integrin activity is regulated by chemokines and their respective G protein-coupled receptors. The phosphatidylinositol-3-kinase catalytic subunit gamma (PI3K gamma) is the PI3K isoform that selectively transduces signals from G protein-coupled receptors. Here, we investigated the role of PI3K gamma as a signaling intermediate in the chemokine-induced integrin-dependent homing functions of progenitor cells. A pharmacological PI3K gamma inhibitor significantly reduced chemokine-induced chemotaxis and stromal cell-derived factor (SDF)1 alpha-induced transmigration of human EPCs. Moreover, the PI3K gamma inhibitor significantly reduced SDF1 alpha-induced adhesion of EPCs to intercellular adhesion molecule-1 and human umbilical vein endothelial cell monolayers. These findings were corroborated with Lin(-) bone marrow-derived progenitor cells from PI3K gamma-deficient mice that displayed reduced SDF1 alpha-induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3K gamma reduced SDF1 alpha-induced integrin activation in human EPCs and in murine Lin(-) BM-derived progenitor cells, respectively. In vivo, the homing of PI3K gamma-deficient Lin(-) progenitor cells to ischemic muscles after intravenous infusion in the model of hindlimb ischemia and their neovascularization-promoting capacity was reduced as compared with wild-type cells. In conclusion, PI3K gamma is integral to the integrin-dependent homing of progenitor cells. C1 [Chavakis, Emmanouil; Carmona, Guillaume; Urbich, Carmen; Zeiher, Andreas M.; Dimmeler, Stefanie] Univ Frankfurt, Dept Internal Med 3, D-60590 Frankfurt, Germany. [Goettig, Stephan; Henschler, Reinhard] Univ Frankfurt, DRK Inst Transfus Med & Immune Hematol, D-60590 Frankfurt, Germany. [Penninger, Josef M.] Inst Mol Biotechnol, Vienna, Austria. [Chavakis, Triantafyllos] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Chavakis, E (reprint author), Univ Frankfurt, Dept Internal Med 3, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM Chavakis@em.uni-frankfurt.de RI Penninger, Josef/I-6860-2013 OI Penninger, Josef/0000-0002-8194-3777 FU Intramural NIH HHS NR 56 TC 38 Z9 41 U1 0 U2 4 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 APR 25 PY 2008 VL 102 IS 8 BP 942 EP 949 DI 10.1161/CIRCRESAHA.107.164376 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 292WH UT WOS:000255296300013 PM 18323525 ER PT J AU Hughes, JE Srinivasan, S Lynch, KR Proia, RL Ferdek, P Hedrick, CC AF Hughes, Jeniter E. Srinivasan, Suseela Lynch, Kevin R. Proia, Richard L. Ferdek, Pawel Hedrick, Catherine C. TI Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages SO CIRCULATION RESEARCH LA English DT Article DE macrophage; sphingosine-1-phosphate; arginase I; iNOS; NF kappa B; inflammation ID NITRIC-OXIDE SYNTHASE; SPHINGOSINE 1-PHOSPHATE; DEFICIENT MICE; ARGININE METABOLISM; RECEPTOR; ACTIVATION; ARGINASE; ATHEROSCLEROSIS; FTY720; ANALOG AB Activated macrophages acquire a proinflammatory ( classic) or antiinflammatory ( alternative) phenotype that influences atherosclerosis. The present study investigated whether sphingosine-1-phosphate ( S1P), with its known antiinflammatory effects, could regulate the inflammatory phenotype of lipopolysaccharide ( LPS)-stimulated mouse macrophages. Activation of macrophages by LPS significantly increases proinflammatory cytokine secretion. Pretreatment of macrophages with 500 nmol/L S1P markedly reduced LPS-mediated secretion of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-12. Such antiinflammatory actions were also evident in LPS-stimulated macrophages treated with the S1P1 receptor-specific agonist SEW2871. Pharmacological antagonism of the S1P1 receptor on macrophages using the S1P1-specific antagonist VPC44116 also blocked proinflammatory cytokine secretion in response to LPS. Studies using bone marrow-derived macrophages from S1P2-deficient mice revealed that the S1P2 receptor did not play a pivotal role in this process. Thus, activation of the S1P1 receptor in mouse macrophages limits the expression of proinflammatory cytokines. Furthermore, we demonstrated that S1P increased arginase I activity and inhibited LPS-induced inducible NO synthase activity in LPS-treated macrophages, again through S1P1 receptor activation on macrophages. Analysis of a 1.7-kb region of the murine inducible NO synthase promoter revealed the presence of putative nuclear factor kappa B, activator protein- 1, and STAT-1 response elements. Using inducible NO synthase promoter-reporter constructs, we found that S1P significantly reduced the nuclear factor kappa B-mediated induction of inducible NO synthase. These findings demonstrate an important role for S1P in the regulation of macrophage phenotypic switching. Therefore, we conclude that S1P promotes the production of an alternative antiinflammatory macrophage phenotype through activation of the macrophage S1P1 receptor. C1 [Hughes, Jeniter E.; Srinivasan, Suseela; Lynch, Kevin R.; Ferdek, Pawel; Hedrick, Catherine C.] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA 22908 USA. [Lynch, Kevin R.; Hedrick, Catherine C.] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA. [Proia, Richard L.] NIDDKD, NIH, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. RP Hedrick, CC (reprint author), Univ Virginia, Cardiovasc Res Ctr, POB 801394,415 Lane Rd,MR5 Rm G123, Charlottesville, VA 22908 USA. EM cch6n@virginia.edu RI Proia, Richard/A-7908-2012; Hedrick, Catherine/D-1106-2012 FU Intramural NIH HHS; NHLBI NIH HHS [HL079621, R01 HL079621, R01 HL079621-01, R01 HL079621-02, R01 HL079621-03, R01 HL079621-04] NR 27 TC 114 Z9 125 U1 2 U2 9 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 APR 25 PY 2008 VL 102 IS 8 BP 950 EP 958 DI 10.1161/CIRCRESAHA.107.170779 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 292WH UT WOS:000255296300014 PM 18323526 ER PT J AU Majumdar, A Muniandy, PA Liu, J Liu, JI Liu, ST Cuenoud, B Seidman, MM AF Majumdar, Alokes Muniandy, Parameswary A. Liu, Jia Liu, Ji-Ian Liu, Su-ting Cuenoud, Bernard Seidman, Michael M. TI Targeted gene knock in and sequence modulation mediated by a psoralen-linked triplex-forming oligonucleotide SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; NUCLEOTIDE EXCISION-REPAIR; INTERSTRAND CROSS-LINK; INDUCED HOMOLOGOUS RECOMBINATION; SISTER-CHROMATID EXCHANGE; MAMMALIAN-CELLS; 2'-O-(2-AMINOETHYL) RESIDUES; DIRECTED REPAIR; HELIX FORMATION; UV-RADIATION AB Information from exogenous donor DNA can be introduced into the genome via homology-directed repair (HDR) pathways. These pathways are stimulated by double strand breaks and by DNA damage such as interstrand cross-links. We have employed triple helix-forming oligonucleotides linked to psoralen (pso-TFO) to introduce a DNA interstrand cross-link at a specific site in the genome of living mammalian cells. Co-introduction of duplex DNA with target region homology resulted in precise knock in of the donor at frequencies 2-3 orders of magnitude greater than with donor alone. Knock-in was eliminated in cells deficient in ERCC1-XPF, which is involved in recombinational pathways as well as cross-link repair. Separately, single strand oligonucleotide donors (SSO) were co-introduced with the pso-TFO. These were 10-fold more active than the duplex knock-in donor. SSO efficacy was further elevated in cells deficient in ERCC1-XPF, in contrast to the duplex donor. Resected single strand ends have been implicated as critical intermediates in sequence modulation by SSO, as well as duplex donor knock in. We asked whether there would be a competition between the donor species for these ends if both were present with the pso-TFO. The frequency of duplex donor knock in was unaffected by a 100-fold molar excess of the SSO. The same result was obtained when the homing endonuclease I-SceI was used to initiate HDR at the target site. We conclude that the entry of double strand breaks into distinct HDR pathways is controlled by factors other than the nucleic acid partners in those pathways. C1 [Majumdar, Alokes; Muniandy, Parameswary A.; Liu, Jia; Liu, Ji-Ian; Liu, Su-ting; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Cuenoud, Bernard] Novartis Inst Biomed Res, CH-4056 Basel, Switzerland. RP Seidman, MM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov FU Intramural NIH HHS NR 63 TC 29 Z9 30 U1 0 U2 5 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 APR 25 PY 2008 VL 283 IS 17 BP 11244 EP 11252 DI 10.1074/jbc.M800607200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 289PW UT WOS:000255067400020 PM 18303025 ER PT J AU Stoecklin, G Tenenbaum, SA Mayo, T Chittur, SV George, AD Baroni, TE Blackshear, PJ Anderson, P AF Stoecklin, Georg Tenenbaum, Scott A. Mayo, Thomas Chittur, Sridar V. George, Ajish D. Baroni, Timothy E. Blackshear, Perry J. Anderson, Paul TI Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; AU-RICH ELEMENT; ZINC-FINGER PROTEINS; PROBE LEVEL DATA; FACTOR-ALPHA; RIBONUCLEOPROTEIN COMPLEXES; DEGRADATION PATHWAY; BINDING PROTEINS; EXPRESSION; TURNOVER AB Tristetraprolin (TTP) is an RNA-binding protein required for the rapid degradation of mRNAs containing AU-rich elements. Targets regulated by TTP include the mRNAs encoding tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, interleukin-2 (IL-2), and immediate early response 3. To identify novel target mRNAs of TTP in macrophages, we used a genome-wide approach that combines RNA immunoprecipitation and microarray analysis. A list was compiled of 137 mRNAs that are associated with TTP with an estimated accuracy on the order of 90%. Sequence analysis revealed a highly significant enrichment of AU-rich element motifs, with AUUUA pentamers present in 96% and UUAUUUAUU nonamers present in 44% of TTP-associated mRNAs. We further show that IL-10 is a novel target regulated by TTP. IL-10 mRNA levels were found to be elevated because of a reduced decay rate in primary macrophages from TTP-/- mice. Our study demonstrates the importance of experimental approaches for identifying targets of RNA-binding proteins. C1 [Stoecklin, Georg] DKFZ ZMBH Alliance, German Canc Res Ctr, D-69120 Heidelberg, Germany. [Stoecklin, Georg; Mayo, Thomas; Anderson, Paul] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA. [Tenenbaum, Scott A.; Chittur, Sridar V.; George, Ajish D.; Baroni, Timothy E.] SUNY Albany, Sch Publ Hlth, Dept Biomed Sci, Gen NY Sis Ctr Excellence Canc Genom, Rensselaer, NY 12144 USA. [Tenenbaum, Scott A.; Chittur, Sridar V.; George, Ajish D.; Baroni, Timothy E.] SUNY Albany, Sch Publ Hlth, Ctr Funct Genom, Rensselaer, NY 12144 USA. [Blackshear, Perry J.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Stoecklin, G (reprint author), DKFZ ZMBH Alliance, German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM g.stoecklin@dkfz.de OI Stoecklin, Georg/0000-0001-9284-9834 FU NHGRI NIH HHS [U01HG004571, R21HG003679]; NIAID NIH HHS [AI-33600, AI-50167] NR 52 TC 145 Z9 146 U1 1 U2 5 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 APR 25 PY 2008 VL 283 IS 17 BP 11689 EP 11699 DI 10.1074/jbc.M709657200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 289PW UT WOS:000255067400069 PM 18256032 ER PT J AU Yang, L Reece, JM Cho, J Bortner, CD Shears, SB AF Yang, Ling Reece, Jeff M. Cho, Jaiesoon Bortner, Carl D. Shears, Stephen B. TI The nucleolus exhibits an osmotically regulated gatekeeping activity that controls the spatial dynamics and functions of nucleolin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BIS-DIPHOSPHOINOSITOL TETRAKISPHOSPHATE; INOSITOL POLYPHOSPHATE PHOSPHATASE; REPLICATION PROTEIN-A; HYPEROSMOTIC STRESS; COMPLEX-FORMATION; DNA-REPLICATION; CELL-DEATH; PYROPHOSPHATES; HEXAKISPHOSPHATE; PENTAKISPHOSPHATE AB We demonstrate that physiologically relevant perturbations in the osmotic environment rheostatically regulate a gatekeeping function for the nucleolus that controls the spatial dynamics and functions of nucleolin. HeLa cells and U2-OS osteosarcoma cells were osmotically challenged with 100-200 mM sorbitol, and the intranuclear distribution of nucleolin was monitored by confocal microscopy. Nucleolin that normally resides in the innermost fibrillar core of the nucleolus, where it assists rDNA transcription and replication, was expelled within 30 min of sorbitol addition. The nucleolin was transferred into the nucleoplasm, but it distributed there non-uniformly; locally high levels accumulated in 4',6-diamidino-2-phenylindole-negative zones containing euchromatic (transcriptionally active) DNA. Inositol pyrophosphates also responded within 30 min of hyperosmotic stress: levels of bisdiphosphoinositol tetrakisphosphate increased 6-fold, and this was matched by decreased levels of its precursor, diphosphoinositol pentakisphosphate. Such fluctuations in inositol pyrophosphate levels are of considerable interest, because, according to previously published in vitro data, they regulate the degree of phosphorylation of nucleolin through a novel kinase-independent phosphotransferase reaction (Saiardi, A., Bhandari, A., Resnick, R., Cain, A., Snowman, A. M., and Snyder, S. H. (2004) Science 306, 2101-2105). However, by pharmacologically intervening in inositol pyrophosphate metabolism, we found that it did not supervise the osmotically driven switch in the biological activities of nucleolin in vivo. C1 [Yang, Ling; Cho, Jaiesoon; Shears, Stephen B.] NIEHS, Inositol Signaling Grp, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Bortner, Carl D.] NIEHS, Mol Endocrinol Grp, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Reece, Jeff M.] Reecent Technol LLC, Durham, NC 27713 USA. RP Shears, SB (reprint author), NIEHS, Inositol Signaling Grp, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM Shears@niehs.nih.gov FU Intramural NIH HHS NR 54 TC 13 Z9 13 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 25 PY 2008 VL 283 IS 17 BP 11823 EP 11831 DI 10.1074/jbc.M800308200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 289PW UT WOS:000255067400081 PM 18299322 ER PT J AU Cao, XL Hu, GH Huo, LS Zhu, XP Li, T Powell, J Ito, Y AF Cao, Xueli Hu, Guanghui Huo, Liangsheng Zhu, Xiaoping Li, Ting Powell, Jimmie Ito, Yoichiro TI Stationary phase retention and preliminary application of a spiral disk assembly designed for high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE high-speed counter-current chromatography; spiral disk assembly; retention of stationary phase; two-phase solvent system; aqueous two-phase system; protein separation ID PURIFICATION; PROTEINS AB A spiral disk assembly composed of five single-channel units was designed for high-speed counter-current chromatography (HSCCC). The retention of different solvent systems ranging from moderately polar to polar organic-aqueous systems to aqueous two-phase systems (ATPs) was investigated under different elution modes. The results indicated that the spiral disk assembly can produce excellent retention of stationary phase for moderately polar organic-aqueous solvent systems, such as chloroform-methanol-water (4:3:2) and hexane-ethyl acetate-methanol-water (1:1:1:1) by pumping lower mobile phase from head (H) to tail (T), and upper mobile phase from tail (T) to head (H) even at a high flow-rate (8 mL/min, S-f > 70%), regardless of whether the inlet is at the inner or outer terminal of the channel. This makes it possible for fast analysis of some small molecular compounds. This has been proved in the separation of mixtures of three flavones, including isorhamnetin, kaempferol, and quercetin. The spiral disk assembly can also provide satisfactory retention for polar to ATPS such as 1-butanol-acetic acid-water (4:1:5) (<3 mL/min, S-f > 70%), 12.5% poly(ethylene glycol) (PEG) 1000-12.5% K2HPO4-75% water (<= 1 mL/min, S-f > 70%) and 4% PEG 8000-5% Dextran T500-91% water (<0.5 mL/min, S-f > 50%) by pumping lower mobile phase from inner terminal (I) to outer terminal (O), and upper mobile phase from outer terminal (O) to inner terminal (I) at a low flow-rate, while this is not possible with the multilayer coil column. Acceptable resolutions were achieved when it was used for the separation of peptides such as Leu-Tyr and Val-Tyr, and proteins including cytochrome c and myoglobin, lysozyme and myoglobin, and fresh chicken egg-white proteins. (C) 2008 Elsevier B.V. All rights reserved. C1 [Ito, Yoichiro] NHLBI, Bioseparat Technol Biochem & Biophys Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Cao, Xueli; Hu, Guanghui; Li, Ting] Beijing Technol & Business Univ, Beijing Key Lab Plant Resource Res, Beijing 100037, Peoples R China. [Huo, Liangsheng; Zhu, Xiaoping] Beijing Technol & Business Univ, Mech Automat Coll, Beijing 100037, Peoples R China. [Powell, Jimmie] NIH, Machine Instrumentat Design & Fabricat, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Bioseparat Technol Biochem & Biophys Ctr, Natl Inst Hlth, Bldg 10,Room 8N230,9000 Rockville Pike, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 9 TC 17 Z9 19 U1 2 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD APR 25 PY 2008 VL 1188 IS 2 BP 164 EP 170 DI 10.1016/j.chroma.2008.02.073 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 296RW UT WOS:000255564500013 PM 18339394 ER PT J AU Minakhin, L Goel, M Berdygulova, Z Ramanculov, E Florens, L Glazko, G Karamychev, VN Slesarev, AI Kozyavkin, SA Khromov, I Ackermann, HW Washburn, M Mushegian, A Severinov, K AF Minakhin, Leonid Goel, Manisha Berdygulova, Zhanna Ramanculov, Erlan Florens, Laurence Glazko, Galina Karamychev, Valeri N. Slesarev, Alexei I. Kozyavkin, Sergei A. Khromov, Igor Ackermann, Hans-W. Washburn, Michael Mushegian, Arcady Severinov, Konstantin TI Genome comparison and proteomic characterization of Thermus thermophilus bacteriophages P23-45 and P74-26: Siphoviruses with triplex-forming sequences and the longest known tails SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Thermus thermophilus; thermophages; virion proteomics; bioinformatics; triplex-forming sequence ID PROTEIN IDENTIFICATION TECHNOLOGY; CODON USAGE BIAS; LENGTH DETERMINATION; HOMOPYRIMIDINE SEQUENCES; SHOTGUN PROTEOMICS; FRIEDREICHS-ATAXIA; DNA POLYMERIZATION; IN-VIVO; REPEAT; PHAGE AB The genomes of two closely related lytic Thermus thermophilus siphoviruses with exceptionally long (similar to 800 nm) tails, bacteriophages P23-45 and P74-26, were sequenced completely. The P23-45 genome consists of 84,201 bp with 117 putative open reading frames (ORFs), and the P74-26 genome has 83, 319 bp and 116 putative ORFs. The two genomes are 92% identical with 113 ORFs shared. Only 25% of phage gene product functions can be predicted from similarities to proteins and protein domains with known functions. The structural genes of P23-45, most of which have no similarity to sequences from public databases, were identified by mass spectrometric analysis of virions. An unusual feature of the P23-45 and P74-26 genomes is the presence, in their largest intergenic regions, of long polypurine-polypyrimidine (R-Y) sequences with mirror repeat symmetry. Such sequences, abundant in eukaryotic genomes but rare in prokaryotes, are known to form stable triple helices that block replication and transcription and induce genetic instability. Comparative analysis of the two phage genomes shows that the area around the triplex-forming elements is enriched in mutational variations. In vitro, phage R-Y sequences form triplexes and block DNA synthesis by Taq DNA polymerase in orientation-dependent manner, suggesting that they may play a regulatory role during P23-45 and P74-26 development. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Minakhin, Leonid; Berdygulova, Zhanna; Severinov, Konstantin] Waksman Inst Microbiol, Piscataway, NJ 08854 USA. [Goel, Manisha; Florens, Laurence; Washburn, Michael; Mushegian, Arcady] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Ramanculov, Erlan] Natl Ctr Biotechnol Republ Kazakhastan, Astana 010000, Kazakhstan. [Glazko, Galina] Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. [Karamychev, Valeri N.; Slesarev, Alexei I.; Kozyavkin, Sergei A.] Fidel Syst Inc, Gaithersburg, MD 20879 USA. [Khromov, Igor; Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow 123182, Russia. [Ackermann, Hans-W.] Univ Laval, Fac Med, Felix Herelle Reference Ctr Bacterial Viruses, Quebec City, PQ G1K 7P4, Canada. [Mushegian, Arcady] Univ Kansas, Med Ctr, Dept Microbiol, Kansas City, KS 66160 USA. RP Minakhin, L (reprint author), Waksman Inst Microbiol, 190 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM minakhiri@waksman.rutgers.edu; severik@waksman.rutgers.edu RI Severinov, Konstantin/C-8545-2016; OI Florens, Laurence/0000-0002-9310-6650; Mushegian, Arcady/0000-0002-6809-9225; Washburn, Michael/0000-0001-7568-2585 FU NIAID NIH HHS [R21 AI074769, R21 AI074769-01]; NIGMS NIH HHS [R01 GM059295, R01 GM059295-06, R01 GM59295] NR 63 TC 24 Z9 26 U1 2 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD APR 25 PY 2008 VL 378 IS 2 BP 468 EP 480 DI 10.1016/j.jmb.2008.02.018 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 293XJ UT WOS:000255368400016 PM 18355836 ER PT J AU Srinivasula, SM Ashwell, JD AF Srinivasula, Srinivasa M. Ashwell, Jonathan D. TI IAPs: What's in a name? SO MOLECULAR CELL LA English DT Review ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; APOPTOSIS PROTEIN XIAP; X-LINKED INHIBITOR; NEGATIVE BACTERIAL-INFECTION; ALPHA-DEPENDENT APOPTOSIS; CELL-DEATH; BACULOVIRAL-INHIBITOR; DROSOPHILA INHIBITOR; NEURONAL APOPTOSIS AB Originally described in insect viruses, cellular proteins with Baculoviral IAP repeat (BIR) motifs have been thought to function primarily as inhibitors of apoptosis. The subsequent finding that a subset of IAPs that contain a RING domain have ubiquitin protein ligase (0) activity implied the presence of other functions. It is now known that IAPs are involved in mitotic chromosome segregation, cellular morphogenesis, copper homeostasis, and intracellular signaling. Here, we review the current understanding of the roles of IAPs in apoptotic and nonapoptotic processes and explore the notion that the latter represents the primary physiologic activities of IAPs. C1 [Srinivasula, Srinivasa M.; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural NIH HHS [Z01 BC010779-01] NR 110 TC 293 Z9 308 U1 4 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 25 PY 2008 VL 30 IS 2 BP 123 EP 135 DI 10.1016/j.molcel.2008.03.008 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 294MN UT WOS:000255410200001 PM 18439892 ER PT J AU McElhinny, SAN Gordenin, DA Stith, CM Burgers, PMJ Kunkel, TA AF McElhinny, Stephanie A. Nick Gordenin, Dmitry A. Stith, Carrie M. Burgers, Peter M. J. Kunkel, Thomas A. TI Division of labor at the eukaryotic replication fork SO MOLECULAR CELL LA English DT Article ID DNA-POLYMERASE-EPSILON; SACCHAROMYCES-CEREVISIAE; MISMATCH REPAIR; CATALYTIC DOMAINS; DELTA; CHECKPOINT; SUBUNIT; REQUIRE; PATHWAY; ERRORS AB DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon) are both required for efficient replication of the nuclear genome, yet the division of labor between these enzymes has remained unclear for many years. Here we investigate the contribution of Pol 8 to replication of the leading and lagging strand templates in Saccharomyces cerevisiae using a mutant Pol 8 allele (pol3-L6121W) whose error rate is higher for one mismatch (e.g., T center dot dGTP) than for its complement (A center dot dCTP). We find that strand-specific mutation rates strongly depend on the orientation of a reporter gene relative to an adjacent replication origin, in a manner implying that > 90% of Pol delta replication is performed using the lagging strand template. When combined with recent evidence implicating Pol E in leading strand replication, these data support a model of the replication fork wherein the leading and lagging strand templates are primarily copied by Pol epsilon an Pol delta, respectively. C1 [McElhinny, Stephanie A. Nick; Gordenin, Dmitry A.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [McElhinny, Stephanie A. Nick; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Stith, Carrie M.; Burgers, Peter M. J.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 NR 36 TC 196 Z9 197 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 25 PY 2008 VL 30 IS 2 BP 137 EP 144 DI 10.1016/j.molcel.2008.02.022 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 294MN UT WOS:000255410200002 ER PT J AU Joshi, A Garg, H Nagashima, K Bonifacino, JS Freed, EO AF Joshi, Anjali Garg, Himanshu Nagashima, Kunio Bonifacino, Juan S. Freed, Eric O. TI GGA and arf proteins modulate retrovirus assembly and release SO MOLECULAR CELL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1 GAG PROTEINS; PLASMA-MEMBRANE; TYPE-1 MATRIX; GOLGI; BINDING; DOMAINS; ALIX/AIP1; INFECTION; TRANSPORT AB The Gag protein is the major structural determinant of retrovirus assembly. Although a number of cellular factors have been reported to facilitate retrovirus release, little is known about the cellular machinery that directs Gag to the site of virus assembly. Here, we report roles for the Golgi-localized gamma-ear containing Arf-binding (GGA) and ADP ribosylation factor (Arf) proteins in retrovirus particle assembly and release. Whereas siRNA-mediated depletion of GGA2 and GGA3 led to a significant increase in particle release in a late domain-dependent manner, GGA overexpression severely reduced retrovirus particle production by impairing Gag trafficking to the membrane. GGA overexpression inhibited retroviral assembly and release by disrupting Arf protein activity. Furthermore, disruption of endogenous Arf activity inhibited particle production by decreasing Gag-membrane binding. These findings identify the GGA proteins as modulators of HIV-1 release and the Arf proteins as critical cellular cofactors in retroviral Gag trafficking to the plasma membrane. C1 [Joshi, Anjali; Freed, Eric O.] NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. [Garg, Himanshu] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Nagashima, Kunio] NCI, SAIC Frederick, Adv Technol Program, Image Anal Lab, Frederick, MD 21702 USA. [Bonifacino, Juan S.] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NCI, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. EM efreed@nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS [Z01 BC010775-01, Z01 BC010776-01] NR 36 TC 37 Z9 40 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 25 PY 2008 VL 30 IS 2 BP 227 EP 238 DI 10.1016/j.molcel.2008.03.015 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 294MN UT WOS:000255410200010 PM 18439901 ER PT J AU Walsh, T McClellan, JM McCarthy, SE Addington, AM Pierce, SB Cooper, GM Nord, AS Kusenda, M Malhotra, D Bhandari, A Stray, SM Rippey, CF Roccanova, P Makarov, V Lakshmi, B Findling, RL Sikich, L Stromberg, T Merriman, B Gogtay, N Butler, P Eckstrand, K Noory, L Gochman, P Long, R Chen, ZG Davis, S Baker, C Eichler, EE Meltzer, PS Nelson, SF Singleton, AB Lee, MK Rapoport, JL King, MC Sebat, J AF Walsh, Tom McClellan, Jon M. McCarthy, Shane E. Addington, Anjene M. Pierce, Sarah B. Cooper, Greg M. Nord, Alex S. Kusenda, Mary Malhotra, Dheeraj Bhandari, Abhishek Stray, Sunday M. Rippey, Caitlin F. Roccanova, Patricia Makarov, Vlad Lakshmi, B. Findling, Robert L. Sikich, Linmarie Stromberg, Thomas Merriman, Barry Gogtay, Nitin Butler, Philip Eckstrand, Kristen Noory, Laila Gochman, Peter Long, Robert Chen, Zugen Davis, Sean Baker, Carl Eichler, Evan E. Meltzer, Paul S. Nelson, Stanley F. Singleton, Andrew B. Lee, Ming K. Rapoport, Judith L. King, Mary-Claire Sebat, Jonathan TI Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia SO SCIENCE LA English DT Article ID CHILDHOOD-ONSET SCHIZOPHRENIA; NEURONAL MIGRATION; COMMON DISEASE; NMDA RECEPTOR; SUSCEPTIBILITY; GLUTAMATE; NEUREGULIN; EXPRESSION; NEUROTRANSMITTERS; DIFFERENTIATION AB Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high- resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young- onset cases, both highly significant differences. The association was independently replicated in patients with childhood- onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia. C1 [McClellan, Jon M.] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Walsh, Tom; Pierce, Sarah B.; Stray, Sunday M.; Lee, Ming K.; King, Mary-Claire] Univ Washington, Dept Med, Seattle, WA 98195 USA. [McCarthy, Shane E.; Kusenda, Mary; Malhotra, Dheeraj; Bhandari, Abhishek; Roccanova, Patricia; Makarov, Vlad; Lakshmi, B.; Sebat, Jonathan] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Addington, Anjene M.; Stromberg, Thomas; Gogtay, Nitin; Butler, Philip; Eckstrand, Kristen; Noory, Laila; Gochman, Peter; Long, Robert; Rapoport, Judith L.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Cooper, Greg M.; Nord, Alex S.; Rippey, Caitlin F.; Baker, Carl; Eichler, Evan E.; King, Mary-Claire] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kusenda, Mary] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY 11794 USA. [Findling, Robert L.] Case Med Ctr, Dept Psychiat, Cleveland, OH 44106 USA. [Sikich, Linmarie] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Merriman, Barry; Chen, Zugen; Nelson, Stanley F.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. [Davis, Sean; Meltzer, Paul S.] NCI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP McClellan, JM (reprint author), Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. EM drjack@u.washington.edu RI Gogtay, Nitin/A-3035-2008; Nelson, Stanley/D-4771-2009; Cooper, Gregory/D-6914-2011; Singleton, Andrew/C-3010-2009; OI Davis, Sean/0000-0002-8991-6458; Cooper, Gregory/0000-0001-5509-9923; Sebat, Jonathan/0000-0002-9087-526X; Walsh, Tom/0000-0002-8875-0310 FU Howard Hughes Medical Institute; Intramural NIH HHS; NCRR NIH HHS [M01 RR000046, RR000046, RR025014, UL1 RR025014]; NICHD NIH HHS [HD043569, R01 HD043569]; NIMH NIH HHS [MH061355, MH061464, MH061528, U01 MH061355, U01 MH061464, U01 MH061528]; NINDS NIH HHS [NS052108, U24 NS052108] NR 42 TC 1039 Z9 1070 U1 9 U2 133 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD APR 25 PY 2008 VL 320 IS 5875 BP 539 EP 543 DI 10.1126/science.1155174 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 292EM UT WOS:000255249300053 PM 18369103 ER PT J AU Belliot, G Sosnovtsev, SV Chang, KO McPhie, P Green, KY AF Belliot, Gaeel Sosnovtsev, Stanislav V. Chang, Kyeong-Ok McPhie, Peter Green, Kim Y. TI Nucleotidylylation of the VPg protein of a human norovirus by its proteinase-polymerase precursor protein SO VIROLOGY LA English DT Article DE norovirus; VPg; polymerase; nucleotidylylation ID DEPENDENT RNA-POLYMERASE; GENOME-LINKED PROTEIN; HEMORRHAGIC-DISEASE VIRUS; COWPEA MOSAIC-VIRUS; FELINE CALICIVIRUS GENOME; POLIOVIRUS RNA; NORWALK VIRUS; NONSTRUCTURAL POLYPROTEIN; MURINE NOROVIRUS; PHOSPHODIESTER LINKAGE AB Caliciviruses have a positive strand RNA genome covalently-linked at the 5'-end to a small protein, VPg. This study examined the biochemical modification of VPg by the ProPol form of the polymerase of human norovirus strain MD145 (GIIA). Recombinant norovirus VPg was shown to be nucleotidylylated in the presence of Mn2+ by MD145 ProPol. Phosphodiesterase I treatment of the nucleotidylylated VPg released the incorporated UMP, which was consistent with linkage of RNA to VPg via a phosphodiester bond. Mutagenesis analysis of VPg identified Tyrosine 27 as the target amino acid for this linkage, and suggested that VPg conformation was important for the reaction. Nucleotidylylation was inefficient in the presence of Mg2+; however the addition of full- and suligenomic-length MD145 RNA transcripts led to a marked enhancement of the nucleotidylylation efficiency in the presence of this divalent cation. Furthermore, evidence was found for the presence of an RNA element near the 3'-end of the polyadenylated genome that enhanced the efficiency of nucleotidylylation in the presence of Mg2+. Published by Elsevier Inc. C1 [Belliot, Gaeel; Sosnovtsev, Stanislav V.; Chang, Kyeong-Ok; Green, Kim Y.] NIAID, Natl Inst Hlth, DHHS, LID, Bethesda, MD 20892 USA. [McPhie, Peter] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Belliot, G (reprint author), CHU Dijon, Lab Virol Serol, Ctr Natl Reference Virus Enter, UFR Med, 1 Blvd Jeanne Arc, F-21079 Dijon, France. EM gael.belliot@u-bourgogne.fr; SSOSNOVTSE@mail.nih.gov; kchang@vet.k-state.edu; pmcphie@helix.nih.gov; kgreen@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000897-07] NR 41 TC 33 Z9 33 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 0042-6822 J9 VIROLOGY JI Virology PD APR 25 PY 2008 VL 374 IS 1 BP 33 EP 49 DI 10.1016/j.virol.2007.12.028 PG 17 WC Virology SC Virology GA 293HA UT WOS:000255325100004 PM 18234264 ER PT J AU Masui, S Ohtsuka, S Yagi, R Takahashi, K Ko, MSH Niwa, H AF Masui, Shinji Ohtsuka, Satoshi Yagi, Rika Takahashi, Kadue Ko, Minoru S. H. Niwa, Hitoshi TI Rex1/Zfp42 is dispensable for pluripotency in mouse ES cells SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID EMBRYONIC STEM-CELLS; ZINC-FINGER GENE; RETINOIC ACID; SELF-RENEWAL; IN-VIVO; EXTRAEMBRYONIC ENDODERM; TARGETED DISRUPTION; PRIMITIVE ENDODERM; PARIETAL ENDODERM; REX-1 ZFP-42 AB Background: Rex1/Zfp42 has been extensively used as a marker for the undifferentiated state of pluripotent stem cells. However, its function in pluripotent stem cells including embryonic stem (ES) cells remained unclear although its involvement in visceral endoderm differentiation in F9 embryonal carcinoma (EC) cells was reported. Results: We showed the function of Rex1 in mouse ES cells as well as in embryos using the conventional gene targeting strategy. Our results clearly indicated that Rex1 function is dispensable for both the maintenance of pluripotency in ES cells and the development of embryos. However, Rex1-/- ES cells showed the defect to induce a subset of the marker genes of visceral endoderm, when differentiated as embryoid body, as found in EC cells. Conclusion: Rex1 should be regarded just as a marker of pluripotency without functional significance like the activity of alkaline phosphatase. C1 [Masui, Shinji; Ohtsuka, Satoshi; Yagi, Rika; Takahashi, Kadue; Niwa, Hitoshi] RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Kobe, Hyogo 6500047, Japan. [Niwa, Hitoshi] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama 3320012, Japan. [Niwa, Hitoshi] Kobe Univ, Grad Sch Med, Lab Dev & Regenerat Med, Chuo Ku, Kobe, Hyogo 6500017, Japan. [Ko, Minoru S. H.] NIA, NIH, Genet Lab, Dev Genom & Aging Sect, Baltimore, MD 21224 USA. [Masui, Shinji] Int Med Ctr Japan, Res Inst, Dept Regenerat Med, Div Mol Biol & Cell Engn,Shinjyuku Ku, Tokyo 1628655, Japan. [Ohtsuka, Satoshi] Toyama Univ, Life Sci Res Ctr, Div Anim Resources & Dev, Toyama 9300194, Japan. RP Niwa, H (reprint author), RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, 2-2-3 Minatojima Minamimachi, Kobe, Hyogo 6500047, Japan. EM masui@ri.imcj.go.jp; sohtsuka@cts.u-toyama.ac.jp; rikanosuke@cdb.riken.jp; kaduemon@cdb.riken.jp; kom@mail.nih.gov; niwa@cdb.riken.jp RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS NR 57 TC 55 Z9 58 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD APR 24 PY 2008 VL 8 AR 45 DI 10.1186/1471-213X-8-45 PG 12 WC Developmental Biology SC Developmental Biology GA 301YT UT WOS:000255933300001 PM 18433507 ER PT J AU Kakareka, JW Smith, PD Pohida, TJ Hendler, RW AF Kakareka, John W. Smith, Paul D. Pohida, Thomas J. Hendler, Richard W. TI Simultaneous measurements of fast optical and proton current kinetics in the bacteriorhodopsin photocycle using an enhanced spectrophotometer SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE high speed spectrophotometer; rapid kinetics; bacteriorhodopsin photocycle; proton pump; energy transduction ID PURPLE MEMBRANE-LIPIDS; HALOBACTERIUM-SALINARIUM; SPECTROSCOPY; TRANSITIONS; ABSORPTION; RESOLUTION; SPECTRA; SIGNALS AB A one-of-a-kind high speed optical multichannel spectrometer was designed and built at NIH and described in this journal in 1997 [J.W. Cole, R.W. Hendler, P.D. Smith, H.A. Fredrickson, T.J. Pohida, W.S. Friauf. A high speed optical multichannel analyzer. J Biochem Biophys Methods 1997;35:16-174.]. The most unique aspect of this instrument was the ability to follow an entire time course from a single activation using a single sample. The instrument has been used to study rapid kinetic processes in the photon-driven bacteriorhodopsin photocycle and electron transport from cytochrome c to cytochrome aa(3) and from cytochrome aa3 to oxygen. The present paper describes a second generation instrument with a number of important enhancements which significantly improve its capabilities for multichannel kinetic studies. An example application is presented in which the kinetics of photon-induced proton flow across the biological membrane is measured simultaneously with the individual steps of the photocycle determined optically. Matching the time constants for the two processes indicates which molecular transformations are associated with major proton movements. Published by Elsevier B.V. C1 [Hendler, Richard W.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Smith, Paul D.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Kakareka, John W.; Pohida, Thomas J.] Ctr Informat Technol, Div Computat Biosci, Bethesda, MD 20892 USA. RP Hendler, RW (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM rwh@helix.nih.gov OI Kakareka, John/0000-0003-0072-0035 FU Intramural NIH HHS [Z01 HL000518-04, Z99 HL999999] NR 25 TC 1 Z9 1 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD APR 24 PY 2008 VL 70 IS 6 BP 1116 EP 1123 DI 10.1016/j.jprot.2007.11.004 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 308MB UT WOS:000256393200047 PM 18160131 ER PT J AU Simeonov, A Jadhav, A Thomas, CJ Wang, YH Huang, RL Southall, NT Shinn, P Smith, J Austin, CP Auld, DS Inglese, J AF Simeonov, Anton Jadhav, Ajit Thomas, Craig J. Wang, Yuhong Huang, Ruili Southall, Noel T. Shinn, Paul Smith, Jeremy Austin, Christopher P. Auld, Douglas S. Inglese, James TI Fluorescence spectroscopic profiling of compound libraries SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID REPORTER-GENE; LIQUID-CHROMATOGRAPHY; IDENTIFICATION; ASSAY; SYSTEM; INTERFERENCE; ANTAGONISTS; RECEPTORS; PROTEASE; SCREEN AB Chromo/fluorophoric properties often accompany the heterocyclic scaffolds and impurities that comprise libraries used for high-throughput screening (HTS). These properties affect assay outputs obtained with optical detection, thus complicating analysis and leading to false positives and negatives. Here, we report the fluorescence profile of more than 70 000 samples across spectral regions commonly utilized in HTS. The quantitative HTS paradigm was utilized to test each sample at seven or more concentrations over a 4-log range in 1536-well format. Raw fluorescence was compared with fluorophore standards to compute a normalized response as a function of concentration and spectral region. More than 5% of library members were brighter than the equivalent of 10 nM 4-methyl umbelliferone, a common UV-active probe. Redshifting the spectral window by as little as 100 nm was accompanied by a dramatic decrease in auto fluorescence. Native compound fluorescence, fluorescent impurities, novel fluorescent compounds, and the utilization of fluorescence profiling data are discussed. C1 [Simeonov, Anton; Jadhav, Ajit; Thomas, Craig J.; Wang, Yuhong; Huang, Ruili; Southall, Noel T.; Shinn, Paul; Smith, Jeremy; Austin, Christopher P.; Auld, Douglas S.; Inglese, James] NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Intramural NIH HHS NR 38 TC 123 Z9 127 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD APR 24 PY 2008 VL 51 IS 8 BP 2363 EP 2371 DI 10.1021/jm701301m PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 290EH UT WOS:000255105600006 PM 18363325 ER EF